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Cancer immunotherapy

Cancer immunotherapy is a form of biological therapy that utilizes the body's to recognize, target, and eliminate cancer cells, often by enhancing natural immune responses or introducing engineered components to overcome cancer's evasion tactics. Unlike traditional treatments such as or , which directly attack rapidly dividing cells, immunotherapy leverages immune mechanisms like T cells and antibodies to provide potentially long-lasting protection against cancer recurrence. The field traces its origins to the late , when surgeon William B. Coley observed tumor regressions in patients treated with bacterial toxins, leading to his development of "" as an early immunotherapeutic approach that achieved remissions in over 1,000 cases of and other cancers. Key theoretical foundations emerged in the mid-20th century, including Frank Macfarlane Burnet's 1957 immunosurveillance hypothesis, which posited that the immune system constantly patrols for and eliminates nascent cancer cells, and Jacques Miller's 1967 discovery of T cells as central orchestrators of adaptive immunity. Modern immunotherapy gained momentum in the 1970s with the approval of bacillus Calmette-Guérin (BCG) for in 1976 and the identification of the first in 1991, paving the way for targeted therapies. Major types of cancer immunotherapy include immune checkpoint inhibitors, which block proteins like PD-1 and CTLA-4 to unleash T-cell attacks on tumors; adoptive cell therapies such as CAR T-cell therapy, where patient T cells are genetically modified to express chimeric antigen receptors targeting specific cancer markers; monoclonal antibodies that bind to cancer cell surfaces or immune modulators; treatment vaccines that stimulate immune recognition of tumor antigens; and immune system modulators like cytokines (e.g., interferons and interleukins) that amplify immune activity. These approaches have been approved by the U.S. Food and Drug Administration (FDA) for over 30 cancer types, including melanoma, lung cancer, and leukemia, with notable milestones such as the 1997 approval of rituximab for non-Hodgkin lymphoma, the 2011 approval of ipilimumab as the first checkpoint inhibitor, and the 2017 approval of the first CAR T-cell therapy for pediatric acute lymphoblastic leukemia. Recent advances underscore immunotherapy's expanding role, with the 2018 Nobel Prize in Physiology or Medicine awarded to James Allison and for their discoveries in checkpoint inhibition that revolutionized treatment for previously intractable cancers. In 2024, the FDA approved lifileucel (Amtagvi), the first tumor-infiltrating lymphocyte (TIL) therapy for advanced , and afamitresgene autoleucel, the first therapy for , demonstrating durable responses in solid tumors. In 2025, the FDA approved the combination of nivolumab and as first-line therapy for adults with unresectable or metastatic dMMR or MSI-H . Clinical trials have also shown neoadjuvant immunotherapy achieving complete responses without additional surgery in rectal cancer patients with mismatch repair deficiency and improving survival in as . Despite challenges like immune-related side effects and resistance mechanisms, ongoing research into combination therapies, biomarkers for response prediction, and influences continues to broaden immunotherapy's efficacy across diverse cancers.

Fundamentals

Role of the Immune System in Cancer

The immune surveillance hypothesis, first articulated by Frank Macfarlane Burnet in 1957, proposes that the acts as a vigilant sentinel, continuously recognizing and destroying nascent cancer cells through the detection of abnormal antigens arising from genetic or cellular transformations. This concept evolved from early observations of and was later formalized in the framework of cancer immunoediting, which encompasses three phases: elimination of transformed cells, equilibrium where the restrains tumor growth, and escape where tumors evade detection. Central to this process is the dual arm of immunity—in innate and adaptive—working synergistically to maintain tissue and suppress oncogenesis. Innate immune components provide the first line of defense against cancer cells. Natural killer (NK) cells, a subset of innate lymphoid cells, patrol peripheral tissues and rapidly lyse tumor cells that downregulate major histocompatibility complex class I (MHC-I) molecules or express stress-induced ligands such as MICA/MICB, which bind activating receptors like on NK cells. Macrophages, another key innate player, engulf and destroy abnormal cells via , often triggered by receptors that detect damage-associated molecular patterns (DAMPs) released by dying tumor cells; they also bridge to adaptive immunity by processing and presenting antigens. These mechanisms ensure early eradication of precancerous lesions without prior sensitization. Adaptive immunity refines this response through antigen-specific recognition, primarily orchestrated by T and B lymphocytes. Cytotoxic CD8+ T cells identify tumor antigens presented on the cell surface via MHC-I molecules by professional antigen-presenting cells (APCs) like dendritic cells, leading to targeted killing through perforin and granzyme release. Helper CD4+ T cells, activated by MHC-II presentation of exogenous antigens, coordinate responses by secreting cytokines that amplify and activity or support B cell differentiation into antibody-producing plasma cells, which opsonize tumor cells for destruction. Tumor antigens driving these responses are classified into tumor-associated antigens (TAAs), which are overexpressed in cancers but also present in normal tissues (e.g., HER2 in ), and tumor-specific antigens (TSAs), including neoantigens generated by somatic mutations unique to the tumor, offering highly immunogenic targets with minimal off-tumor effects. Despite these protective mechanisms, tumors frequently evade immune detection through multifaceted strategies that disrupt recognition and effector functions. A common tactic is the downregulation or loss of MHC-I expression, rendering tumor cells invisible to CD8+ T cells while potentially increasing susceptibility to NK cells, though tumors often counteract this by secreting soluble MHC-I or upregulating inhibitory ligands. Additionally, tumors induce an immunosuppressive microenvironment by expressing programmed death-ligand 1 (PD-L1), which engages PD-1 on T cells to inhibit their activation and promote exhaustion. Recruitment of regulatory T cells (Tregs), characterized by FoxP3 expression, suppresses effector T cell proliferation via IL-10 and TGF-β secretion, while myeloid-derived suppressor cells (MDSCs) deplete arginine and produce reactive oxygen species to impair T cell signaling and survival. These evasion tactics collectively foster tumor progression by subverting both innate and adaptive arms of immunity.

Principles of Immunotherapy

Cancer immunotherapy represents a therapeutic approach that modulates the host immune system to recognize and eliminate malignant cells, distinguishing it from conventional treatments such as chemotherapy, which directly target and kill rapidly proliferating tumor cells through cytotoxic mechanisms. By leveraging the specificity and memory capabilities of the adaptive immune system, immunotherapy seeks to restore or enhance natural antitumor immunity that has been suppressed by tumor evasion strategies, such as altered antigen presentation or inhibitory signaling. The core principles of cancer immunotherapy revolve around four interrelated strategies: improving to prime immune recognition, amplifying functions to mount a robust attack, alleviating tumor-induced to sustain immune activity, and promoting the development of long-term immunological memory to prevent recurrence. Enhancing involves strategies that increase the visibility of tumor-associated antigens to antigen-presenting cells like dendritic cells, thereby initiating T-cell activation. Boosting , such as cytotoxic T lymphocytes and natural killer cells, focuses on expanding their numbers and potency to directly lyse tumor targets. Relieving targets mechanisms that dampen immune responses, allowing unchecked effector function. Finally, inducing memory responses ensures that surviving immune cells, particularly memory T cells, provide durable protection against residual or metastatic disease. Key concepts underpinning these principles include the and epitope spreading, which illustrate the potential for systemic and broadening immune responses. The describes the regression of non-irradiated tumors following localized therapy, driven by radiation-induced release of tumor antigens that trigger a widespread adaptive via activated T cells. Epitope spreading refers to the diversification of the antitumor , where initial targeting of specific tumor antigens leads to of additional, previously ignored epitopes, thereby broadening the immune attack and reducing the risk of antigen escape. Ultimately, the goals of cancer immunotherapy are to achieve sustained, durable clinical responses, particularly in immunogenic or "" tumors characterized by high immune cell infiltration and burden, which respond more readily than "" tumors with sparse immune presence and low . In tumors, therapies can amplify existing immune pressure for complete remissions, whereas in tumors, the challenge lies in converting an immunosuppressive microenvironment to one conducive to effective immunity, often requiring combination approaches to ignite initial responses.

Historical Development

Early Observations and Concepts

The earliest observations linking infections to cancer regression date back to the late 19th century, when physicians noted spontaneous remissions in tumors following acute febrile illnesses, suggesting an immune-mediated response to microbial stimuli. These anecdotal reports gained traction through the work of surgeon William B. Coley, who in 1891 observed a patient with inoperable sarcoma whose tumor regressed after developing , a streptococcal . Inspired by this, Coley developed "," a mixture of heat-killed and bacteria, which he administered to over 1,000 cancer patients starting in 1893; in some cases, particularly sarcomas, tumors regressed, with long-term remissions reported in up to 20% of treated individuals, though mechanisms were then attributed to fever and inflammation rather than specific immunity. In the early 1900s, Paul Ehrlich advanced theoretical foundations for targeted cancer therapies with his "magic bullet" concept, proposing that specific antibodies could selectively bind and destroy pathogens or abnormal cells, much like a directed projectile. Ehrlich extended this to cancer, hypothesizing in his side-chain theory that the immune system recognizes altered self-antigens on tumor cells and that vaccines could enhance this recognition, laying groundwork for immunotherapeutic ideas despite initial focus on infectious diseases. By the mid-20th century, the immune surveillance theory formalized the notion that the continuously monitors and eliminates nascent cancer cells. In 1957, proposed this concept, arguing that lymphocytes detect and destroy mutant cells expressing neoantigens, preventing tumor formation as a natural evolutionary adaptation. extended the theory in 1959, emphasizing the role of cellular immunity in recognizing tumor-specific antigens and integrating it with broader , influencing subsequent research on immune-cancer interactions. Concurrent discoveries highlighted soluble immune factors with anticancer potential. In 1957, Alick Isaacs and Jean Lindenmann identified , a protein secreted by virus-infected cells that inhibits and later demonstrated antitumor effects in preclinical models by activating immune responses. Building on bacterial immunostimulation concepts, early 1970s experiments by Alvaro Morales explored intravesical Bacillus Calmette-Guérin (BCG), an attenuated vaccine; in a 1976 trial of nine patients, BCG reduced tumor recurrence rates dramatically compared to historical controls, marking the first clinical evidence of bacterial immunotherapy's efficacy.

Key Milestones and Regulatory Approvals

The development of hybridoma technology in 1975 by Georges Köhler and César Milstein revolutionized antibody production by enabling the creation of monoclonal antibodies through the fusion of antibody-producing B cells with myeloma cells, allowing continuous culture of hybrid cells secreting antibodies of predefined specificity. This breakthrough earned them the Nobel Prize in Physiology or Medicine in 1984, laying the foundation for antibody-based cancer immunotherapies. Building briefly on early 19th-century observations such as William Coley's use of bacterial toxins to stimulate immune responses against tumors, these advancements shifted immunotherapy toward targeted, reproducible interventions. The first major regulatory milestone came in 1997 with the FDA approval of rituximab (Rituxan), the inaugural for cancer treatment, indicated for relapsed or refractory low-grade or follicular CD20-positive , marking the entry of targeted antibody therapies into clinical practice. Subsequent approvals expanded the field, including (Keytruda) in 2014 as the first PD-1 inhibitor for unresectable or metastatic , demonstrating durable responses in checkpoint blockade . That same year, (Blincyto) received accelerated approval as the first bispecific T-cell engager antibody for relapsed or refractory Philadelphia chromosome-negative precursor B-cell , redirecting T cells to tumor cells. Adoptive cell therapies achieved pivotal approvals in 2017, with the FDA granting approval to (Kymriah), the first CAR-T cell therapy, for pediatric and young adult patients with relapsed or refractory B-cell precursor . Shortly after, (Yescarta) was approved for relapsed or refractory large B-cell lymphoma, establishing CAR-T as a transformative approach for hematologic malignancies. Earlier, in 2011, (Yervoy) became the first approved by the FDA for unresectable or metastatic , based on phase III trial data showing improved overall survival. Recent years have seen further diversification, with elranatamab (Elrexfio) approved in 2023 for relapsed or refractory after at least four prior lines of , representing a bispecific antibody targeting BCMA and CD3. In 2024, lifileucel (Amtagvi) received accelerated FDA approval as the first tumor-infiltrating () for adult patients with unresectable or metastatic previously treated with a PD-1 and if BRAF V600 mutation-positive. In May 2025, the FDA approved nivolumab plus as first-line for unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) , based on phase 3 8HW trial data demonstrating improved and overall survival. Post-2020, mRNA-based cancer vaccines have advanced through key clinical trials, including Moderna's mRNA-4157 entering phase III in 2022 for high-risk in combination with , showing promising immune activation and tumor response rates in earlier phases. Progress in inhibitors has been highlighted by phase 2 data from 2024, such as the EDGE-Gastric trial where domvanalimab plus zimberelimab and demonstrated a exceeding one year in first-line unresectable or metastatic gastric, gastroesophageal junction, or esophageal , though other candidates like Roche's tiragolumab faced setbacks in studies.
YearTherapyClassIndicationSource
1997Rituximab (Rituxan)Relapsed/ + FDA Approval History
2011 (Yervoy)CTLA-4 inhibitorUnresectable/metastatic FDA Approval
2014 (Keytruda)PD-1 inhibitorUnresectable/metastatic FDA Approval
2014 (Blincyto)Bispecific antibodyRelapsed/ Ph- B-cell ALLFDA Approval
2017 (Kymriah)CAR-T cell therapyRelapsed/ B-cell ALL (pediatric/young adult)FDA Approval
2017 (Yescarta)CAR-T cell therapyRelapsed/ large B-cell lymphomaFDA Approval
2023Elranatamab (Elrexfio)Bispecific antibodyRelapsed/ (≥4 prior lines)FDA Approval
2024Lifileucel (Amtagvi)TIL therapyUnresectable/metastatic (post-PD-1/)FDA Approval
2025 combinationFirst-line MSI-H/dMMR unresectable/metastatic FDA Approval

Cellular Immunotherapies

Dendritic Cell-Based Therapies

Dendritic cells (DCs) serve as professional antigen-presenting cells that capture, process, and present tumor antigens to T cells, thereby initiating and amplifying adaptive immune responses against cancer. In DC-based therapies, autologous DCs are harvested from the patient's peripheral blood via , cultured to expand and mature them, loaded with tumor-specific antigens such as peptides, tumor lysates, or mRNA, and then reinfused to prime antitumor T-cell responses. This approach leverages the DCs' ability to migrate to lymph nodes and activate naive T cells, offering a personalized strategy that avoids off-the-shelf limitations while minimizing graft-versus-host risks. A landmark example is (Provenge), the first FDA-approved DC-based vaccine for metastatic castration-resistant in 2010. In its manufacturing process, peripheral blood mononuclear cells are isolated from products, and monocytes are differentiated into DCs using (GM-CSF); these DCs are then activated by co-culture with the (PAP)-GM-CSF, matured with cytokines including interleukin-1β, tumor necrosis factor-α, and interleukin-6, and infused back into the patient in three biweekly doses. The pivotal phase 3 IMPACT trial, involving 512 patients, demonstrated a 22% reduction in the risk of death ( 0.78; 95% , 0.62 to 0.98), with median overall of 25.8 months versus 21.7 months in the group, establishing sipuleucel-T's in extending without significant . Beyond , other DC-based approaches include pulsing autologous DCs with tumor-specific peptides, such as those derived from melanoma-associated antigens like gp100 or NY-ESO-1, followed by maturation and intradermal or intravenous administration. In advanced , phase 2 trials have shown that peptide-pulsed DC vaccines can induce antigen-specific T-cell responses and objective responses in up to 10-20% of patients, with some achieving durable when combined with checkpoint inhibitors. For , DCs electroporated with tumor mRNA, such as Wilms' tumor 1 (WT1) mRNA, have been tested in phase 1/2 trials, demonstrating safety, immunogenicity through WT1-specific T-cell expansion, and median overall survival of 15-18 months in recurrent cases post-standard therapy. Despite these advances, DC-based therapies face challenges including suboptimal DC maturation, which can impair and T-cell priming, and limited migration to draining , with studies reporting only 1-5% of injected mature DCs reaching lymphoid tissues in patients. These issues contribute to variable clinical efficacy, prompting ongoing research into adjuvants like agonists to enhance maturation and modifications to improve homing.

Adoptive Cell Transfer Therapies

Adoptive cell transfer therapies involve the extraction, modification, and reinfusion of a patient's own immune cells to enhance their tumor-targeting capabilities, primarily focusing on T cells and natural killer () cells engineered for direct against cancer. These approaches leverage the patient's autologous cells to minimize rejection risks while amplifying anti-tumor responses, often following lymphodepleting to create a favorable microenvironment for engraftment. Unlike indirect methods, such as dendritic cell therapies that prime systemic immunity, adoptive transfers deliver pre-activated cells directly into circulation for immediate tumor engagement. Tumor-infiltrating lymphocyte (TIL) therapy extracts T cells from a patient's resected tumor, expands them using interleukin-2 to enrich for tumor-reactive clones, and reinfuses them to target heterogeneous tumor antigens. This method harnesses naturally occurring TILs that have already infiltrated the , recognizing multiple neoantigens for broader efficacy against antigen escape. In February 2024, the FDA granted accelerated approval to lifileucel (Amtagvi), the first TIL therapy, for adults with unresectable or metastatic previously treated with other therapies, based on an objective response rate of 31.4% in a phase 2 trial. Chimeric antigen receptor (CAR) T-cell therapy engineers patient T cells to express synthetic , which combine an antigen-binding domain—typically a from an —with intracellular signaling domains from CD3ζ and costimulatory molecules like or 4-1BB to activate upon target engagement. Initially developed for B-cell malignancies, CD19-targeted CAR-T cells have shown durable remissions; for instance, (Kymriah) received FDA approval in August 2017 for relapsed or pediatric and young adult B-cell , achieving a 82% complete remission rate in pivotal trials. Similarly, (Yescarta) was approved in October 2017 for large , with a 72% objective response rate and 52% complete responses. Expansion of CAR-T therapy to solid tumors targets surface antigens like GD2 in and H3K27M-mutated gliomas, or HER2 in and gastric cancers, though challenges include tumor heterogeneity and immunosuppressive microenvironments. Phase 1 trials of -CAR-T cells in H3K27M-altered diffuse midline gliomas reported clinical improvements and tumor reductions in 9 of 11 patients, with some durable responses exceeding two years. HER2-targeted CAR-T therapies have demonstrated feasibility in solid tumors, with ongoing trials showing partial responses in gastric and colorectal cancers without severe on-target toxicities when using lower-affinity binders. T-cell receptor (TCR) T-cell therapy genetically engineers peripheral blood T cells to express tumor-specific TCRs that recognize intracellular antigens presented on MHC class I molecules, enabling targeting of neoantigens unique to cancer cells. This approach is particularly suited for solid tumors, where neoantigens arise from mutations; clinical trials have tested TCR-T cells against public neoantigens like KRAS G12D in colorectal and pancreatic cancers, achieving objective responses in up to 33% of patients with minimal off-tumor toxicity. Ongoing phase 1/2 studies focus on personalized neoantigen-specific TCRs identified via tumor sequencing, with preliminary data showing T-cell persistence and tumor infiltration in melanoma and synovial sarcoma. NK cell therapies, including CAR-NK and cytokine-induced killer (CIK) cells, offer advantages over T-cell approaches by avoiding (GVHD) due to the absence of TCR-mediated alloreactivity, allowing potential allogeneic "off-the-shelf" use. CAR-NK cells express targeting tumor antigens like or HER2, combined with IL-15 for enhanced persistence; early trials in and solid tumors report complete remissions without in some patients. CIK cells, generated by culturing peripheral blood mononuclear cells with interferon-γ and IL-2, exhibit a mixed T/NK phenotype with non-MHC-restricted killing, showing safety and modest efficacy in when combined with .

Antibody-Based Therapies

Monoclonal Antibodies

Monoclonal antibodies (mAbs) represent a cornerstone of antibody-based cancer immunotherapy, consisting of unmodified or minimally modified immunoglobulin molecules designed to bind specific tumor-associated antigens or immune regulators on cancer cells. These naked mAbs, lacking chemical conjugates or bispecific , harness the to target and eliminate malignant cells while sparing healthy tissues. Approved examples include rituximab, a chimeric anti-CD20 mAb approved by the U.S. (FDA) on November 26, 1997, for the treatment of relapsed or refractory CD20-positive, B-cell low-grade or follicular non-Hodgkin's . Similarly, , a humanized anti-HER2 mAb, received FDA approval on September 25, 1998, for patients with whose tumors overexpress the HER2 protein and who have undergone prior or, in combination with , for those without prior metastatic chemotherapy. More recent approvals include , a chimeric anti-GD2 mAb approved on March 10, 2015, for pediatric patients with high-risk following initial . The therapeutic efficacy of these naked mAbs primarily arises from three key mechanisms: (ADCC), (CDC), and direct blockade of tumor-promoting signaling pathways. In ADCC, the Fc region of the mAb binds to Fcγ receptors on effector cells such as natural killer cells, recruiting them to lyse antibody-coated tumor cells. CDC involves the activation of the upon binding, forming a membrane attack complex that perforates the tumor . Direct signaling blockade occurs when mAbs bind to receptors like HER2, inhibiting ligand-induced signals in cancer cells. For instance, rituximab targets the CD20 on B-cell lymphomas, primarily inducing cell death via ADCC and CDC. blocks HER2 dimerization and downstream signaling in cells, complemented by ADCC. binds the GD2 glycolipid on cells, triggering lysis through ADCC and CDC. In investigational settings, magrolimab, a humanized anti-CD47 mAb, disrupts the CD47-SIRPα interaction to remove the "don't eat me" signal on cancer cells, thereby promoting macrophage-mediated ; it received FDA designation in 2020 for untreated intermediate- or high-risk ; however, development was discontinued in 2024 following a clinical hold due to safety concerns. To mitigate immunogenicity associated with early murine-derived mAbs, which elicited human anti-mouse antibody responses limiting repeated dosing, humanization techniques evolved progressively. Chimeric antibodies, such as rituximab developed in the , fused murine variable regions to human constant regions, reducing immunogenicity while retaining antigen specificity. Humanized mAbs like , approved shortly thereafter, further minimized murine content by grafting only the complementarity-determining regions (CDRs) onto human frameworks, enhancing tolerability and efficacy in clinical use. The advent of technology in 1990 enabled the selection of fully human antibodies from large synthetic or immune libraries, bypassing animal and yielding candidates with near-native human sequences; this approach underpins later mAbs, though its first major cancer application came with approvals like in 2006 targeting in .

Bispecific Antibodies and Conjugates

Bispecific antibodies (BsAbs) represent an advanced class of engineered immunotherapeutics designed to simultaneously bind two distinct antigens or epitopes, thereby enhancing tumor targeting and immune activation in . Unlike traditional monoclonal antibodies, BsAbs facilitate dual functionality, such as redirecting T cells to tumor cells or blocking multiple pathways, which has led to improved in hematologic malignancies and emerging applications in tumors. These molecules are typically constructed using formats like single-chain fragments or full-length IgG scaffolds to achieve stable heterodimerization. A prominent subclass of BsAbs includes T-cell engagers, which link tumor-associated antigens on cancer cells to on T cells, promoting cytotoxic formation and tumor cell . , a /CD3 bispecific T-cell engager, was granted accelerated FDA approval in December 2014 for relapsed or refractory B-cell precursor (ALL) in adults and children, demonstrating a complete remission rate of 44% in pivotal trials. More recently, elranatamab, a /CD3 bispecific , received accelerated FDA approval in August 2023 for relapsed or refractory after at least four prior lines of therapy, with an objective response rate of 61% observed in the MagnetisMM-1 study. These approvals highlight the clinical impact of T-cell engagers in redirecting endogenous T cells without prior manipulation. Antibody-drug conjugates (ADCs) extend the immunotherapy paradigm by conjugating monoclonal antibodies to cytotoxic payloads via chemical linkers, enabling targeted delivery of chemotherapeutics to tumor cells while minimizing systemic . , an HER2-targeted with a topoisomerase I inhibitor payload, was approved by the FDA in December 2019 under accelerated approval for unresectable or metastatic HER2-positive following prior anti-HER2 therapies, based on a confirmed objective response rate of 37.1% in the DESTINY-Breast01 . In 2025, the FDA expanded approval of fam-trastuzumab deruxtecan for unresectable or metastatic hormone receptor-positive, HER2-low or ultralow previously treated with endocrine and . Similarly, , a Trop-2-directed linked to (an metabolite), received accelerated FDA approval in April 2020 for metastatic after two prior therapies, with median of 5.6 months versus 1.7 months for single-agent in the ASCENT ; full approval followed in April 2021. These ADCs leverage linker stability and bystander killing effects to enhance potency against heterogeneous tumors. Beyond ADCs, other conjugates include radioimmunoconjugates, where antibodies are labeled with radionuclides to deliver targeted . , an conjugated to or , was approved by the FDA in 2002 for relapsed or refractory low-grade or follicular , offering improved response rates when combined with rituximab compared to rituximab alone. Bispecific T-cell engagers targeting non-CD3 moieties, such as or , are also under investigation to broaden immune effector engagement. Engineering strategies for BsAbs often employ the knob-into-hole (KiH) technology, introduced in 1996, which introduces specific mutations in the Fc region's CH3 domains—one chain with a bulky "knob" residue (e.g., T366W) and the other with a complementary "hole" (e.g., T366S/L368A/Y407V)—to favor heterodimer assembly over homodimerization, achieving over 95% correct pairing in production. This approach has facilitated scalable manufacturing of clinical-grade BsAbs. In solid tumors, BsAbs are demonstrating clinical advantages in ongoing trials as of 2025, including enhanced tumor infiltration and reduced escape mechanisms; for instance, phase II studies of EGFR/CD3 engagers report objective response rates up to 40% in advanced colorectal cancer, with multiple trials advancing to registrational intent.

Immune Checkpoint Blockade

CTLA-4 and PD-1/PD-L1 Inhibitors

Immune checkpoint inhibitors targeting CTLA-4 represent a foundational advance in cancer immunotherapy by augmenting early T-cell activation. , a fully human against CTLA-4, was approved by the (FDA) on March 25, 2011, as the first therapy for unresectable or metastatic , marking the initial demonstration of prolonged survival with checkpoint blockade. CTLA-4, expressed on activated T cells, competes with the co-stimulatory receptor for binding to B7 ligands on antigen-presenting cells, thereby dampening T-cell priming in lymph nodes; blocks this interaction to promote robust T-cell proliferation and anti-tumor responses. This mechanism primarily acts in secondary lymphoid tissues during the priming phase of the , distinguishing it from other checkpoints. PD-1 inhibitors disrupt a key inhibitory pathway in the , reinvigorating exhausted T cells. Nivolumab, an IgG4 , received FDA approval on December 22, 2014, for the treatment of unresectable or metastatic after progression on and, if BRAF V600 mutation-positive, a BRAF inhibitor. Similarly, pembrolizumab, a humanized IgG4 , was approved on September 4, 2014, for -refractory advanced . Both agents bind directly to PD-1 on the surface of T cells, preventing engagement with its ligands and PD-L2, which tumors exploit to suppress cytotoxic activity and foster immune evasion. PD-L1 inhibitors complement PD-1 blockade by targeting the ligand often overexpressed on tumor cells and associated immune cells. , a humanized IgG1 , became the first PD-L1 inhibitor approved by the FDA on May 18, 2016, for locally advanced or metastatic urothelial progressing after platinum-containing . , another human IgG1κ antibody, followed with FDA approval on May 1, 2017, for platinum-refractory advanced or metastatic urothelial . These inhibitors bind to PD-L1, blocking its interaction with PD-1 on T cells and on antigen-presenting cells, thereby relieving T-cell suppression within the tumor niche. These agents have yielded durable clinical responses across malignancies, with demonstrating a doubling of 10-year overall survival rates in metastatic compared to historical controls. In non-small cell , like nivolumab and have produced objective response rates of 20-30% and extended in advanced cases, often with responses lasting beyond two years. Combinations, such as plus nivolumab, further improve outcomes, achieving 5-year survival rates exceeding 50% in . Predictive biomarkers include instability-high (MSI-H) status, which correlates with higher response rates due to increased neoantigen load, and elevated (TMB), where high-TMB tumors show hazard ratios for as low as 0.47 with PD-1 blockade.

Novel Checkpoint Targets

Immune checkpoints beyond CTLA-4 and PD-1/, such as LAG-3, , TIM-3, and , have emerged as promising targets in cancer immunotherapy to overcome resistance mechanisms, particularly in immunologically "cold" tumors characterized by low T-cell infiltration and poor response to PD-1 blockade. These molecules are often co-expressed on exhausted T cells in the , where they sustain even after PD-1 inhibition, providing a rationale for dual or multi-checkpoint blockade strategies to reinvigorate antitumor immunity. By targeting these pathways, therapies aim to enhance T-cell activation and infiltration in resistant tumors, with ongoing trials evaluating combinations to broaden efficacy across solid malignancies. LAG-3 (lymphocyte-activation gene 3) is an inhibitory receptor expressed on activated and exhausted + T cells and regulatory T cells, where it interacts with class II to dampen T-cell proliferation and production, contributing to immune evasion in tumors. The first LAG-3 inhibitor, , a IgG4 , was approved by the FDA in March 2022 as part of the fixed-dose combination Opdualag (relatlimab plus nivolumab) for adult and pediatric patients (aged 12 and older) with unresectable or metastatic , based on the phase 3 RELATIVITY-047 trial demonstrating a median of 10.1 months versus 4.6 months with nivolumab alone ( 0.75). As of 2025, LAG-3 combinations continue in trials for other indications, though the phase 3 RELATIVITY-098 adjuvant study in resected missed its primary endpoint for disease-free survival when added to nivolumab. TIGIT (T-cell immunoreceptor with Ig and ITIM domains) functions as an inhibitory receptor on T cells and natural killer cells, competing with the costimulatory receptor DNAM-1 for ligands like and CD112 to suppress cytotoxic responses and promote regulatory T-cell activity in the . , an anti- , has been investigated in combination with (anti-PD-L1), showing early promise in the phase 2 trial for non-small cell (NSCLC) with an objective response rate of 37% versus 21% for alone. However, phase 3 results as of 2025 have been disappointing: the SKYSCRAPER-01 trial reported no significant improvement in (median 7.0 months versus 5.6 months) or overall survival with the addition of tiragolumab in PD-L1-high untreated NSCLC, while SKYSCRAPER-02 similarly failed to show benefit in extensive-stage small cell when combined with and (median PFS 5.4 months versus 5.6 months). TIM-3 (T-cell immunoglobulin and mucin-domain containing-3) is another exhaustion marker on T cells and natural killer cells, binding ligands like galectin-9 to induce and inhibit IFN-γ production, often upregulated alongside PD-1 in resistant tumors to perpetuate T-cell dysfunction. As of 2025, TIM-3 inhibitors remain in early clinical development, with the phase 1 trial of INCAGN02390 (a fully human anti- ) demonstrating tolerability and preliminary antitumor activity as monotherapy or in combination with PD-1 inhibitors across advanced solid tumors, including reduced exhausted + T cells in preclinical models. Ongoing trials, such as combinations with PD-1 blockade in and , aim to address resistance by enhancing T-cell infiltration, with phase 1b/2 data supporting triplet regimens including LAG-3 for improved event-free survival. VISTA (V-domain Ig suppressor of T-cell ) acts as an inhibitory on myeloid cells and T cells, suppressing T-cell via VSIG-3 interaction and promoting an immunosuppressive microenvironment, particularly in acidic tumor conditions that favor its expression. In 2025, VISTA-targeted therapies are primarily in preclinical and early-phase trials, with monoclonal antibodies showing enhanced antitumor effects in combination with PD-1/ inhibitors in models of and by blunting radiotherapy-induced myeloid suppression. Bispecific antibodies targeting VISTA and have demonstrated superior tumor inhibition in preclinical studies of endometrial and cancers compared to monotherapies, supporting ongoing phase 1 evaluations for broader application in immunotherapy-resistant settings.

Cytokine-Based Therapies

Interferons

Interferons are a family of cytokines that play a pivotal role in cancer immunotherapy by modulating immune responses and directly inhibiting tumor growth. Type I interferons, including IFN-α and IFN-β, bind to a common receptor to activate the , which induces the expression of genes promoting antiviral states, , and immune cell activation. This pathway specifically enhances natural killer (NK) cell and T-cell , contributing to antitumor effects in various malignancies. Type II interferon, IFN-γ, signals through a distinct receptor but also engages JAK-STAT to upregulate ( molecules on tumor cells, improving to cytotoxic T cells, while simultaneously inhibiting by downregulating (VEGF) expression. IFN-α has been a cornerstone of cytokine-based cancer therapy since its recombinant form was first approved by the U.S. Food and Drug Administration (FDA) in 1986 for hairy cell leukemia, where it induces tumor cell differentiation and immune-mediated clearance, achieving response rates of up to 80% in early studies. In 1995, high-dose IFN-α-2b was approved as adjuvant therapy for high-risk resected melanoma, demonstrating improvements in relapse-free survival by 9-12 months in pivotal trials through enhanced NK and T-cell activity via JAK-STAT signaling. Pegylated formulations, such as peginterferon alfa-2b (Sylatron), were later approved in 2011 for adjuvant melanoma treatment, offering sustained release with a longer half-life (approximately 40 hours [range 22-60 hours] versus ~5 hours for standard IFN-α), which reduces dosing frequency from daily to weekly and improves patient compliance while maintaining efficacy in preventing recurrence. These pegylated versions have also been combined with chemotherapy agents like dacarbazine in metastatic melanoma, showing synergistic effects by sensitizing tumor cells to apoptosis and boosting immune surveillance, with response rates around 20-30% in phase II trials. IFN-β and IFN-γ have been explored primarily in investigational settings, particularly for brain tumors like . IFN-β inhibits angiogenesis by suppressing VEGF production and has shown modest activity in phase II trials for recurrent , with some patients achieving stable disease for over 6 months when administered intratumorally or systemically. IFN-γ upregulates on cells, potentially enhancing T-cell recognition, and preclinical studies indicate it curbs tumor vascularization; however, clinical trials in high-grade s have yielded mixed results, with limited survival benefits when added to standard chemotherapy, prompting ongoing research into optimized delivery methods. Prior to the advent of inhibitors in the , interferons represented one of the earliest approved immunotherapies, with IFN-α serving as a standard for hematologic and solid tumors from the onward, though its use declined due to profiles. Common side effects include flu-like symptoms such as fever, chills, fatigue, and myalgias, affecting up to 70% of patients, alongside hematologic toxicities like and elevated liver enzymes, which are often dose-dependent and manageable with supportive care or dose reductions.

Interleukins

Interleukins represent a class of pivotal in cancer immunotherapy, particularly for their role in stimulating immune effector cells against tumors. Among them, (IL-2), marketed as aldesleukin, has been a cornerstone therapy due to its ability to drive the expansion and activation of T lymphocytes and cells, thereby enhancing antitumor immune responses. High-dose IL-2 administration promotes robust proliferation of cytotoxic T cells and NK cells by binding to the high-affinity (IL-2Rαβγ), leading to downstream signaling via JAK/STAT pathways that amplify effector functions and production. The U.S. (FDA) approved high-dose aldesleukin in 1992 for metastatic and in 1998 for metastatic , based on clinical trials demonstrating durable complete responses in approximately 5-10% of patients, though with significant including vascular leak and requiring intensive . Dosing typically involves intravenous bolus infusions of 600,000-720,000 IU/kg every 8 hours for up to 14 doses per cycle, with toxicity management strategies such as premedication with antihistamines and fluid support to mitigate capillary permeability issues. Low-dose IL-2 regimens have emerged as a strategy to preferentially expand regulatory T cells (Tregs) expressing high levels of CD25 (IL-2Rα), aiming to modulate the immunosuppressive while minimizing systemic . At doses around 1-3 million /m² subcutaneously, low-dose IL-2 sustains Treg populations to prevent but, in cancer settings, has shown potential to enhance effector T-cell function when combined with inhibitors like PD-1 blockers. Ongoing trials from 2020-2025, such as those combining low-dose IL-2 with nivolumab in and , report improved rates (e.g., up to 40% at 12 months in select cohorts) by balancing immune activation and suppression, though challenges remain in optimizing dosing to avoid over-stimulation of Tregs. at these levels is generally mild, limited to flu-like symptoms, contrasting sharply with high-dose regimens. Beyond , other interleukins like IL-15 and IL-12 are under investigation for their complementary roles in expansion and immune polarization. IL-15 , such as NKTR-255—a pegylated IL-15 receptor —selectively stimulate + T cells and cells without activating Tregs, showing promise in phase 1/2 trials through 2025 when combined with CAR-T therapies for B-cell malignancies, where complete response rates reached 70-80% at 6 months versus 50% with CAR-T alone. IL-12 drives a Th1 immune shift by inducing interferon-γ (IFN-γ) production from and T cells, promoting cytotoxic responses and inhibition, with intratumoral delivery strategies in recent trials demonstrating tumor regression in solid tumors like without severe systemic effects. Clinical studies, including phase 1 evaluations of recombinant IL-12, highlight its efficacy in shifting the cytokine milieu toward Th1 dominance, though dose-limiting has prompted localized administration approaches. Advances as of 2025 focus on engineered IL-2 variants to enhance specificity and curb toxicity, such as tumor-targeted immunocytokines fusing IL-2 to antibodies against tumor-associated antigens like PD-1 or CD8β. These variants, including nemvaleukin alfa (an IL-2 mutein lacking α-receptor binding), achieve selective delivery to the tumor site, reducing vascular leak while boosting intratumoral T-cell infiltration and yielding objective response rates of 20-30% in phase 2 trials for advanced solid tumors when paired with checkpoint inhibitors. Combinatorial strategies, such as co-administration with JAK inhibitors like , further abrogate systemic exposure, enabling safer high-potency dosing and improved tolerability in ongoing studies.

Oncolytic Virus Therapy

Mechanisms of Action

Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses that selectively infect and replicate within tumor cells, leading to their and the release of tumor antigens and danger signals that stimulate an anti-tumor . This dual mechanism distinguishes OVs from traditional chemotherapies by combining direct with immunogenic modulation of the . The selectivity of OVs for cancer cells arises from inherent tumor vulnerabilities, such as defective antiviral signaling pathways, and targeted to attenuate in normal cells while preserving replication in malignant ones. A key example of engineered selectivity is seen in (T-VEC), a modified type 1 (HSV-1) where both copies of the ICP34.5 gene are deleted. The ICP34.5 protein normally counters host antiviral responses by dephosphorylating eIF2α, but its absence restricts in healthy cells with intact signaling; in contrast, tumor cells often exhibit dysregulated pathways or impaired R (PKR) activation, allowing selective viral propagation and subsequent cell lysis. Similarly, the oncolytic adenovirus H101 features a deletion in the E1B-55K gene, enabling replication in p53-deficient cancer cells—common in —while sparing normal p53-proficient cells; H101 received approval in in 2005 for this indication. Reoviruses, such as reolysin, demonstrate natural oncolysis without genetic modification, exploiting activated oncogenic pathways like to bypass the need for junction oncogene adhesion molecule A (JAM-A) in normal cells, thus preferentially infecting and lysing transformed cells. Beyond direct tumor cell destruction, OVs induce immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 () from lysed cells, which acts as a danger signal to recruit and activate innate immune cells. binds to receptors like TLR4 on dendritic cells (DCs), promoting their maturation and enhancing of tumor-associated antigens to CD8+ T cells, thereby priming adaptive anti-tumor immunity; this process briefly leverages DC antigen presentation mechanisms to amplify systemic responses. The resulting inflammation transforms immunologically "cold" tumors into "hot" ones, fostering T-cell infiltration and long-term immune memory. While the primary effects of OV therapy are local—confined to injected tumor sites—the immune activation often yields systemic benefits, including abscopal responses where uninjected distant metastases regress due to primed T-cell trafficking. Preclinical and early clinical observations with viruses like T-VEC and adenoviral OVs have demonstrated these abscopal effects, underscoring the potential for broad anti-tumor activity beyond direct .

Clinical Examples and Applications

Talimogene laherparepvec (T-VEC), a modified type 1, was approved by the U.S. Food and Drug Administration in 2015 for the local treatment of unresectable cutaneous, subcutaneous, and nodal in patients with no evidence of visceral metastases. Administered via intralesional injection, T-VEC selectively replicates in tumor cells, leading to direct oncolysis and induction of systemic antitumor immunity. In the phase III OPTiM trial (NCT00769704), involving 436 patients with advanced , T-VEC demonstrated a durable response rate (DRR) of 16.3% compared to 2.1% with subcutaneous (GM-CSF), with median overall survival of 23.3 months versus 18.9 months, respectively. The therapy's safety profile was favorable, with common adverse events including , chills, and injection-site reactions, and no treatment-related deaths reported. H101 (Oncorine), an E1B-55K gene-deleted , became the world's first approved therapy when it received approval from China's State Food and Drug Administration in 2005 for the treatment of advanced , particularly , in combination with and 5-fluorouracil . Delivered via intratumoral injection, H101 targets p53-deficient tumor cells common in these cancers, enhancing efficacy through and immune activation. Phase III clinical trials in showed that the combination improved objective response rates to 78.8% compared to 39.6% with alone, with median survival extended to 12.1 months versus 9.9 months, and a tolerable safety profile dominated by flu-like symptoms and mild injection-site pain. H101 has been used in numerous patients in since approval, underscoring its established role in this indication. Pexa-Vec (pexastimogene devacirepvec), a thymidine kinase-deleted vaccinia virus engineered to express GM-CSF, has been investigated for advanced hepatocellular carcinoma (HCC) and other solid tumors but faced setbacks in late-stage development. The phase III PHOCUS trial (NCT02562755), evaluating intravenous Pexa-Vec followed by sorafenib in 600 patients with advanced HCC, was terminated early in 2019 after an interim futility analysis showed no improvement in overall survival (median 12.7 months [95% CI: 9.89-14.95] for combination versus 14.0 months [95% CI: 11.01-17.22] for sorafenib alone), with inferior outcomes in key subgroups. Despite this failure, data from a phase I/II study in refractory metastatic colorectal cancer combining intravenous Pexa-Vec with durvalumab (anti-PD-L1) and/or tremelimumab (anti-CTLA-4) showed objective response rates of up to 6.25% and disease control rates of 12.5-16.7%, with no unexpected toxicities beyond grade 1-2 flu-like symptoms. Ongoing trials continue to explore these synergies, particularly in immunologically "cold" tumors like HCC. Oncolytic virus therapies, including T-VEC and H101, have primarily found applications in accessible solid tumors such as , head and neck cancers, and HCC, where direct injection facilitates tumor targeting and immune priming. Combinations with PD-1 inhibitors have shown additive effects by enhancing T-cell infiltration and systemic responses; for instance, T-VEC plus in neoadjuvant yielded a pathologic complete response rate of 44% in a phase II . Similarly, integration with addresses solid tumor barriers like , with preclinical and early clinical data indicating that oncolytic viruses precondition the to boost CAR-T persistence and efficacy, achieving up to 80% tumor regression in mouse models of and . Emerging examples include cretostimogene grenadenorepvec, an oncolytic adenovirus showing promising phase 3 results (BOND-003 ) for high-risk BCG-unresponsive non-muscle-invasive , with a complete response rate of 75.2% at any time and durability in 51% of responders at 12 months as of 2025, pending U.S. FDA approval following a planned Biologics License Application submission in Q4 2025. These approaches are advancing toward broader use in refractory solid malignancies, emphasizing multimodal strategies to overcome monotherapy limitations.

Cancer Vaccines

Preventive and Therapeutic Vaccines

Preventive vaccines in cancer immunotherapy target oncogenic viruses to inhibit cancer development before it occurs. The human papillomavirus () vaccine , approved by the FDA in , prevents cervical, vulvar, vaginal, and anal cancers caused by HPV types 16 and 18 by inducing neutralizing antibodies that block viral entry into host cells. Clinical trials demonstrated over 90% efficacy in preventing HPV-related precancerous lesions in women aged 9-26. Similarly, the hepatitis B virus (HBV) vaccine, recommended by the CDC and WHO since the 1980s, prevents chronic HBV infection, which is a major risk factor for , reducing incidence by up to 70% in vaccinated populations through the generation of protective anti-HBs antibodies. These vaccines exemplify how immunization against viral carcinogens can significantly lower cancer rates at the population level. Therapeutic vaccines, in contrast, aim to elicit immune responses against established tumors by presenting tumor-associated antigens to stimulate antigen-specific T cells and antibodies. They induce both humoral immunity, via B-cell production of tumor-targeting antibodies, and cellular immunity, through CD8+ cytotoxic T lymphocytes that recognize and lyse cancer cells. Adjuvants such as granulocyte-macrophage colony-stimulating factor (GM-CSF) enhance these responses by recruiting and activating dendritic cells at the vaccination site, promoting and presentation. These mechanisms differ from dendritic cell-based therapies, which involve manipulation of patient-derived cells but share the goal of boosting adaptive immunity. Examples of therapeutic vaccines include whole-cell approaches like GVAX for , which uses irradiated allogeneic prostate cancer cell lines ( and PC-3) engineered to secrete GM-CSF, thereby presenting multiple tumor antigens to induce broad T-cell responses; phase II trials showed immune activation but mixed survival benefits. vaccines, such as PROSTVAC, employ recombinant poxviruses ( prime followed by boosts) encoding (PSA) and costimulatory molecules (TRICOM), leading to PSA-specific T-cell proliferation; a phase II trial in metastatic castration-resistant prostate cancer reported an 8.5-month overall survival extension versus , though a subsequent phase III trial failed to meet its primary endpoint of for overall survival. Polysaccharide vaccines like (PSK), derived from and approved in in 1977 as an adjuvant for gastric cancer, activate innate immunity via TLR2 agonism, enhancing NK cell and T-cell activity to prolong disease-free survival when combined with .

Personalized Neoantigen Vaccines

Personalized neoantigen vaccines are designed to elicit immune responses against tumor-specific mutations unique to an individual's cancer, offering a tailored approach to immunotherapy. Neoantigens arise from somatic mutations in tumor DNA, and their identification begins with next-generation sequencing (NGS) of tumor and matched normal tissue to detect these alterations, followed by human leukocyte antigen (HLA) typing to determine how neoantigens are presented on the cell surface. Bioinformatics algorithms then predict peptide binding to HLA molecules and assess potential immunogenicity by evaluating factors such as binding affinity, stability, and similarity to self-antigens to prioritize candidates likely to trigger T-cell responses. Advanced machine learning models integrate proteogenomic data to rank neoantigens, improving accuracy in selecting those with high therapeutic potential. Vaccine platforms for delivering these neoantigens vary, with mRNA-based approaches enabling rapid, individualized manufacturing by encoding selected neoantigen sequences into nanoparticles for direct in dendritic cells. For instance, BNT111, an targeting four melanoma-associated neoantigens, has been evaluated in phase II trials for advanced , often combined with PD-1 inhibitors to enhance efficacy. Similarly, Moderna's mRNA-4157 (also known as V940), which encodes up to 34 patient-specific neoantigens, initiated phase III trials starting in 2023 for in high-risk , with a phase III trial for non-small cell beginning in 2024; phase II data indicated a relapse-free of approximately 75% at 18 months, and 3-year follow-up as of 2024 showed a sustained 49% reduction in the risk of recurrence or death compared to alone. Peptide-based platforms, such as NeoVax, use synthetic long peptides mixed with adjuvants like poly-ICLC to mimic natural , targeting up to 20 neoantigens per patient in settings. Clinical trials combining personalized neoantigen vaccines with checkpoint inhibitors have shown promising immune activation and antitumor activity, particularly in . In the phase II BNT111-01 trial, BNT111 plus achieved an objective response rate of 18.1% in PD-(L)1-refractory patients, with vaccine-specific T-cell responses correlating to clinical benefit. For mRNA-4157 combined with in resected high-risk , phase II data indicated a relapse-free of approximately 75% at 18 months, highlighting the synergy of neoantigen targeting with blockade. NeoVax trials in stage III/IV reported durable T-cell responses and a median of over two years in small cohorts, underscoring the approach's potential for long-term control. These vaccines hold particular promise for tumors with low (TMB), where shared antigens are limited, as neoantigens can still be derived from non-coding , variants, or frameshifts to drive specific immunity without off-target effects. By 2025, advances in have enhanced prediction, with models achieving higher accuracy in forecasting HLA presentation and , reducing false positives and accelerating design for broader applicability. Such integrations, including transformer-based architectures, enable more precise selection of neoantigens even in immunologically "" tumors.

Biomarkers and Patient Selection

Genetic and Molecular Biomarkers

Genetic and molecular biomarkers play a crucial role in predicting responses to cancer immunotherapy by identifying tumor-intrinsic alterations that influence immune recognition and checkpoint inhibitor efficacy. Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors exhibit enhanced responsiveness to PD-1/PD-L1 inhibitors due to increased neoantigen load and immune activation. In 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab in unresectable or metastatic MSI-H or dMMR solid tumors, marking the first tissue-agnostic approval based on this biomarker, with subsequent companion diagnostics like the MMR IHC 4-in-1 pharmDx and FoundationOne CDx enabling its clinical use. Similarly, tumor mutational burden (TMB), defined as the number of nonsynonymous mutations per megabase of genome, serves as a proxy for neoantigen immunogenicity; tumors with TMB greater than 10 mutations per megabase (mut/Mb) demonstrate higher objective response rates to immune checkpoint inhibitors across various cancers, including non-small cell lung cancer and melanoma, though thresholds may vary by tumor type. Certain genetic alterations confer resistance to , highlighting the need for targeted genomic profiling. Loss-of-function mutations in JAK1 or JAK2 disrupt interferon-gamma signaling, impairing and leading to primary or acquired resistance to PD-1 blockade in and other solid tumors. In , BRAF V600 mutations, present in approximately 50% of cases, influence immunotherapy outcomes; while these tumors respond to checkpoint inhibitors, BRAF status guides sequential or combinatorial strategies with targeted BRAF/MEK inhibitors to enhance immune infiltration and response durability. Recent as of 2025 has identified loss-of-function mutations in PPP2R1A, a encoding a subunit, as associated with significantly prolonged overall and in patients receiving immunotherapy, particularly in and high-risk , suggesting potential as a novel positive predictive . These findings underscore the prognostic value of specific mutations in stratifying patients for immunotherapy. Next-generation sequencing (NGS) panels are the primary method for detecting these biomarkers, enabling comprehensive tumor profiling. The MSK-IMPACT assay, a hybridization capture-based NGS panel targeting over 400 cancer-associated genes, accurately quantifies TMB and identifies status by comparing tumor and matched normal DNA, facilitating precision decisions for eligibility. As of 2025, liquid biopsy techniques using (ctDNA) have advanced TMB assessment, offering non-invasive monitoring; studies demonstrate that blood-based TMB correlates with tissue TMB and predicts in immunotherapy-treated patients, though standardization of cutoffs remains a challenge for broader adoption.

Tumor Microenvironment and Immune Biomarkers

The tumor microenvironment (TME) plays a pivotal role in modulating immune responses to cancer, with biomarkers assessing its composition providing critical insights for predicting immunotherapy efficacy. These markers evaluate the balance between immune activation and suppression within the tumor ecosystem, distinguishing immunologically "hot" tumors—characterized by robust T-cell infiltration and responsiveness to checkpoint inhibitors—from "cold" tumors with sparse immune engagement. Key TME biomarkers include surface protein expression on tumor cells, densities of infiltrating immune cells, suppressive elements, and even distal influences like the gut microbiome, which collectively inform patient stratification for therapies such as PD-1/PD-L1 inhibitors. Additionally, systemic inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) derived from complete blood count, serum lactate dehydrogenase (LDH), and albumin levels have been recommended by the Society for Immunotherapy of Cancer (SITC) consensus in 2025 as essential for inclusion in clinical trials to predict response and toxicity across tumor types. PD-L1 expression, assessed via immunohistochemistry (IHC), remains a cornerstone for selecting patients for anti-PD-1/PD-L1 therapies. The tumor proportion score (), which quantifies the percentage of viable tumor cells exhibiting partial or complete PD-L1 membrane staining, guides eligibility for in non-small cell (NSCLC); for instance, a TPS of ≥50% identifies patients suitable for first-line monotherapy, based on FDA-approved companion diagnostics like the Dako PD-L1 IHC 22C3 pharmDx assay. This threshold correlates with improved in metastatic NSCLC cohorts treated with plus , where high PD-L1 expression enhances antitumor T-cell reactivation. Automated TPS analysis has further standardized scoring, reducing inter-observer variability and confirming its prognostic value across NSCLC subtypes. Immune cell infiltration patterns within the TME offer additional predictive power, particularly through metrics of cytotoxic T-cell density and organized structures. High + T-cell density in tumor cores and invasive margins pre-treatment predicts overall survival in patients receiving inhibitors (ICIs), as visualized via whole-body imaging or multiplexed assays, reflecting an active antitumor response. Tertiary lymphoid structures (TLS)—ectopic lymphoid aggregates containing B cells, T cells, and dendritic cells—further stratify ; their presence in the TME associates with favorable outcomes and enhanced ICI responses across solid tumors, including and , by fostering local T- and B-cell priming against neoantigens. In , TLS maturity (e.g., formation) correlates with reduced recurrence risk post-. Emerging as of October 2025, thymic health—assessed via AI-derived algorithms on imaging of the —has been linked to improved progression-free and overall survival with immunotherapy across diverse cancers like , , and , highlighting the role of peripheral immune organ function in T-cell repertoire diversity and response prediction. Suppressive elements in the TME, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), counteract immune activation and serve as inverse biomarkers of response. , identified by IHC or , indicate an immunosuppressive milieu; however, in advanced , higher baseline intratumoral FOXP3+ Treg levels combined with TGF-β expression predict favorable anti-PD-1 responses, possibly due to heightened reliance on PD-1 blockade for Treg modulation. Elevated Ki67+ proliferating Tregs pre-treatment, conversely, signal poor event-free survival in sarcomas under ICIs, as low levels allow better T-effector dominance post-therapy. For MDSCs, arginase-1 (ARG1) expression—measured via qPCR or IHC—marks their immunosuppressive activity by depleting L-arginine essential for T-cell function; high ARG1+ MDSC infiltration in peripheral blood or tumors correlates with reduced ICI efficacy in NSCLC and correlates with advanced disease stages. The gut influences systemic immunity and TME dynamics, emerging as a non-invasive for ICI outcomes. Enrichment of species, such as B. longum or B. bifidum, in responders' fecal metagenomes associates with augmented function and + T-cell activation; clinical trials in patients demonstrate that oral supplementation enhances anti-PD-1 efficacy by promoting IFN-γ production and reducing Treg activity. In non-responders, with low diversity predicts progression, underscoring microbiome profiling via 16S rRNA sequencing as a tool for response prediction. By 2025, advances in multiplex IHC and have refined TME biomarker assessment, enabling precise classification of hot versus cold tumors. Multiplex IHC panels, staining up to 40 markers simultaneously, map heterogeneous immune landscapes , revealing that hot tumors with clustered + T cells near tumor nests respond better to ICIs than cold tumors lacking such infiltration. , integrating NanoString GeoMx or Visium platforms, quantifies gene expression gradients across TME compartments, identifying immunosuppressive signatures (e.g., ARG1 upregulation in stromal regions) that predict resistance; and cancers, these tools have validated TLS proximity to tumor edges as a superior prognostic metric over bulk . Such technologies facilitate personalized strategies to "heat up" cold tumors via combination therapies.

Approved Therapies and Clinical Use

List of FDA-Approved Agents

Cancer immunotherapy has seen numerous FDA approvals across various agent classes, beginning with monoclonal antibodies in the late and expanding to advanced cellular therapies by 2025. These agents target specific immune pathways or cancer antigens to enhance the body's antitumor response, with approvals granted for hematologic and solid tumors based on data demonstrating and . The following catalogs key approved agents by class, highlighting initial approval dates and primary indications; many have received subsequent label expansions for additional cancers or settings.

Checkpoint Inhibitors

These agents block inhibitory signals on T cells, such as CTLA-4 or PD-1/PD-L1, to unleash immune attacks on tumors. Ipilimumab (Yervoy), a CTLA-4 monoclonal antibody, received FDA approval on March 25, 2011, for the treatment of unresectable or metastatic melanoma in adults and children aged 12 years and older. Pembrolizumab (Keytruda), a PD-1 inhibitor, was first approved on September 4, 2014, for unresectable or metastatic melanoma, with over 30 subsequent expansions by 2025 for cancers including non-small cell lung cancer, head and neck squamous cell carcinoma, and microsatellite instability-high solid tumors. Atezolizumab (Tecentriq), a PD-L1 inhibitor, gained approval on May 18, 2016, for locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. Durvalumab (Imfinzi), a PD-L1 inhibitor, was approved on March 28, 2025, with gemcitabine and cisplatin as neoadjuvant treatment followed by single-agent durvalumab as adjuvant therapy for muscle-invasive bladder cancer. Nivolumab (Opdivo) in combination with ipilimumab (Yervoy) was approved on April 8, 2025, for unresectable or metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer. Retifanlimab-dlwr (Zynyz), a PD-1 inhibitor, was approved on May 15, 2025, in combination with carboplatin and paclitaxel as first-line treatment for locally recurrent or metastatic anal squamous cell carcinoma. Penpulimab-kcqx was approved on April 23, 2025, in combination with cisplatin or carboplatin and gemcitabine, and as monotherapy, for recurrent or metastatic non-keratinizing nasopharyngeal carcinoma. Cemiplimab-rwlc (Libtayo), a PD-1 inhibitor, received approval on October 8, 2025, as adjuvant treatment for high-risk cutaneous squamous cell carcinoma following surgery and radiation.

CAR-T Cell Therapies

Chimeric antigen receptor (CAR) T-cell therapies involve engineering patient T cells to target cancer-specific antigens, primarily for hematologic malignancies. Tisagenlecleucel (Kymriah) was approved on August 30, 2017, for pediatric and young adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Axicabtagene ciloleucel (Yescarta) received approval on October 18, 2017, for adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Idecabtagene vicleucel (Abecma) was approved on March 26, 2021, for adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy.

Monoclonal Antibodies and Bispecific Engagers

Early immunotherapies include antibodies that bind tumor antigens or bridge immune effector cells to cancer cells. Rituximab (Rituxan), an anti-CD20 monoclonal antibody, was approved on November 26, 1997, for relapsed or refractory low-grade or follicular CD20-positive B-cell non-Hodgkin lymphoma. Trastuzumab (Herceptin), targeting HER2, received approval on December 3, 1998, as adjuvant therapy for HER2-overexpressing node-positive breast cancer. Blinatumomab (Blincyto), a bispecific T-cell engager targeting CD19 and CD3, was approved on December 3, 2014, for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Linvoseltamab-gcpt (Lynozyfic), a bispecific BCMA-directed CD3 T-cell engager, was approved on July 2, 2025, for adults with relapsed or refractory multiple myeloma after at least four prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Oncolytic Virus Therapies

(T-VEC, Imlygic), a genetically modified , was approved on October 27, 2015, for the local treatment of lesions in patients with unresectable cutaneous, subcutaneous, or nodal lesions.

Cancer Vaccines and TIL Therapies

(Provenge), an autologous cellular , was approved on April 29, 2010, for asymptomatic or minimally symptomatic metastatic castration-resistant . Lifileucel (Amtagvi), the first tumor-infiltrating (TIL) therapy, received accelerated approval on February 16, 2024, for adults with unresectable or metastatic previously treated with a PD-1 blocking and if BRAF V600 mutation-positive.

Antibody-Drug Conjugates (Recent Updates)

Datopotamab deruxtecan (Datroway), a Trop-2-directed antibody-drug conjugate, was approved on January 17, 2025, for unresectable or metastatic hormone receptor-positive, HER2-negative after endocrine therapy and prior , and on June 23, 2025, for previously treated locally advanced or metastatic EGFR-mutated non-small cell .
ClassAgentInitial Approval DatePrimary Indication
Checkpoint InhibitorMarch 25, 2011Unresectable/metastatic
Checkpoint InhibitorSeptember 4, 2014Unresectable/metastatic (expansions ongoing)
Checkpoint InhibitorMay 18, 2016Locally advanced/metastatic urothelial
Checkpoint InhibitorMarch 28, 2025Neoadjuvant/adjuvant muscle-invasive
Checkpoint InhibitorNivolumab + April 8, 2025MSI-H/dMMR metastatic
Checkpoint InhibitorRetifanlimab-dlwrMay 15, 2025Locally recurrent/metastatic anal (first-line with chemo)
Checkpoint InhibitorPenpulimab-kcqxApril 23, 2025Recurrent/metastatic non-keratinizing
Checkpoint InhibitorCemiplimab-rwlcOctober 8, 2025Adjuvant high-risk
CAR-TAugust 30, 2017Relapsed/refractory B-cell ALL (pediatric/young adult)
CAR-TOctober 18, 2017Relapsed/refractory large B-cell
CAR-TIdecabtagene vicleucelMarch 26, 2021Relapsed/refractory
Monoclonal AntibodyNovember 26, 1997Relapsed/refractory
Monoclonal AntibodyDecember 3, 1998HER2+ (adjuvant)
Bispecific EngagerDecember 3, 2014Relapsed/refractory B-cell ALL
Bispecific EngagerLinvoseltamab-gcptJuly 2, 2025Relapsed/refractory (after ≥4 lines)
Oncolytic Virus (T-VEC)October 27, 2015Unresectable lesions
VaccineApril 29, 2010Metastatic castration-resistant
TIL TherapyLifileucelFebruary 16, 2024Unresectable/metastatic (post-PD-1)
ADCJanuary 17, 2025 (breast); June 23, 2025 (lung)HR+/HER2- ; EGFR-mutated NSCLC

Combination Strategies

Combination strategies in cancer immunotherapy aim to enhance efficacy by leveraging synergistic effects between immune-modulating agents and conventional therapies, addressing limitations such as tumor heterogeneity and immune resistance. These approaches often combine multiple checkpoint inhibitors to broaden T-cell activation or pair immunotherapies with or to improve and reduce immunosuppressive microenvironments. Clinical evidence supports their use in various solid tumors, with ongoing trials exploring novel pairings to expand applicability. Dual checkpoint inhibition, such as the combination of nivolumab (anti-PD-1) and (anti-CTLA-4), has demonstrated superior outcomes in advanced compared to monotherapy. In the phase 3 CheckMate 067 trial, the combination yielded a higher objective response rate (58%) and longer (median 11.5 months) than ipilimumab alone (median 2.9 months). Long-term follow-up at 10 years revealed melanoma-specific survival rates of 96% among patients progression-free at 3 years, establishing this regimen as a standard for first-line treatment. Integrating checkpoint inhibitors with chemotherapy has improved survival in non-small cell lung cancer (NSCLC). The KEYNOTE-189 trial showed that pembrolizumab plus pemetrexed-platinum resulted in significantly longer overall survival (median 22.0 months) and (median 9.0 months) compared to alone (median 10.7 and 4.9 months, respectively) in metastatic nonsquamous NSCLC, irrespective of expression levels. This combination enhances T-cell priming by chemotherapy-induced immunogenic , leading to FDA approval as a first-line option. in combination with trastuzumab and (fluoropyrimidine- and platinum-containing) was approved on March 19, 2025, for HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction with CPS ≥1. Chimeric receptor () T-cell therapies are being combined with cytokines or oncolytic viruses to overcome challenges in solid tumors, such as poor infiltration and exhaustion. Preclinical and early clinical studies indicate that pairing CAR-T cells with cytokine-armed oncolytic adenoviruses boosts T-cell persistence and antitumor activity in immunosuppressive environments like , with enhanced tumor regression observed in mouse models. Similarly, oncolytic viruses improve CAR-T trafficking and antigen escape evasion in solid tumors, as evidenced in phase 1 trials showing increased response rates. Bispecific antibodies targeting immune checkpoints or tumor antigens are under investigation in combination with antibody-drug conjugates (ADCs) to potentiate in hematologic and solid malignancies. In relapsed large , trials combining bispecific T-cell engagers with ADCs have reported favorable complete response rates exceeding 50%, attributed to synergistic direct tumor killing and immune activation. Emerging bispecific ADCs, which incorporate dual targeting to enhance delivery, are in phase 2 studies for and cancers, showing improved and reduced off-target . As of 2025, trends emphasize triple combinations incorporating ADCs with and for resistant tumors, such as HER2-negative gastric cancer, where preliminary data indicate extensions of up to 6 months over doublets. modulation strategies, including fecal microbiota transplantation, are gaining traction to augment responses by enriching beneficial gut bacteria that correlate with higher efficacy, as supported by meta-analyses of multi-microbiome predictors in ICI-treated patients.

Challenges and Future Directions

Immune-Related Adverse Events and Resistance

Immune-related adverse events (irAEs) are a significant challenge in cancer immunotherapy, particularly with inhibitors (ICIs), where they arise from dysregulated immune activation against healthy tissues. Common irAEs include , characterized by and due to immune-mediated of the ; , involving that can lead to dyspnea and ; and endocrinopathies such as , , or , resulting from autoimmune attack on endocrine glands. These events occur in approximately 43% of patients receiving ICIs, with severe ( 3 or higher) cases affecting about 14%, though incidence varies by agent class—higher with CTLA-4 inhibitors compared to PD-1/ blockers. The severity of irAEs is graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, which categorizes events from 1 (mild, ) to 5 (), guiding decisions such as holding for 2 events or permanent discontinuation for 4. Management of irAEs emphasizes prompt intervention to prevent progression, starting with corticosteroids (0.5–2 mg/kg/day equivalent) for grade 2 or higher events, tapered over 4–6 weeks once symptoms resolve to grade 1 or below. For steroid-refractory (grade 3–4), anti-TNF agents like are recommended, reducing the need for in severe cases; typically responds to high-dose steroids, with or mycophenolate considered for non-responders; endocrinopathies often require lifelong rather than , as they may not fully reverse. In CAR-T , distinct toxicities include (CRS), a systemic inflammatory response driven by elevated IL-6 and other cytokines, manifesting as fever, , and , and immune effector cell-associated neurotoxicity syndrome (ICANS), involving , , and altered mental status due to blood-brain barrier disruption. CRS affects up to 90% of patients but is mostly low-grade, while severe ICANS occurs in 10–30% of cases, particularly with CD19-targeted therapies. Both are graded using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria, aligned with CTCAE, with (IL-6 ) as first-line for CRS grade 2 or higher, often combined with steroids for ICANS; supportive care like vasopressors and prophylaxis is essential. Recent 2025 analyses link gut composition to irAE risk, with (e.g., reduced ) associated with higher incidence of and , suggesting potential for microbiome modulation in prevention. Resistance to cancer immunotherapy encompasses primary (innate) non-response, adaptive (secondary) evasion, and acquired mechanisms post-initial efficacy, limiting durable responses in up to 60–70% of patients. In CAR-T therapy, antigen loss—such as downregulation or mutation of target antigens like —enables tumor from T-cell recognition, observed in 10–20% of relapsed cases via selective pressure. Upregulation of alternative immune checkpoints, including TIM-3, LAG-3, and , promotes T-cell exhaustion following initial ICI blockade, contributing to adaptive resistance through compensatory signaling pathways. Tumor evolution, tracked via next-generation sequencing (NGS), reveals for resistant subpopulations, such as loss of neoantigens or in interferon signaling (e.g., JAK1/2), driving progression in responsive tumors. As a key resistance , beta-2-microglobulin (B2M) loss impairs antigen , rendering tumors invisible to + T cells; homozygous B2M correlate with poor outcomes in ICI-treated patients, detectable in 10–15% of resistant cases across solid tumors. These mechanisms highlight the need for biomarkers like B2M status to guide patient selection, integrating with tumor microenvironment assessments for personalized strategies.

Emerging Technologies and Research

Recent advancements in gene editing technologies, particularly CRISPR-Cas9, have enabled precise modifications to immune cells to enhance their anti-tumor activity. One prominent application involves editing the PD-1 gene in T cells to disrupt the PD-1/PD-L1 inhibitory pathway, thereby improving T cell persistence and efficacy against solid tumors. Clinical trials, such as those evaluating CRISPR-engineered T cells for refractory cancers, have demonstrated feasibility and safety, with ongoing phase 1 studies in 2025 showing preliminary anti-tumor responses in patients with advanced solid malignancies. However, off-target effects remain a significant concern, as unintended edits can lead to genomic instability or unintended immune dysregulation, necessitating advanced delivery systems like lipid nanoparticles to minimize these risks. Nanotechnology is playing a pivotal role in improving the delivery and efficacy of cancer immunotherapies, with lipid nanoparticles (LNPs) emerging as a key platform for mRNA-based vaccines. LNPs protect mRNA from degradation, facilitate targeted delivery to antigen-presenting cells, and enhance immune activation, as evidenced by their success in vaccines and adaptation for neoantigen vaccines in clinical trials for and other cancers. In 2025, novel LNP formulations have shown potential to reduce required vaccine dosages by up to 50% while boosting cytotoxic T-cell responses in preclinical models. Complementing this, gold nanoparticles (AuNPs) are being explored to augment checkpoint inhibitors by delivering anti-PD-L1 antibodies directly to tumor sites, leveraging their photothermal properties to increase local drug release and immune infiltration. Studies indicate that AuNP-conjugated therapies can enhance tumor inhibition in models by synergizing photothermal ablation with immunotherapy. Modulation of the gut represents another frontier in enhancing immunotherapy responses, with fecal microbiota transplantation (FMT) and showing promise in overcoming resistance. FMT restores beneficial microbial communities to boost inhibitor efficacy, as supported by a 2025 demonstrating improved objective response rates in advanced cancers when combined with PD-1 inhibitors. At the 2025 Society for Immunotherapy of Cancer (SITC) Annual Meeting, presentations highlighted second-generation microbiome interventions, including targeted , that enhance T-cell infiltration and reduce toxicity in solid tumors. These approaches leverage microbial metabolites to reprogram the , with ongoing trials evaluating like Akkermansia muciniphila supplementation for patients. Artificial intelligence (AI) is transforming the design of personalized immunotherapies by integrating multi-omics data to predict neoantigens and forecast resistance mechanisms. models, such as those using random forests on genomic and transcriptomic datasets, achieve over 90% accuracy in identifying immunogenic neoantigens for development in . In 2025, AI-driven frameworks have enabled multi-omics integration to stratify patients for blockade, predicting responses with improved precision by analyzing alongside profiles. These tools prioritize high-impact neoantigens, reducing off-target effects and accelerating clinical translation in solid tumors.

References

  1. [1]
    Immunotherapy for Cancer - NCI - National Cancer Institute
    Sep 24, 2019 · Immunotherapy is a type of cancer treatment that helps your immune system fight cancer. The immune system helps your body fight infections and other diseases.Cancer Treatment Vaccines · Immune Checkpoint Inhibitors · Side Effects
  2. [2]
    The Intriguing History of Cancer Immunotherapy - PMC - NIH
    Dec 17, 2019 · The following paper tracks cancer immunotherapy from its known beginnings up until recent events, including the 2018 Nobel Prize award to James Allison and ...
  3. [3]
    Advances in cancer immunotherapy: historical perspectives, current ...
    May 7, 2025 · On February 16, 2024, the U.S. FDA granted accelerated approval for lifileucel (Amtagvi), an adoptive immune cell therapy utilizing autologous ...
  4. [4]
    One Year in Cancer Research and Much to Celebrate - NCI
    Dec 20, 2024 · NCI Director Dr. Kimryn Rathmell reviews some of the most noteworthy cancer research findings from 2024, including advances in immunotherapy ...<|control11|><|separator|>
  5. [5]
    Cancer immunoediting from immune surveillance to immune escape
    In the mid-20th century, 50 years later, Burnet and Thomas postulated that the control of nascent transformed cells may represent an ancient immune system, ...
  6. [6]
    Immunosurveillance and immunotherapy of tumors by innate ... - NIH
    The innate immune system plays a significant role in recognizing and eliminating tumor cells. Innate cells and particularly NK cells express a fixed set of ...
  7. [7]
    Cancer immunoediting by the innate immune system in the absence ...
    Aug 27, 2012 · In the absence of adaptive immunity, NK cells polarize M1 macrophages to facilitate cancer immunoediting.
  8. [8]
    T Cells and MHC Proteins - Molecular Biology of the Cell - NCBI - NIH
    Whereas B cells recognize intact antigen, T cells recognize fragments of protein antigens that have been partly degraded inside the antigen-presenting cell. ...
  9. [9]
    Role of B cells as antigen presenting cells - PMC - PubMed Central
    Cabrita and colleagues showed that B cells within TLS have high expression of MHC I and MHC II, suggesting that these B cells are capable of presenting antigens ...
  10. [10]
    Uncovering the Tumor Antigen Landscape: What to Know about the ...
    Tumor antigens can generally be categorized into tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs) based on the expression pattern of the ...
  11. [11]
    PD-1/PD-L1 Blockade Therapy for Tumors with Downregulated ...
    The downregulation of surface MHC-I expression is a frequent mechanism for immune escape in various human malignancies, ranging from 15% in renal carcinoma to ...
  12. [12]
    Revealing the mechanism of PD-1 / PD-L1-mediated tumor immune ...
    Among these, the PD-1/PD-L1 signaling pathway is a well-known immunological checkpoint, which is significant in the regulation of immune evasion by tumors.
  13. [13]
    The Functional Crosstalk between Myeloid-Derived Suppressor ...
    The bidirectional crosstalk between myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) contributes to immune evasion, limiting the success of ...Missing: paper | Show results with:paper
  14. [14]
    Cancer Immunotherapy, Part 1: Current Strategies and Agents - PMC
    CANCER IMMUNOTHERAPY APPROACHES. The principle goal of cancer immunotherapy is to resurrect the patient's suppressed immune system so that it is again capable ...
  15. [15]
    Principles of Immunotherapy: Implications for Treatment Strategies ...
    Modern cancer immunotherapy approaches include biologics that selectively deplete suppressor cell populations, like Tregs. One such agent, a diphtheria toxin ( ...
  16. [16]
    A Review of the Abscopal Effect in the Era of Immunotherapy - PMC
    Sep 26, 2022 · This review focuses on recent advances in the understanding of the effect of radiation and immunotherapy in the context of the abscopal effect.
  17. [17]
    The Role of Antigen Spreading in the Efficacy of Immunotherapies
    This review will focus on experimental and clinical evidence for the induction of epitope spreading and its role in the maintenance of an efficient antitumor ...Abstract · Introduction · Cross-presentation as a... · Epitope Spreading Associated...
  18. [18]
    Cold and hot tumors: from molecular mechanisms to targeted therapy
    Oct 18, 2024 · Immunotherapy aims to restore the innate antitumor immune response, revitalizing and maintaining the tumor-specific immune pathway. The ...
  19. [19]
    Immunological Classification of Tumor Types and Advances in ...
    Conversely, cold tumors are characterized by the absence of stimulatory signals and a low expression of neoantigens, which cause poor tumor immunogenicity. The ...
  20. [20]
    The spontaneous remission of cancer: Current insights and ... - NIH
    Jul 6, 2021 · Spontaneous remission (SR) of cancer is a rare but well-documented phenomenon. Mechanisms of SR are described in detail.
  21. [21]
    The Toxins of William B. Coley and the Treatment of Bone and Soft ...
    Coley injected streptococcal organisms into a cancer patient in order to cause erysipelas and stimulate the immune system. The patient's tumor disappeared, ...
  22. [22]
    What Ever Happened to Coley's Toxins? - Cancer Research Institute
    Apr 2, 2015 · Coley was a surgeon at Memorial Hospital who developed an approach to treating cancer that involved injecting patients with a mixture of heat-killed bacteria.
  23. [23]
    MSK Immunotherapy — Timeline of Progress
    In 1893, surgeon William Coley began treating cancer patients with a mixture of heat-killed bacteria (“Coley's toxins”) after noticing that patients with ...
  24. [24]
    Paul Ehrlich's magic bullet concept: 100 years of progress - Nature
    May 12, 2008 · Cancer therapy progress since Ehrlich's side-chain theory. These immunological achievements evolved into what became Ehrlich's 'magic bullet ...
  25. [25]
    Paul Ehrlich's magic bullet concept: 100 years of progress - PubMed
    The declared paradigm is the development of 'personalized and tailored drugs' that precisely target the specific molecular defects of a cancer patient.
  26. [26]
    The concept of immune surveillance against tumors: The first theories
    Sir Frank Mac Farlane Burnet (Figure 3) hypothesize that tumor cell neo-antigens induce an immunological reaction against cancer and subsequently formulated the ...
  27. [27]
    Does the Immune System Naturally Protect Against Cancer? - Frontiers
    Lewis Thomas and Frank Macfarlane Burnet proposed the concept of immunological surveillance of cancer more than five decades ago (1–4). It was defined by Burnet ...
  28. [28]
    Virus interference. I. The interferon - Biological Sciences - Journals
    Isaacs Alick and; Lindenmann J. 1957Virus interference. I. The interferonProc. R. Soc. Lond. B147258–267http://doi.org/10.1098/rspb.1957.0048. Section. You ...
  29. [29]
    History of Bacillus Calmette-Guerin and Bladder Cancer
    Morales devised the original BCG protocol against blad- der tumors in 1972. For convenience of packaging and avail- ability, the vaccine manufactured by the ...
  30. [30]
    Milestones in Cancer Research and Discovery - NCI
    Apr 18, 2025 · This timeline shows a few key milestones in the history of cancer research. 1775: Chimney Soot & Squamous Cell CarcinomaMissing: Kohler Milstein bispecific
  31. [31]
    Recent Progress in Dendritic Cell-Based Cancer Immunotherapy
    Here we focus on the recent progress in DC-based cancer vaccines and especially the use of the XCR1 and its ligand XCL1 axis for the targeted delivery of ...
  32. [32]
    Dendritic Cell-Based Immunotherapy: A Basic Review ... - PubMed
    Dendritic cells (DCs) are considered a very promising arm to activate the immune system in immunotherapeutic strategies against cancer.
  33. [33]
    Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer
    Jul 29, 2010 · Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration- ...
  34. [34]
    Dendritic cell vaccines for melanoma: past, present and future - PMC
    Administering dendritic cells (DC) loaded with tumor-associated antigens (TAA) ex vivo is a promising strategy for therapeutic vaccines in advanced melanoma.
  35. [35]
    Adjuvant dendritic cell therapy in stage IIIB/C melanoma - Nature
    Feb 23, 2024 · Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients.
  36. [36]
    WT1-mRNA dendritic cell vaccination of patients with glioblastoma ...
    Jan 23, 2025 · These data indicate that WT1-mRNA/DC vaccination is feasible, safe, and immunogenic and shows clinical activity in patients with advanced solid tumors.
  37. [37]
    Effective Migration of Antigen-pulsed Dendritic Cells to Lymph ...
    Injection of DCs directly into a lymph node resulted in a large variation in the migratory capacity within the immature as well as the mature DC population.Missing: challenges | Show results with:challenges
  38. [38]
    Dendritic Cell-Based Immunotherapy: The Importance of ... - NIH
    Apr 8, 2024 · This paper reviews the importance of DC migration and current research progress in the context of DC-based immunotherapy.
  39. [39]
    FDA grants accelerated approval to lifileucel for unresectable or ...
    Feb 16, 2024 · On February 16, 2024, the Food and Drug Administration granted accelerated approval to lifileucel (Amtagvi, Iovance Biotherapeutics, Inc.), ...
  40. [40]
    FDA Approves First Cellular Therapy to Treat Patients with ...
    Feb 16, 2024 · The FDA approved Amtagvi, the first cellular therapy for the treatment of adults with unresectable or metastatic melanoma previously treated ...
  41. [41]
    FDA approves first tumour-infiltrating lymphocyte (TIL) therapy ...
    Feb 19, 2024 · The US FDA has granted an accelerated approval to Iovance's lifileucel (Amtagvi) for patients with unresectable or metastatic melanoma.
  42. [42]
    [PDF] Package Insert - AMTAGVI - FDA
    AMTAGVI is a tumor-derived autologous T cell immunotherapy indicated for the treatment of adult patients with unresectable or metastatic melanoma previously ...Missing: infiltrating | Show results with:infiltrating
  43. [43]
    CAR T Cell Therapy: A Versatile Living Drug - PMC - PubMed Central
    CAR T cells are engineered from a cancer patient's own lymphocytes to better target and kill their cancer cells.
  44. [44]
    [PDF] August 30, 2017 Summary Basis for Regulatory Action - KYMRIAH
    Aug 30, 2017 · KYMRIAH is composed of autologous T cells that are genetically modified with a lentiviral vector encoding a chimeric antigen receptor (CAR). The ...Missing: Yescarta seminal paper
  45. [45]
    FDA Approves Second CAR T-Cell Therapy - National Cancer Institute
    Oct 25, 2017 · FDA has approved the CAR T-cell therapy axicabtagene ciloleucel (Yescarta™) for patients with advanced non-Hodgkin lymphoma, as this Cancer ...Missing: design seminal paper
  46. [46]
    Advancements and challenges in CAR-T cell therapy for solid tumors
    Aug 23, 2025 · In 2022, first-in-human phase I clinical trial involving GD2-CAR-T cells for the treatment of H3K27M-mutated diffuse intrinsic pontine ...
  47. [47]
    Research progress on HER2-specific chimeric antigen receptor T ...
    May 20, 2025 · The above clinical trial results indicate that HER2 targeted specific CAR-T cell therapy has a broad application prospect in solid tumors, and ...Introduction · Difficulties and optimization... · HER2-CAR-T cell in human...
  48. [48]
    CAR-T cells in solid tumors: Challenges and breakthroughs
    Sep 12, 2025 · A phase 1 clinical study of disialoganglioside (GD2)-CAR-T cells reported clinical improvements and tumor volume reductions in 9/11 patients ...
  49. [49]
    TCR-engineered T cell therapy in solid tumors: State of the art ... - NIH
    Feb 15, 2023 · TCR-T cells targeting these public neoantigens are now being tested in clinical trials. In a recent study, a screening was performed to identify ...
  50. [50]
    Neoantigen identification and TCR-T therapy development for solid ...
    Aug 5, 2025 · Recently, T cells expressing engineered T cell receptor (TCR-T cells) have become recognized as a promising tumor cell therapy for solid tumors ...3. Neoantigens... · 4.1. Tcr Sequencing · 7.1. Neoantigen Vaccines
  51. [51]
    TCR engineered T cells for solid tumor immunotherapy - PMC - NIH
    Jun 20, 2022 · Clinical trials of TCR-T cells in the treatment of solid tumors were first performed in patients with melanoma. A variety of melanoma-associated ...
  52. [52]
    Next-generation cell therapies: the emerging role of CAR-NK cells
    Next generation natural killer cells for cancer immunotherapy: the ... cytokine-induced killer cells against nasopharyngeal carcinoma stem cell-like cells.
  53. [53]
    Novel insights in CAR-NK cells beyond CAR-T cell technology
    Natural killer cells (NK) could be transplanted without alloreactivity, making them as an off-the-shelf product. CAR-NK (chimeric antigen receptor NK cell) ...
  54. [54]
    Cytokine-induced killer cells: new insights for therapy of hematologic ...
    Aug 13, 2024 · CIK cells have lower levels of NKp30 than NK cells and do not express NKp44, NKp46, inhibitory killer immunoglobulin-like receptors, NKG2A, and ...
  55. [55]
    [PDF] Rituxan - accessdata.fda.gov
    See full prescribing information for. RITUXAN. RITUXAN® (rituximab) injection, for intravenous use. Initial U.S. Approval: 1997. WARNING: FATAL INFUSION-RELATED ...
  56. [56]
    [PDF] Trastuzumab, Genentech Herceptin approval letter
    Trastuzumab is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more ...Missing: original paper
  57. [57]
    [PDF] 125516Orig1s000 - accessdata.fda.gov
    Feb 12, 2015 · The mechanism of action for dinutuximab is induction of cell lysis of GD2-expressing cells through antibody-dependent cell-mediated cytotoxicity ...
  58. [58]
    Gilead's Magrolimab, an Investigational Anti-CD47 Monoclonal ...
    The FDA granted Breakthrough Therapy designation for magrolimab based on positive results of an ongoing Phase 1b study, which evaluated magrolimab in ...
  59. [59]
    Development of therapeutic antibodies for the treatment of diseases
    Jan 2, 2020 · Based on the success of humanized mAbs in the clinic, a key discovery technology to obtain fully human mAbs (Fig. 2d) was developed in 1990 by ...Humanization Of Mabs · Immunogenicity Of... · Single B Cell Antibody...
  60. [60]
    Bispecific Antibodies in Cancer Immunotherapy: A Novel Response ...
    Jun 11, 2022 · A Review of Bispecific Antibodies and Antibody Constructs in Oncology and Clinical Challenges. Pharmacol. Ther. 2019;201:103–119. doi ...Missing: seminal papers
  61. [61]
    FDA grants regular approval to blinatumomab and expands ...
    Jul 12, 2017 · Blinatumomab received accelerated approval in December 2014 for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell ...
  62. [62]
    FDA grants accelerated approval to elranatamab-bcmm for multiple
    Aug 14, 2023 · On August 14, 2023, the Food and Drug Administration granted accelerated approval to elranatamab-bcmm (Elrexfio, Pfizer, Inc.), a bispecific B-cell maturation ...
  63. [63]
    Bispecific antibodies in the treatment of multiple myeloma - Nature
    Sep 12, 2024 · Bispecific antibodies are dual antigen targeting constructs that engage the T cells to plasma cells through various target antigens.G Protein Coupled Receptor... · Efficacy In Relapsed And... · Safety Profile And Side...
  64. [64]
    FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or ...
    Dec 20, 2019 · On December 20, 2019, the Food and Drug Administration granted accelerated approval to fam-trastuzumab deruxtecan-nxki (ENHERTU®, Daiichi ...
  65. [65]
    FDA grants accelerated approval to sacituzumab govitecan-hziy for ...
    Apr 22, 2020 · FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. On April 22, 2020, the Food and ...
  66. [66]
    Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer
    Apr 21, 2021 · FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. April 22, 2020 (https://www.fda ...
  67. [67]
    Accelerated Approval of Sacituzumab Govitecan-hziy for Third-line ...
    Apr 1, 2021 · FDA Approval Summary: Accelerated Approval of Sacituzumab Govitecan-hziy for Third-line Treatment of Metastatic Triple-negative Breast Cancer.
  68. [68]
    Bispecific Immunomodulatory Antibodies for Cancer Immunotherapy
    In this review, we focus on emerging and novel mechanisms of action of bispecific antibodies interacting with immune cells with at least one of their arms.
  69. [69]
    'Knobs-into-holes' engineering of antibody CH3 domains for heavy ...
    'Knobs-into-holes' is demonstrated here as a novel and effective design strategy for engineering antibody heavy chain homodimers for heterodimerization.
  70. [70]
    Bispecific Antibodies in Hematologic and Solid Tumors
    Apr 8, 2025 · The efficacy of bsAbs in clinical trials has led to their approval for both hematologic and solid malignancies, with numerous agents in ...
  71. [71]
    Bispecific antibodies: unleashing a new era in oncology treatment
    Aug 4, 2025 · This review offers an in-depth analysis of research advancements in BsAbs with anti-tumor potential up to May 2025, covering the mechanisms of ...
  72. [72]
    Ipilimumab and Cancer Immunotherapy: A New Hope for Advanced ...
    March 25, 2011, FDA approves ipilimumab for treatment of malignant melanoma ; June 5, 2011, Phase III data officially published in NEJM supporting improved ...
  73. [73]
    Ipilimumab: An Anti-CTLA-4 Antibody for Metastatic Melanoma - PMC
    Here, we review the mechanism of action, preclinical data, and multiple clinical trials that led to FDA approval of ipilimumab for metastatic melanoma.
  74. [74]
    Development of PD-1 and PD-L1 inhibitors as a form of cancer ... - NIH
    Jan 23, 2018 · On December 22, 2014, nivolumab was first approved as second-line treatment of unresectable or metastatic melanoma based on the CheckMate 037 ...
  75. [75]
    Nivolumab - StatPearls - NCBI Bookshelf
    Mechanism of Action​​ [10][11] By inhibiting PD-1 function, nivolumab releases immune cells from pathological immune suppression, allowing them to recognize and ...
  76. [76]
    Product review on the Anti-PD-L1 antibody atezolizumab - PMC
    Atezolizumab is a monoclonal antibody that targets PD-L1, the first PD-L1 inhibitor to receive FDA approval and one whose use is rapidly expanding. While ...
  77. [77]
    The evolving landscape of biomarkers for checkpoint inhibitor ...
    The humanized anti-cytotoxic T lymphocyte antigen 4 (CTLA4) antibody ipilimumab has doubled 10-year survival for metastatic melanoma compared with historical ...Tumour Genomes And Response · Tumour Antigens And Mutation... · Neoantigen-Based Prediction...
  78. [78]
    A Comprehensive Review of US FDA-Approved Immune Checkpoint ...
    Atezolizumab is a human IgG1k antibody against the PD-L1 checkpoint. The US FDA-accelerated approval was obtained by the results of the IMvigor-210 study, a ...
  79. [79]
    Combination of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment ...
    Oct 13, 2025 · To date, thirteen FDA-approved agents targeting PD-1, PD-L1 or CTLA-4 are used in the treatment of multiple cancer types, including melanoma, ...
  80. [80]
    Biomarkers of immune checkpoint inhibitor efficacy in cancer - PMC
    The two main classes of immune checkpoint inhibitors currently in widespread clinical use specifically target the immune checkpoints ctla-4 and PD-1 or PD-L1.
  81. [81]
    The Predictive Value of Tumor Mutation Burden on Clinical Efficacy ...
    Results: Patients with high TMB showed significantly improved OS (HR = 0.49, 95% CI: 0.33, 0.73; p = 0.001) and PFS (HR = 0.47, 95% CI: 0.33, 0.68; p < 0.001) ...
  82. [82]
    Addressing resistance to PD-1/PD-(L)1 pathway inhibition
    May 3, 2023 · Generally, tumors with low tumor mutational burden or low immune cell infiltration in the TME (cold tumors) respond poorly to immunotherapies.
  83. [83]
    Advancing Cancer Treatment: A Review of Immune Checkpoint ...
    Re-expression of alternative immune checkpoints, such as LAG-3, TIM-3, and TIGIT, contributes to tumor immune escape and resistance to PD-1/PD-L1 blockade.
  84. [84]
    Immune checkpoint inhibitors: breakthroughs in cancer treatment
    Jun 15, 2024 · This review focuses on progress in immune checkpoints in cancer treatment, as well as clinical trials of immune checkpoint combination therapies.
  85. [85]
    Relatlimab: a novel drug targeting immune checkpoint LAG-3 ... - NIH
    On 18 March 2022, the U.S. FDA approved the fixed-dose combination of relatlimab and nivolumab for the treatment of unresectable or metastatic melanoma in adult ...
  86. [86]
    FDA approves Opdualag for unresectable or metastatic melanoma
    Mar 21, 2022 · Opdualag is a fixed-dose combination of the LAG-3-blocking antibody relatlimab and the programmed death receptor-1 blocking antibody nivolumab.
  87. [87]
    Opdualag Approved to Treat Advanced Melanoma - NCI
    Apr 6, 2022 · Relatlimab is the first FDA-approved drug to block the activity of LAG-3. Unlike other FDA-approved combinations of immune checkpoint ...
  88. [88]
    Relatlimab and Nivolumab versus Nivolumab in Untreated ...
    Jan 5, 2022 · RELATIVITY-047 is a phase 3 trial that evaluated the dual inhibition of LAG-3 and PD-1 using a new combination of relatlimab, a human IgG4 LAG-3 ...
  89. [89]
    Opdualag Misses Primary Endpoint in Phase III RELATIVITY-098 ...
    Feb 28, 2025 · The FDA approved Opdualag in March 2022 to treat patients aged 12 years and older with unresectable or metastatic melanoma. 4. Trial Design. The ...
  90. [90]
    Tiragolumab and TIGIT: pioneering the next era of cancer ... - NIH
    Jun 11, 2025 · Phase II and III trials, including the CITYSCAPE trial for non-small cell lung cancer (NSCLC), have shown improved objective response rates (37% ...
  91. [91]
    Phase 3 SKYSCRAPER-01 Study: Final PFS, OS Analyses ...
    Apr 29, 2025 · The phase 3 trial is evaluating the efficacy and safety of first-line tiragolumab, an anti-TIGIT monoclonal antibody, plus atezolizumab in patients with ...
  92. [92]
    Tiragolumab Plus Atezolizumab Fails to Meet Survival End Points in ...
    Apr 28, 2025 · First-line tiragolumab plus atezolizumab did not improve PFS and OS vs atezolizumab alone in PD-L1–high, unresectable or metastatic NSCLC.
  93. [93]
    SKYSCRAPER-02: Tiragolumab in Combination With Atezolizumab ...
    Nov 17, 2023 · Tiragolumab did not provide additional benefit over atezolizumab and CE in untreated ES-SCLC. The combination was well tolerated with no new safety signals.
  94. [94]
    TIM-3 teams up with PD-1 in cancer immunotherapy - NIH
    May 7, 2025 · TIM-3 inhibits T and natural killer (NK) cell responses by interacting with its ligands, thereby facilitating tumor cells' evasion of immune ...
  95. [95]
    First-in-human phase I open-label study of the anti–TIM-3 ...
    Jul 9, 2025 · This phase 1 study evaluated INCAGN02390, a novel, fully human Fc-engineered antibody against TIM-3.
  96. [96]
    Identification of anti-TIM-3 based checkpoint inhibitor combinations ...
    Aug 18, 2025 · The TIM-3-based triplet decreased exhausted CD8+T cells and regulatory T cells, increased numbers of gp-100 reactive CD8+T cells and increased ...
  97. [97]
    the randomized phase 1b/2 Morpheus-Melanoma trial - Nature
    Sep 24, 2025 · In the phase 2 SWOG-1801 study, event-free survival (EFS) at 2 years was 72% in patients who received neoadjuvant–adjuvant pembrolizumab versus ...
  98. [98]
    Promising new combo therapy found for drug-resistant melanoma
    Aug 18, 2025 · In this study, researchers tested combinations of drugs that block immune checkpoints, molecules like PD-1, LAG-3 and TIM-3 that regulate immune ...
  99. [99]
    VISTA-mediated immune evasion in cancer - Nature
    Nov 1, 2024 · The role of VISTA in cancer immune evasion has been determined, but its mechanisms in the tumor microenvironment remain to be further elucidated.
  100. [100]
    A New VISTA in Intracellular Checkpoint Signaling in Triple ...
    Sep 15, 2025 · Immune checkpoint inhibitors have transformed treatment paradigms in multiple tumor types including triple-negative breast cancer.
  101. [101]
    VISTA immune checkpoint blunts radiotherapy-induced antitumor ...
    Jun 27, 2025 · In this study, we examine the role of V-domain immunoglobulin suppressor of T cell activation (VISTA) on myeloid cells during RT. We discovered ...
  102. [102]
    The bispecific antibody targeting VISTA and PD-L1 shows enhanced ...
    The bispecific antibody targeting VISTA and PD-L1 shows enhanced tumor inhibitory activity in pancreatic, endometrial and breast cancersAbstract · Introduction · Materials and methods · Results
  103. [103]
    Viewing the immune checkpoint VISTA: landscape and outcomes ...
    Mar 18, 2024 · To date, several in vivo studies have shown the effectiveness of VISTA-targeted drugs in combination with PD-1/PD-L1 or CTLA-4 inhibitors, ...
  104. [104]
    Direct and indirect effects of IFN-α2b in malignancy treatment - NIH
    IFN-α2b can function not only by enhancing the systematic immune response but also by directly killing tumour cells. Different parts of JAK-STAT pathway ...
  105. [105]
    JAK/STAT Cytokine Signaling at the Crossroad of NK Cell ...
    Type I IFN contributes to NK cell homeostasis, activation, and antitumor function. ... T cell activation: a mediator of the transition from innate to ...
  106. [106]
    Roles of IFN-γ in tumor progression and regression: a review
    Sep 29, 2020 · Interferon-γ (IFN-γ) plays a key role in activation of cellular immunity and subsequently, stimulation of antitumor immune-response.
  107. [107]
    The Interactions Between Cancer Stem Cells and the Innate ...
    In addition, sarcoma, melanoma and leukemia tumor cells have been described to secrete IFN-α in response to doxorubicin treatment (166). Moreover, inflammatory ...
  108. [108]
    Mechanism of interferon action in hairy cell leukemia - PubMed
    Mar 1, 1992 · The primary mechanism of action of IFN alpha in HCL involves the induction of hairy cell differentiation towards a stage less responsive to growth factor ...Missing: JAK- STAT approvals melanoma
  109. [109]
    Interferon Alfa-2b Adjuvant Therapy of High-Risk Resected ...
    Jan 17, 2023 · IFN alpha-2b is the first agent to show a significant benefit in relapse-free and overall survival of high-risk melanoma patients in a randomized controlled ...Missing: approval | Show results with:approval
  110. [110]
    Update on PEG-Interferon α-2b as Adjuvant Therapy in Melanoma
    The US Food Drug Administration (US FDA) has approved interferon α for adjuvant treatment of melanoma and recently also PEG-interferon α-2b (PEG-IFN) for ...
  111. [111]
    Combined treatment with pegylated interferon–α‐2a and ...
    Jul 9, 2008 · Dacarbazine (DTIC) and pegylated interferon (IFN)–α-2a have both demonstrated some efficacy as single agents in metastatic melanoma.Missing: sustained release
  112. [112]
    Pegylated IFN-α sensitizes melanoma cells to chemotherapy and ...
    Aug 26, 2010 · The use of pegylated IFN-α2b in monotherapy and in combination with chemotherapy has been evaluated in several different types of cancers.Missing: sustained | Show results with:sustained
  113. [113]
    Interferon-β inhibits glioma angiogenesis through downregulation of ...
    In this study, we investigated the antiangiogenic effect of IFN-β for malignant gliomas in vitro and in vivo, especially about VEGF production, angiogenic ...Missing: MHC | Show results with:MHC
  114. [114]
    Phase II trial of interferon-β for treatment of recurrent glioblastoma ...
    Twelve patients were admitted to a Phase II study on the treatment of recurrent glioblastoma multiforme with interferon-β (IFN-β).
  115. [115]
    Adjuvant Temozolomide Chemotherapy With or Without Interferon ...
    Jan 27, 2023 · Adjuvant temozolomide chemotherapy with or without interferon alfa among patients with newly diagnosed high-grade gliomas: a randomized clinical trial.
  116. [116]
    Interferon Therapy: A Growing Family Feeds New Interest in an ...
    Apr 1, 2013 · IFNα is the only IFN that the FDA has approved for use in cancer patients; specifically, it is indicated for use in patients with hairy cell ...<|control11|><|separator|>
  117. [117]
    Side effects of interferon-alpha therapy - PubMed
    Many side-effects are clearly dose-dependent. Taken together, occurrence of flu-like symptoms, hematological toxicity, elevated transaminases, nausea, fatigue, ...Missing: historical pre- checkpoint inhibitors
  118. [118]
    Cancer Immunotherapy, Part 2: Efficacy, Safety, and Other Clinical ...
    The most common AEs observed with IFN-α treatment are flu-like symptoms, including chills, fever, headache, and myalgias. These effects may be severe and have ...
  119. [119]
    IL-2 based cancer immunotherapies: an evolving paradigm - PMC
    High-dose IL-2 treatment was the first FDA-approved immunotherapy for renal cell carcinoma and melanoma, achieving single agent complete and durable responses, ...
  120. [120]
    Rethinking Oncologic Treatment Strategies with Interleukin-2 - NIH
    May 5, 2023 · High-dose IL-2 therapy was approved by the FDA for the treatment of ... renal cell carcinoma in 1992 and for metastatic melanoma in 1998 [18].
  121. [121]
    IL-2 and Beyond in Cancer Immunotherapy - PMC - PubMed Central
    The Food and Drug Administration (FDA) approved IL-2 for the treatment of renal cell carcinoma in 1992 and metastatic melanoma in 1998 (Rosenberg 2014).
  122. [122]
    IL-2 based cancer immunotherapies: an evolving paradigm - Frontiers
    In this review we discuss the biological characteristics of IL-2 and its receptors, as well as its efficacy and treatment limiting toxicities in cancer ...
  123. [123]
    Reigniting hope in cancer treatment: the promise and pitfalls of IL-2 ...
    Jul 29, 2023 · This review discusses the pivotal roles of IL-2 and IL-2R in tumorigenesis, shedding light on their potential as diagnostic and prognostic markers and their ...
  124. [124]
    Temporal optimization of CD25-biased IL-2 agonists and immune ...
    Aug 11, 2025 · IL-2 plays a key role in promoting the proliferation, survival, and effector functions of T and NK cells. However, IL-2 is also essential for ...
  125. [125]
    https://pmc.ncbi.nlm.nih.gov/articles/PMC5815463/
  126. [126]
    Interleukin 12: still a promising candidate for tumor immunotherapy?
    Rather, IL-12 acts as a major orchestrator of Th1-type immune response against cancer. Another important notion is that IL-12 appears to elicit more potent ...
  127. [127]
    Regulation of Antitumor Immune Responses by the IL-12 Family ...
    IL-12 induces IFN-γ production by NK and T cells and differentiation to Th1 cells. IL-23 induces IL-17 production by memory T cells and expands and maintains ...
  128. [128]
    Novel engineered IL-2 Nemvaleukin alfa combined with PD1 ...
    Sep 2, 2024 · Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity. J Clin Invest 132 (2022). Sun ...<|control11|><|separator|>
  129. [129]
    Combinatorial treatment with upadacitinib abrogates systemic ...
    May 11, 2025 · Combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor-targeted IL-2 fusion protein ... Prolonged signaling inhibition ...
  130. [130]
    Oncolytic virotherapy: basic principles, recent advances and future ...
    Apr 11, 2023 · In this review, we summarized the basic principles of OVs in terms of their classifications, as well as the recent advances in OV-modification strategies.
  131. [131]
    Mechanism of Action for Talimogene Laherparepvec, a New ...
    In T-VEC, both copies of the ICP34.5 gene have been deleted (18). This deletion has implications for eliminating the pathogenesis of HSV-1 and also enhances ...Abstract · Background · Clinical–Translational Advances
  132. [132]
    The End of the Beginning: OncolyticVirotherapy Achieves Clinical ...
    Feb 1, 2006 · H101 is an oncolytic adenovirus with an E1B-55kD gene deletion, similar to that present in the Onyx-015 (dl1520) oncolytic adenovirus. The E1B- ...
  133. [133]
    Reovirus: A Targeted Therapeutic—Progress And Potential
    Incidentally, reovirus is intrinsically oncolytic without need for any genetic manipulation. It is a naturally occurring virus that possesses the right level ...
  134. [134]
    Immunogenic cell death: The cornerstone of oncolytic viro ... - Frontiers
    Jan 22, 2023 · Specifically, oncolytic viruses (OVs) can infect and destroy targeted cancer cells and stimulate the immune system by exposing pathogen- ...
  135. [135]
    Dendritic Cells in Oncolytic Virus-Based Anti-Cancer Therapy - PMC
    Dec 9, 2015 · Appropriately activated DCs can induce anti-tumor immunity by activating innate immune cells and tumor-specific lymphocytes that target cancer cells.
  136. [136]
    Oncolytic viruses for cancer immunotherapy
    Jun 29, 2020 · In this review, we discuss the use of oncolytic viruses in cancer immunotherapy treatments in general, with a particular focus on adenoviruses.
  137. [137]
    Talimogene Laherparepvec and Beyond - PMC - PubMed Central
    Oct 17, 2025 · Based on these data, T-VEC was approved by the Food and Drug Administration (FDA) for the treatment of unresectable melanoma with cutaneous, ...
  138. [138]
    Efficacy and safety of talimogene laherparepvec versus granulocyte ...
    Nov 16, 2016 · In the randomized, open-label Phase III OPTiM trial (NCT00769704), talimogene laherparepvec significantly improved durable response rate (DRR) ...
  139. [139]
    Talimogene laherparepvec: overview, combination therapy ... - NIH
    Following results of a Phase III trial demonstrating a significantly higher DRR of 16.3% in patients treated with T-VEC versus 2.1% in those treated with GM-CSF ...
  140. [140]
    Fighting Cancer with Viruses: Oncolytic Virus Therapy in China
    In 2005, the China Food and Drug Administration approved its first OV drug, Oncorine (H101), for treatment of advanced head and neck cancer. To explore new ...
  141. [141]
    Oncolytic viruses in head and neck cancers - Frontiers
    Aug 12, 2025 · In 2005, China approved Ad-H101, an oncolytic adenovirus for head and neck cancer after phase III studies showed a higher response rate for Ad- ...
  142. [142]
    The combination treatment of oncolytic adenovirus H101 with ...
    Feb 7, 2024 · Approved in China for advanced nasopharyngeal carcinoma since 2005, H101 represents the first OV to gain regulatory approval. Currently, over 30 ...
  143. [143]
    PHOCUS: A Phase 3, Randomized, Open-Label Study of Sequential ...
    Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The ...
  144. [144]
    Phase I/II study of PexaVec in combination with immune checkpoint ...
    Feb 8, 2023 · Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities ...Missing: failures | Show results with:failures
  145. [145]
    Advances in cancer immunotherapy: historical perspectives, current ...
    May 7, 2025 · No dose-limiting toxicities were observed, and the most common adverse events were flu-like symptoms. Further studies are necessary to ...
  146. [146]
    Oncolytic Virotherapy in Solid Tumors: A Current Review - PMC
    Sep 24, 2025 · New evidence suggests that in addition to direct antitumoral efficacy, OVs can serve as adjunct perioperative therapies that counteract surgery- ...
  147. [147]
    Oncolytic viruses as anticancer agents: clinical progress and ...
    Sep 20, 2025 · Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial.
  148. [148]
    Oncolytic virus and CAR-T cell therapy in solid tumors - Frontiers
    Recent research has found that combining oncolytic viruses with CAR-T cells enhances anti-tumor effects. However, delivering treatment to distant or metastatic ...
  149. [149]
    A Review of CAR-T Combination Therapies for Treatment of ... - NIH
    Jun 15, 2024 · One innovative approach to enhance the efficacy of CAR-T therapy in solid tumors is the combination with oncolytic viruses [9]. Oncolytic ...
  150. [150]
    Advances in the development of personalized neoantigen-based ...
    Jan 20, 2021 · For example, the identification of targetable neoantigens could be improved through development of better prediction algorithms. Various vaccine ...
  151. [151]
    A comprehensive proteogenomic pipeline for neoantigen discovery ...
    Oct 11, 2024 · An ML algorithm, specifically trained on a complex matrix of tens of features, prioritizes likely immunogenic HLA-I neoantigens (minimal ...
  152. [152]
    NCT04526899 | A Study to Investigate the Novel Agent BNT111 and ...
    This is an open-label, randomized, multi-site, Phase II, interventional trial designed to evaluate the efficacy, tolerability, and safety of BNT111 + cemiplimab
  153. [153]
    Merck and Moderna Initiate Phase 3 Trial Evaluating Adjuvant V940 ...
    Oct 28, 2024 · Merck and Moderna have initiated Phase 3 randomized clinical trials evaluating mRNA-4157 (V940) in combination with KEYTRUDA as an adjuvant ...
  154. [154]
    NeoVax Cancer Vaccine - Dana-Farber Cancer Institute
    This vaccine is administered to the corresponding patient with the goal of stimulating the immune system to specifically attack their cancer.Missing: DNA | Show results with:DNA
  155. [155]
    Phase 2 BNT111/Cemiplimab Data Prove Positive in PD-(L)1 ...
    Oct 18, 2025 · BNT111 plus cemiplimab achieved an 18.1% ORR in PD-(L)1–refractory melanoma, meeting its primary end point in the phase 2 BNT111-01 trial.
  156. [156]
    Individualised neoantigen therapy mRNA-4157 (V940 ... - The Lancet
    Jan 18, 2024 · Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, ...<|separator|>
  157. [157]
    Cancer vaccines: current status and future directions
    Feb 17, 2025 · For example, Neovax, a long-peptide vaccine targeting up to 20 neoantigens per melanoma patient, achieved a median PFS of 25 months in six ...<|separator|>
  158. [158]
    Targeting the tumor mutanome for personalized vaccination in a ...
    Mar 31, 2022 · 11 12 However, neoantigens can also be potentially identified in low TMB cancers, where mutational frameshifts, splice variants or gene fusions ...Genomic Evaluation And Tumor... · Assessment Of Tcr Repertoire · In Silico Neoepitope...<|separator|>
  159. [159]
    AI-driven epitope prediction: a systematic review, comparative ...
    Aug 30, 2025 · Integrating AI into epitope prediction is transforming vaccine design by delivering unprecedented accuracy, speed, and efficiency.
  160. [160]
    Sliding-attention transformer neural architecture for predicting T cell ...
    Sep 27, 2024 · Neoantigens are promising targets for immunotherapy by eliciting immune response and removing cancer cells with high specificity, ...
  161. [161]
    Significance and implications of FDA approval of pembrolizumab for ...
    May 14, 2018 · To date, no formal MSI-H/dMMR companion diagnostic accompanies approval of pembrolizumab for biomarker-based disease. Additionally, MSI-H/dMMR ...Msi-H/dmmr As A Biomarker... · Drug Development For... · Abbreviations<|separator|>
  162. [162]
    [PDF] CENTER FOR DRUG EVALUATION AND RESEARCH
    May 23, 2017 · the treatment of patients with microsatellite instability high (MSI-H) metastatic colorectal ... appear to be the result of a higher PD-L1 tumor ...
  163. [163]
    Tumor Mutational Burden (TMB) as a Predictive Biomarker in Solid ...
    3A–D, a cutoff of 10 mut/Mb corresponded to a sensitivity of approximately 75% for melanoma, lung and bladder cancers although specificity varied widely and was ...
  164. [164]
    Tumor Mutational Burden Predicting the Efficacy of Immune ...
    Although studies have confirmed that patients with TMB ≥ 10 mut/Mb have generally higher response rates to ICI treatment in many tumors (34), the predictive ...
  165. [165]
    Mutations Associated with Acquired Resistance to PD-1 Blockade in ...
    Jul 13, 2016 · JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative ...
  166. [166]
    Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations
    Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be ...
  167. [167]
    Effects of BRAF mutations and BRAF inhibition on immune ... - NIH
    Almost 50% of melanomas harbor targetable activating mutations of BRAF which promote RAS-RAF-MEK-ERK pathway activation and melanoma proliferation. Recent ...
  168. [168]
    Immunotherapy Combination for BRAF+ Melanoma - NCI
    Dec 17, 2021 · The results from the trial show that, in general, initial immunotherapy results in better overall survival for people with advanced BRAF+ melanoma.
  169. [169]
    MSK-IMPACT: A Comprehensive Tumor Sequencing Test to Detect ...
    MSK-IMPACT uses hybridization capture and next-generation sequencing to identify tumor-specific genomic alterations in all exons of all targeted genes. The ...
  170. [170]
    DNA-protein biomarkers for immunotherapy in the era of precision ...
    The most widely used panels are the MSK-IMPACT panel, which in its latest version targets 468 genes (1.22 Mb of the genome), and the Foundation Medicine Panel, ...
  171. [171]
    Circulating tumor DNA concentrations and blood tumor mutation ...
    May 28, 2025 · Circulating tumor DNA (ctDNA) and tumor mutation burden (TMB) have demonstrated value as biomarkers of response in oncology clinical trials.
  172. [172]
    Blood-based tumor mutational burden impacts clinical outcomes of ...
    Dec 2, 2024 · New technologies for evaluating TMB have emerged and continue to evolve, including liquid biopsy. Circulating tumor DNA (ctDNA) present in ...
  173. [173]
    Quantifying and interpreting biologically meaningful spatial ... - Nature
    Mar 11, 2025 · The tumor microenvironment (TME) plays a crucial role in orchestrating tumor cell behavior and cancer progression.
  174. [174]
    Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell ...
    Apr 16, 2018 · Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic ...
  175. [175]
    Automated tumor proportion score analysis for PD-L1 (22C3 ...
    Aug 5, 2021 · The Dako PD-L1 IHC 22C3 and 28-8 pharmaDx assays employ tumor proportion score (TPS) to measure PD-L1 expression.
  176. [176]
    Analysis of Immune Checkpoint Drug Targets and Tumor ... - Nature
    Jun 17, 2020 · The most widely used immune checkpoint measurement is IHC analysis of PD-L1. We used the FDA-approved PD-L1 IHC 22C3 pharmDx assay to perform PD ...
  177. [177]
    Whole-body CD8 + T cell visualization before and during cancer ...
    Dec 5, 2022 · We demonstrated that CD8+ T cell presence in tumor lesions imaged before ICI could be predictive for OS, highlighting the potential of CD8 ...
  178. [178]
    A Composite Decision Rule of CD8 + T-cell Density in Tumor ...
    We propose that a composite score of CD8+ T-cell density in paired biopsies taken before and on-treatment may be a new biomarker to inform on clinical outcomes ...
  179. [179]
    Tertiary lymphoid structures in cancer - Science
    Jan 7, 2022 · With few exceptions, the presence of TLSs in tumors correlates with better prognosis and clinical outcome upon immunotherapy, but, in spite of ...<|separator|>
  180. [180]
    Regulatory (FoxP3+) T cells and TGF-β predict the response to anti ...
    Nov 4, 2020 · Our results suggest that higher levels of FoxP3 + Treg cells and TGF-β can predict a favorable response to anti-PD-1 immunotherapy in patients with advanced ...
  181. [181]
    biomarker analysis from the phase 3 CONTINUUM and DIPPER trials
    Oct 23, 2024 · Ki67 + Tregs in tumors could predict immunotherapy benefit, with aPD1 improving EFS only in patients with low baseline levels of Ki67 + Tregs.
  182. [182]
    Landscape of Myeloid-derived Suppressor Cell in Tumor ...
    Oct 24, 2021 · In this review, we highlight the clinical value of MDSC in predicting prognosis of cancer patients and the responses of immunotherapies.
  183. [183]
    Gut microbiota shapes cancer immunotherapy responses - Nature
    Jul 25, 2025 · A clinical trial in CRC patients found that supplementation with Bifidobacterium lactis and Lactobacillus increased butyrate-producing bacteria ...
  184. [184]
    Gut Bacteria Affect Immunotherapy Response - NCI
    Feb 5, 2018 · The team hopes to start a clinical trial this year giving patients oral doses of the most prevalent species of “good” bacteria identified in ...
  185. [185]
    The tumor immune microenvironment: implications for cancer ...
    Multiplex immunohistochemistry (IHC) and imaging mass cytometry provide high-resolution spatial mapping of protein expression, allowing for precise ...
  186. [186]
    Turning cold tumors into hot tumors to ignite immunotherapy
    Oct 14, 2025 · Immunologically “cold” tumors are inherently resistant to immunotherapy, a phenomenon that is systematically classified by the immunoscore ...
  187. [187]
    Oncology (Cancer)/Hematologic Malignancies Approval Notifications
    On September 19, 2025, the Food and Drug Administration approved pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex, Merck) for subcutaneous injection ...FDA approves darolutamide... · FDA grants accelerated... · FDA approves belzutifan
  188. [188]
    FDA approves datopotamab deruxtecan-dlnk for unresectable or ...
    Jan 17, 2025 · On January 17, 2025, the Food and Drug Administration approved datopotamab deruxtecan-dlnk (Datroway, Daiichi Sankyo, Inc.), a Trop-2-directed ...
  189. [189]
    FDA grants accelerated approval to datopotamab deruxtecan-dlnk
    Jun 23, 2025 · On June 23, 2025, the Food and Drug Administration granted accelerated approval to datopotamab deruxtecan-dlnk (Datroway, Daiichi Sankyo, Inc.) for adults.
  190. [190]
    Development of Immunotherapy Combination Strategies in Cancer
    We review the current approved immunotherapy combinations, before discussing promising combinatorial approaches in clinical trials.Missing: 2024 2025 ADCs
  191. [191]
    Overall Survival with Combined Nivolumab and Ipilimumab in ...
    Sep 11, 2017 · Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial.
  192. [192]
    Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ...
    Sep 15, 2024 · Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97 ...
  193. [193]
    Pancreatic cancer therapy with combined mesothelin ... - JCI Insight
    Apr 5, 2018 · Combining cytokine-armed oncolytic adenovirus to enhance the efficacy of CAR T cell therapy is a promising approach to overcome the immunosuppressive TME for ...<|separator|>
  194. [194]
    CAR-T cell combination therapy: the next revolution in cancer ...
    Nov 24, 2022 · This study aimed to comprehensively discuss different cancer treatment methods in combination with CAR-T cell therapy and their therapeutic outcomes.
  195. [195]
    https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancerhematologic-malignancies-approval-notifications
  196. [196]
    Antibody–Drug Conjugates (ADCs): current and future ...
    Apr 30, 2025 · These features position bispecific ADCs as a promising advancement in cancer therapy, offering potential solutions to challenges faced by ...
  197. [197]
    Current Advances and Future Directions for Sensitizing Gastric ...
    Jul 21, 2025 · Immunotherapy combined with chemotherapy has become the standard treatment for HER2-negative gastric cancer ... (ADCs) combined with immunotherapy ...<|control11|><|separator|>
  198. [198]
    Microbiome meets immunotherapy: unlocking the hidden predictors ...
    Sep 2, 2025 · This meta-analysis highlights that multi-microbiome combinations exhibit stronger predictive value for ICI efficacy compared to single microbial ...Missing: triple ADCs
  199. [199]
    Combination strategies of gut microbiota in cancer therapy through ...
    Jun 5, 2025 · Gut microbiota enhances the efficacy of cancer therapies by activating the immune system and facilitating the biotransformation of drugs.Missing: ADCs | Show results with:ADCs
  200. [200]
    Adverse drug events of immune checkpoint inhibitors
    Aug 11, 2025 · In this study, we analyzed retrospectively documented irAEs associated with CTLA-4 inhibitors, PD-1 and PD-L1 inhibitors in a real-world sample.
  201. [201]
    Management of Immune-Related Adverse Events in Patients ...
    Severe cutaneous toxicities of grade 3 or higher, per CTCAE criteria, are observed in 3% or fewer individuals receiving monotherapy. Despite the potential for ...
  202. [202]
    Advances in the mechanisms and management of CAR T-cell toxicities
    Jan 1, 2025 · Neurologic toxicities. 1. ICANS. Neurologic toxicity remains a major concern and barrier to use of CAR T-cell therapy. The diverse constellation ...
  203. [203]
    Gut microbiome and immune checkpoint inhibitor toxicity
    Feb 5, 2025 · The gut microbiome has been associated with immune checkpoint inhibitor (ICI) efficacy. •. Studies on immune-related adverse events (irAEs) are ...
  204. [204]
    Resistance mechanisms to immune checkpoint inhibitors
    Jan 15, 2025 · In the current review, we summarize what is known so far about the mechanisms of resistance in terms of being tumor-intrinsic or tumor-extrinsic.Missing: NGS | Show results with:NGS
  205. [205]
    The role of B2M in cancer immunotherapy resistance - Frontiers
    Mar 20, 2025 · Accumulating evidence indicates that B2M mutation/defect is one of the key mechanisms underlying tumor immunotherapy resistance.
  206. [206]
    In vivo gene editing of T-cells in lymph nodes for enhanced cancer ...
    Nov 25, 2024 · Carl et al. reported a human phase 1 clinical trial to manufacture CRISPR-Cas9 edited T-cells for refractory cancer, which also showed ...
  207. [207]
    CRISPR/Cas9‐edited tumor‐associated immune cells in cancer ...
    Apr 28, 2025 · Based on this first human clinical trial, CRISPR-engineered T cells may prove to be safe and feasible for cancer therapy. However, most of the ...
  208. [208]
    https://insight.jci.org/articles/view/99573
  209. [209]
    https://pmc.ncbi.nlm.nih.gov/articles/PMC9685957/
  210. [210]
    Lipid nanoparticles for mRNA delivery | Nature Reviews Materials
    Aug 10, 2021 · Various cancer vaccines based on lipid nanoparticle–mRNA formulations are currently in clinical trials (Table 1).
  211. [211]
    Lipid nanoparticle-assisted mRNA therapy for cancer treatment
    Sep 8, 2025 · Among these, LNPs have become the most effective delivery platform in clinical settings, seen in the success of COVID-19 mRNA vaccines. LNPs are ...
  212. [212]
    Harnessing an integrated glyco-nanovaccine technology for ... - Nature
    Aug 29, 2025 · Enhancing breast Cancer immunotherapy using gold nanoparticles carrying tumor antigens. Article Open access 14 May 2025. A nanovaccine for ...
  213. [213]
    The Application of and Strategy for Gold Nanoparticles in Cancer ...
    Jun 7, 2021 · AuNPs can not only act as immune regulators but also deliver immune drugs for cancer. Therefore, AuNPs are candidates for enhancing the ...
  214. [214]
    Microbiota boost immunotherapy? A meta-analysis dives into fecal ...
    Jun 9, 2025 · This meta-analysis provides preliminary evidence supporting the use of FMT as a strategy to enhance the efficacy of ICIs in patients with advanced or ...Missing: probiotics | Show results with:probiotics
  215. [215]
    SITC 2025 Annual Meeting Schedule
    View Full Session Schedule. 1:45 p.m., From FMT to Second Generation Microbiome Interventions to Increase Cancer Immunotherapy Efficacy Bertrand Routy, MD ...Missing: probiotics | Show results with:probiotics
  216. [216]
    Harnessing the Gut Microbiome in Cancer Immunotherapy
    Aug 28, 2025 · For immunotherapy outcomes improvement, immune responses modulation and gut microbiome diversity enhancement show probiotics important promise.
  217. [217]
    Multi-omics and AI-driven immune subtyping to optimize neoantigen ...
    Jun 2, 2025 · This study provides a machine learning- driven framework to identify tumor antigens and immune targets, offering a promising strategy for CRC immunotherapy.
  218. [218]
    Artificial intelligence and neoantigens: paving the path for precision ...
    The use of AI for neoantigen prediction enhances the accuracy, efficiency, and personalized nature of cancer immunotherapy development by effectively analyzing ...
  219. [219]
    Harnessing multi-omics and machine learning for predicting immune ...
    Aug 31, 2025 · We aim to offer comprehensive insights into how artificial intelligence can optimize patient stratification for ICB therapy. Keywords. Immune ...