SEARCH · PubMed Health

Results for “Immune checkpoint blockade”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

70 records · Page 4Linked to original sources

PubMed2006

Checkpoint blockade in cancer immunotherapy.

The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such immunological molecular adjuvants are showing promise in early clinical trials. This review focuses on the results of the archetypal example of checkpoint blockade, anti-CTLA-4, in preclinical tumor models and clinical trials, while also highlighting other possible targets for immunological checkpoint blockade.

Animals↗

PubMed2006

Effective cancer therapy through immunomodulation.

MAbs directed toward tumor cells, tumor neovasculature, and host negative immunoregulatory elements (checkpoints) have emerged as useful immunotherapeutic agents against cancer. However, effective active modulation of the immune response with anticancer vaccines will require identifying appropriate tumor-rejection antigens; optimizing the interactions of peptides, antigen-presenting cells, and T cells; and blockading negative immunological checkpoints that impede an effective immune response. Checkpoints being targeted include CTLA-4 and PD1 that are negative signaling receptors expressed on activated T cells, CD4+CD25+ Foxp3-expressing Tregs (suppressor T cells), IL-2-mediated activation-induced cell death (AICD), and the cytokine TGFbeta.

Antibodies, Monoclonal↗

PubMed2026

Proteomic and Metabolomic Analysis of Immune-Related Adverse Events in Patients Treated with PD-1 Inhibitors.

As a class of immune checkpoint inhibitors (ICIs), programmed cell death protein-1 (PD-1) blockade has demonstrated remarkable efficacy in the treatment of various malignancies. However, their clinical application is constrained by the high incidence of immune-related adverse events (irAEs), which arise from nonspecific immune activation and can affect multiple organ systems, with severe cases posing life-threatening risks. This study integrated high-throughput proteomic and metabolomic analyses to systematically characterize the molecular features associated with irAEs in cancer patients receiving PD-1 inhibitor therapy. The results showed that, following the first treatment, patients who developed irAEs exhibited potential involvement of the NF-κB pathway, along with lower baseline levels of SNRPA and higher expression of CD63. Metabolomic analyses further revealed that the kynurenine/tryptophan ratio was significantly elevated in the irAE group both at baseline and post-treatment compared with patients who did not develop irAEs. In addition, significant differences in the abundance of specific lipids were observed between the two groups prior to the administration of immunotherapy. Our findings provide exploratory insights into immune and metabolic alterations associated with PD-1 blockade treatment and may help generate hypotheses for future studies on early irAE risk assessment in cancer patients undergoing PD-1 blockade therapy.

Humans↗

PubMed2026

Beyond oncogenesis: The emerging role of EZH2 in tumor microenvironment.

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and the catalytic component of Polycomb Repressive Complex 2, facilitates epigenetic modifications via the repressive H3K27me3 mark, consequently modulating the expression of numerous genes implicated in cellular proliferation and survival. Overexpression or dysregulation of EZH2 has been observed extensively across several malignancies, where it plays a major role in shaping the tumor microenvironment, promoting angiogenesis, cytokine secretion, and matrix remodeling. EZH2 mediates immune evasion, particularly in response to immunotherapy and checkpoint blockade. These interactions also position EZH2 as a key mediator of therapy resistance to chemotherapy, immunotherapy, and targeted therapy. Consequently, a comprehensive understanding of EZH2's function and its interactions within the TME and during cancer progression is crucial. This review aims to enhance the current understanding of EZH2 and its roles in the TME, cancer development, and therapeutic responses. This review will discuss the canonical and non-canonical functions of EZH2, summarize its established and evolving roles in cancer and the TME, and highlight its effects on tumor immunity and therapeutic efficacy.

Humans↗

PubMed2025

Comprehensive clinical and genetic characterization of hyperprogressive biliary tract cancer during PD-1 blockade monotherapy: case report and literature review.

BACKGROUND: Some genetically characterized patients show the rapid disease progression during immune checkpoint inhibitors (ICIs) monotherapy, a phenomenon known as hyperprogressive disease (HPD). CASE PRESENTATION: Herein we report a relevant case of biliary tract cancer (BTC) that initially responded to gemcitabine plus oxaliplatin (GEMOX) and PD-1 blockade but subsequently developed HPD in the process of PD-1 blockade maintenance therapy, leading to death within two weeks. Genomic analysis revealed mutations in CDKN2A, PIK3CA, KRAS and EPHA2 in both baseline and hyperprogressive plasma and tumor samples. Notably, higher KRAS mutation abundance was observed in plasma and ascites after disease progression. CONCLUSIONS: These findings suggest a potential association between these negative genes especially KRAS mutation and HPD. Therefore, administration of PD-1 blockade monotherapy in this subgroup of patients harboring KRAS mutation should be performed with caution. Further studies are warranted to confirm these results and explore the correlation between genomic mutations and HPD.

Humans↗

PubMed2023

One-carbon unit supplementation fuels tumor-infiltrating T cells and augments checkpoint blockade.

Nucleotides perform important metabolic functions, carrying energy and feeding nucleic acid synthesis. Here, we use isotope tracing-mass spectrometry to quantitate the contributions to purine nucleotides of salvage versus de novo synthesis. We further explore the impact of augmenting a key precursor for purine synthesis, one-carbon (1C) units. We show that tumors and tumor-infiltrating T cells (relative to splenic T cells) synthesize purines de novo. Purine synthesis requires two 1C units, which come from serine catabolism and circulating formate. Shortage of 1C units is a potential bottleneck for anti-tumor immunity. Elevating circulating formate drives its usage by tumor-infiltrating T cells. Orally administered methanol functions as a formate pro-drug, with deuteration enabling control of formate-production kinetics. In MC38 tumors, safe doses of methanol raise formate levels and augment anti-PD-1 checkpoint blockade, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.

Preprint↗

PubMed2025

HLA-E and NKG2A Mediate Resistance to BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) is the first-line therapy for high-grade non-muscle-invasive bladder cancer (NMIBC), yet many patients experience recurrence due to immune evasion. We identify HLA-E and NKG2A as mediators of adaptive resistance involving chronic activation of NK and T cells in BCG-unresponsive tumors. Prolonged IFN-γ exposure enhances HLA-E and PD-L1 expression on recurrent tumors, accompanied by the accumulation of NKG2A+ NK and CD8 T cells. HLA-Ehigh tumor cells preferentially cluster near CXCL12-rich stromal regions with dense effector cell presence, underscoring a spatially segregated tumor architecture. Although cytotoxic lymphocytes retain effector potential, their activity is restrained by HLA-E/NKG2A and PD-L1/PD-1 pathways located in their immediate neighborhood within the bladder tumor microenvironment. These data reveal a spatially organized immune escape program that limits anti-tumor immunity. Our findings support dually targeting NKG2A and PD-L1 checkpoint blockade as a rational, bladder-sparing strategy for patients with BCG-unresponsive NMIBC.

BCG-unresponsive↗

PubMed2024

One-carbon unit supplementation fuels purine synthesis in tumor-infiltrating T cells and augments checkpoint blockade.

Nucleotides perform important metabolic functions, carrying energy and feeding nucleic acid synthesis. Here, we use isotope tracing-mass spectrometry to quantitate contributions to purine nucleotides from salvage versus de novo synthesis. We further explore the impact of augmenting a key precursor for purine synthesis, one-carbon (1C) units. We show that tumors and tumor-infiltrating T cells (relative to splenic or lymph node T cells) synthesize purines de novo. Shortage of 1C units for T cell purine synthesis is accordingly a potential bottleneck for anti-tumor immunity. Supplementing 1C units by infusing formate drives formate assimilation into purines in tumor-infiltrating T cells. Orally administered methanol functions as a formate pro-drug, with deuteration enabling kinetic control of formate production. Safe doses of methanol raise formate levels and augment anti-PD-1 checkpoint blockade in MC38 tumors, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.

Animals↗

PubMed2026

Programmed cell death-1: from a T-cell immune checkpoint to a regulator of Natural Killer cell biology.

Programmed cell death protein 1 (PD-1, CD279) is a pivotal inhibitory immune checkpoint receptor that plays a central role in maintaining immune homeostasis and peripheral tolerance. Originally characterized as a negative regulator of T-cell activation, PD-1 limits excessive immune responses and prevents autoimmunity, while its sustained expression under conditions of chronic antigen stimulation contributes to T-cell dysfunction and exhaustion. The discovery that blockade of the PD-1 pathway can restore anti-tumor immunity has revolutionized cancer therapy and established immune checkpoint inhibition as a cornerstone of modern oncology. Although PD-1 has traditionally been viewed as a key regulator of adaptive immunity, accumulating evidence indicates that its biological functions extend beyond T cells. In recent years, PD-1 expression has been identified in several innate immune cell populations, particularly Natural Killer (NK) cells, where it has emerged as an important modulator of effector functions, cytokine production, metabolic fitness, and antitumor activity. These findings have challenged the classical view of PD-1 biology and revealed unexpected similarities between NK-cell dysfunction and the exhausted phenotype described in chronically stimulated T cells. In the tumor microenvironment, PD-1 expression on NK cells has been associated with impaired cytotoxicity and reduced immune surveillance, suggesting that NK cells may also represent relevant targets of PD-1-mediated immunosuppression. At the same time, the mechanisms regulating PD-1 expression and signaling in NK cells appear to differ, at least in part, from those operating in T lymphocytes, highlighting the complexity of this pathway across distinct immune cell subsets. In this review, we summarize the current knowledge of PD-1 biology, from its established role in T-cell regulation to its emerging functions in NK cells. We discuss the molecular mechanisms governing PD-1 expression and signaling, its contribution to immune dysfunction in cancer and chronic diseases, and the potential implications of targeting the PD-1 axis to enhance both adaptive and innate antitumor immunity.

Natural Killer (NK) cells↗

PubMed2024

The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial.

Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3-11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment.

Humans↗

PubMed2026

Engineered Bacteriophages in Cancer Immunotherapy: Emerging Concepts and Potential Integration with CAR-T Cell Therapy.

Due to antigen heterogeneity, restricted immune cell trafficking and an immunosuppressive, nutrient-restricted tumour microenvironment, solid tumours remain resistant to modern immunotherapies. Engineered bacteriophages offer a modular framework to overcome these obstacles: programmable virus-like particles with scalable production. Through genome engineering, capsid decoration with mammalian cell-targeting ligands, or hybrid AAV/phage systems, engineered bacteriophages can display tumour-associated antigens, enhance receptor-mediated uptake and deliver therapeutic payloads such as cytokines, chemokines and suicide genes without naturally infecting mammalian cells. These features support their use as vaccine platforms, immunological adjuvants and targeted gene-delivery vehicles. These may enable more precise, tumour-localized therapeutic intervention. Phages can engage innate immune pathways, including TLR9, TLR3/7/8, cGAS-STING and AIM2, promoting dendritic cell maturation and inflammatory mediators that may convert immunologically "cold" tumours into inflamed microenvironments. Their multivalent antigen display enhances B- and T-cell priming, while cDC1-mediated cross-presentation supports cytotoxic CD8+ T-cell responses and immunological memory. In CAR-T therapy, engineered phages may improve tumour homing through chemokine modulation, support persistence through local cytokine delivery, reduce antigen escape by presenting multiple tumour epitopes, and limit T-cell exhaustion through dominant-negative receptor strategies or local checkpoint blockade. This review summarizes engineering approaches, delivery systems, manufacturing, biodistribution, dosing, and safety issues, including immunogenicity, pre-existing anti-phage antibodies and horizontal gene transfer. It also distinguishes therapeutic engineered phage particles from phage display technologies used for molecular discovery. Despite encouraging results integrating modified bacteriophages with CAR-T cell therapy, the evidence remains mostly preclinical, indicating both substantial translational prospects and crucial obstacles for future clinical development.

CAR-T cell therapy↗

PubMed2001

Signal via lymphotoxin-beta R on bone marrow stromal cells is required for an early checkpoint of NK cell development.

NK cells play an important role in the immune system but the cellular and molecular requirements for their early development are poorly understood. Lymphotoxin-alpha (LTalpha)(-/-) and LTbetaR(-/-) mice show a severe systemic reduction of NK cells, which provides an excellent model to study NK cell development. In this study, we show that the bone marrow (BM) or fetal liver cells from LTalpha(-/-) or LTbetaR(-/-) mice efficiently develop into mature NK cells in the presence of stromal cells from wild-type mice but not from LTalpha(-/-) or LTbetaR(-/-) mice. Direct activation of LTbetaR-expressing BM stromal cells is shown to promote to early NK cell development in vitro. Furthermore, the blockade of the interaction between LT and LTbetaR in adult wild-type mice by administration of LTbetaR-Ig impairs the development of NK cells in vivo. Together, these results indicate that the signal via LTbetaR on BM stromal cells by membrane LT is an important pathway for early NK cell development.

Adoptive Transfer↗

PubMed2001

Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance.

The study of human B cell tolerance has been hampered by difficulties in identifying a sizable population of autoreactive B lymphocytes whose fate could be readily determined. Hypothesizing that B cells expressing intrinsically autoreactive antibodies encoded by the VH4-34 heavy chain gene (VH4-34 cells) represent such a population, we tracked VH4-34 cells in healthy individuals. Here, we show that naive VH4-34 cells are positively selected and mostly restricted to the follicular mantle zone. Subsequently, these cells are largely excluded from the germinal centers and underrepresented in the memory compartment. In healthy donors but not in patients with systemic lupus erythematosus (SLE), these cells are prevented from differentiating into antibody-producing plasma cells. This blockade can be overcome ex vivo using cultures of naive and memory VH4-34 cells in the presence of CD70, IL-2, and IL-10. VH4-34 cells may therefore represent an experimentally useful surrogate for autoantibody transgenes and should prove valuable in studying human B cell tolerance in a physiological, polyclonal environment. Our initial results suggest that both positive and negative selection processes participate in the maintenance of tolerance in autoreactive human B cells at multiple checkpoints throughout B cell differentiation and that at least some censoring mechanisms are faulty in SLE.

B-Lymphocytes↗

PubMed2006

Central and peripheral RAG protein re-expression: underestimate mechanisms of tolerance?

The generation of developing B cells in the bone marrow is regulated by recombination activating genes RAG1 and RAG2 proteins. They contribute to the synthesis of functional antibodies (Abs) that can present self-reactivities following V(D)J (V, variable; D, diversity and J, joining) recombination. The emergence of autoreactive B cells is prevented by deletion through apoptosis, by stimulation blockade through anergy, or by synthesis of a new B-cell receptor through receptor edition. In the periphery, somatic hypermutation during the course of germinal centre (GC) responses can lead to the appearance of autoreactive and low-affinity Ab-producing B cells. Apoptotic deletion and receptor revision regulate these autoreactive and inappropriate B cells. Moreover, the presence of RAG-positive B cells outside GCs suggest that still uncharacterized regulation checkpoint, associated with secondary V(D)J recombination, also contribute to the regulation of autoreactivities. Failure in central and/or peripheral tolerance mechanisms associated with RAG expression could contribute to the terminal differentiation of autoreactive B cells leading to autoimmune states.

Animals↗

PubMed2026

Long-term follow-up of a phase 1/2 trial of anti-GDF-15 antibody visugromab plus anti-PD-1 antibody nivolumab in anti-PD-1/-L1 relapsed/refractory solid tumors.

BACKGROUND: Resistance to anti-PD-1/PD-L1 therapy is a major unmet need. Growth Differentiation Factor 15 (GDF-15) has been identified as a key resistance factor for anti-PD-1/PD-L1 immunotherapy. Visugromab, a neutralizing anti-GDF-15 antibody, plus the anti-PD-1 antibody nivolumab (V+N) was evaluated in the first-in-human phase 1/2a GDFATHER-01 trial in heavily pretreated participants with locally advanced/metastatic non-squamous non-small-cell lung cancer (nsq NSCLC), urothelial carcinoma (UC), or hepatocellular carcinoma (HCC), stringently defined as anti-PD-1/PD-L1-relapsed/refractory, and showed encouraging objective responses. This analysis reports long-term follow-up of these three phase 2 expansion cohorts of the GDFATHER-01 trial. METHODS: Seventy-seven participants with nsq NSCLC (N=22), UC (N=27), and HCC (N=28) received visugromab (10 mg/kg) plus nivolumab (240 mg) every two weeks until disease progression or unacceptable toxicity. RESULTS: Objective response rates (RECIST v1.1) were 18.2% for nsq NSCLC (4/22; 95%CI 5.2-40.3), 18.5% for UC (5/27; 95%CI 6.3-38.1), and 14.3% for HCC (4/28; 95%CI 4.0-32.7). Median duration of response (DoR) was 32.2 months (95%CI 5.5-38.0), 28.8 months (95%CI 7.4-39.4), and 19.4 months (95%CI 5.8-39.7; with protracted recruitment), respectively, with 7/13 responses (53.8%) ongoing. Confirmed complete response or complete metabolic response (CR or CMR) among responders was 61.5% (8/13), with 7/8 ongoing. In addition, 46.2% (6/13) of responders achieved a deeper response on V+N per RECIST v1.1 than with the prior anti-PD-(L)1 therapy; median DoR on V+N was 28.8 months (95%CI 7.4-38.0) versus 12.0 months (95%CI 8.0-24.0) on initial anti-PD-1/PD-L1 treatment. V+N was generally well tolerated. CONCLUSIONS: In heavily pretreated, advanced/metastatic participants with nsq NSCLC, UC, or HCC who were anti-PD-1/PD-L1-relapsed/refractory, V+N achieved deep and durable objective responses. The observed DoR, depth of response, and CR+CMR rate among responders exceeded those reported for their initial anti-PD-1/PD-L1 therapy. These findings suggest that GDF-15 blockade with visugromab can overcome resistance and enhance the magnitude and durability of anti-PD-1/PD-L1 responses, and warrant further exploration in randomized trials. REGISTRY: ClinicalTrials.gov, TRN: NCT04725474, Registration date: 25 January 2021; EudraCT, TRN: 2020-002103-19, Registration date 16 Dec 2020.

Humans↗

PubMed2025

Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy.

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types1, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (Ifnar1-/-) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.

Animals↗