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PubMed2026

Pembrolizumab-Chemotherapy Versus Pembrolizumab in Head and Neck Squamous Cell Carcinoma: A PD-L1 CPS-Stratified Analysis of Updated KEYNOTE-048 Data.

Based on KEYNOTE-048, pembrolizumab monotherapy and pembrolizumab-chemotherapy are established category 1 first-line treatments for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1. We compared their efficacy using updated trial data. We analyzed 4-year progression-free survival on next-line therapy (PFS2) and 5-year overall survival (OS) data from KEYNOTE-048 by reconstructing time-to-event data using KMSubtraction. Efficacy was compared in CPS 1-19 and CPS ≥ 20 subgroups using Kaplan-Meier estimates, Cox models, restricted mean survival time (RMST), and landmark analyses. Among 499 patients with CPS ≥ 1, 240 (48.1%) had CPS 1-19 and 259 (51.9%) had CPS ≥ 20. In the CPS 1-19 subgroup, pembrolizumab-chemotherapy showed numerically longer median PFS2 (10.1 vs. 8.0 months; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.62-1.06) and OS (12.8 vs. 10.8 months; HR: 0.87; 95% CI: 0.67-1.15) versus monotherapy, without statistical significance. For CPS ≥ 20 patients, efficacy was comparable between regimens, with similar median PFS2 (11.3 vs. 11.7 months; HR: 0.95) and OS (14.7 vs. 14.9 months; HR: 0.96). RMST and landmark analyses showed an early PFS2 benefit and a trend toward OS benefit with pembrolizumab-chemotherapy in CPS 1-19, with comparable outcomes in CPS ≥ 20. Pembrolizumab-chemotherapy showed a trend toward improved outcomes in the CPS 1-19 subgroup, with comparable efficacy in the CPS ≥ 20 subgroup, supporting a refined first-line strategy: monotherapy for CPS ≥ 20 to minimize toxicity, and combination therapy for CPS 1-19 to potentially enhance disease control.

Humans↗

PubMed2026

Icaritin Sensitizes Hepatocellular Carcinoma to PD-L1 Therapy by NQO1-Dependent Ferroptosis Induction.

Hepatocellular carcinoma (HCC) remains challenging with limited immunotherapy response. Despite its clinical promise in advanced HCC, the mechanisms of icaritin, especially concerning ferroptosis induction and immune modulation, remain elusive. This study aims to determine if the antitumor effect of icaritin involves the induction of ferroptosis via NAD(P)H quinone oxidoreductase 1 (NQO1) and if it can augment the efficacy of programmed cell death 1 ligand 1 (PD-L1) therapy by potentiating natural killer (NK) cell activity. Using human HCC cell lines (Huh7, Hep3B, PLC/PRF/5, SNU-449, and MHCC97-H) and two synergistic mouse models (Hepa1-6 and SgPten/c-Met), we examined icaritin's inhibition of tumor growth and induction of ferroptosis via the NQO1 pathway, monitoring key markers (reactive oxygen species [ROS], glutathione peroxidase 4 [GPX4], ferritin heavy chain 1 [FTH1]). The NQO1 inhibitor dicoumarol was employed to validate the pathway. Tumor microenvironment (TME) remodeling was assessed through cancer-associated fibroblasts (CAFs) markers and immune cell profiling, focusing on NK cell infiltration. Combination therapy with anti-PD-L1 was tested in vivo. Icaritin significantly inhibited HCC growth in vitro and in vivo. Its antitumor effect was mediated by NQO1-mediated ferroptosis, via elevated ROS, diminished mitochondrial membrane potential, and downregulated GPX4 and FTH1. Analysis of The Cancer Genome Atlas (TCGA) data revealed that NQO1 is overexpressed in human HCC tissues. Icaritin enhanced NK cell infiltration while reducing CAF abundance and suppressing recombinant focal adhesion kinase (FAK) and discoidin domain receptor 1 (DDR1) signaling. Notably, icaritin synergized with anti-PD-L1 therapy to enhance tumor suppression without increasing toxicity, correlating with potentiated NK cell immunity. Our findings demonstrate that icaritin triggered NQO1-mediated ferroptosis and remodeled TME to enhance NK cell recruitment and PD-L1 therapy efficacy. This provides rationale for evaluating icaritin-based combination immunotherapy in HCC through dual action on ferroptosis and NK cell activation.

Ferroptosis↗

PubMed2026

Respiratory viral infections prime accelerated lung cancer growth.

The COVID-19 pandemic has highlighted the long-term consequences of viral pneumonia, yet its impact on cancer development remains unclear. Here, we show that patients previously hospitalized with severe COVID-19 have an increased risk of subsequent lung cancer. Across multiple murine models, severe respiratory viral infections accelerated lung cancer growth, whereas vaccination mitigated infection-enhanced tumor progression. Mechanistically, prior viral pneumonia reprogrammed the lung into a pro-tumor microenvironment marked by the sustained accumulation of tumor-associated neutrophils and heightened immunosuppression. We observed persistent chromatin remodeling at key cytokine loci in immune and structural cells, linking inflammatory memory to tumor-promoting signals. Therapeutically, combined blockade of neutrophil recruitment and programmed death-ligand 1 (PD-L1) restored CD8+ T cell function and suppressed tumor growth. Together, these findings establish a causal link between prior viral pneumonia and lung tumorigenesis, underscoring the need for enhanced surveillance and targeted interventions to reduce post-COVID cancer risk.

Animals↗

PubMed2025

DNA damage repair gene alterations influence the tumor immune microenvironment in advanced non-small cell lung cancer.

PURPOSE: DNA damage response and repair (DDR) gene alterations contribute to genomic instability and increased tumor immunogenicity, yet their clinical significance in non-small cell lung cancer (NSCLC) remains unclear. Using a large real-world dataset, we evaluated the prevalence of DDR alterations and their relation to the tumor immune microenvironment in metastatic NSCLC. EXPERIMENTAL DESIGN: We retrospectively analyzed real-world data from patients with metastatic NSCLC using the Tempus AI database. Tumors were sequenced with Tempus xT DNA and xR RNA assays and classified based on the presence (DDRmt) or absence (DDRwt) of a pathogenic somatic alteration or copy number deletion in a DDR pathway gene. Associations between DDR alterations and immune cell infiltration, PD-L1 immunohistochemistry, tumor mutational burden (TMB), and microsatellite instability (MSI-H) were examined. RESULTS: Among 14,127 patients (median age = 67, 49% female), 5,276 (37%) were DDRmt. There was a higher prevalence of current/former smokers in the DDRmt group (86% vs. 82%; p<0.001). DDRmt tumors were more likely to have higher levels of TMB (median: 5.4 vs. 4.6; p<0.001), MSI-H (1.1 % vs. <0.1 %; p<0.001), and infiltrating CD8+ T cells (p=0.003) compared to DDRwt tumors. A lower frequency of macrophages (p<0.001) were observed among DDRmt compared with DDRwt tumors with no difference in PDL1 positivity. CONCLUSIONS: Among patients with metastatic NSCLC, 37% present with DDRmt tumors characterized by higher TMB, frequency of MSI-H, and changes in immune cell infiltrates. These findings provide insight into the immunogenic landscape of DDR-altered NSCLC and may inform biomarker selection and therapeutic strategies.

Humans↗

PubMed2026

A novel neoadjuvant immunotherapy confers improved overall survival in oral cancer patients with low tumor PD-L1 expression The IT-MATTERS Clinical trial - Prognostic role of tumor PD-L1 expression.

OBJECTIVE: Five-year overall survival (OS) remains < 50% for patients with resectable, locally advanced (LA) primary oral squamous cell carcinoma (OSCC) and soft palate, receiving current standard of care (SOC). The aim of our study was to examine neoadjuvant Leukocyte Interleukin Injection (LI) with CIZ (intravenous low dose cyclophosphamide, indomethacin and zinc multivitamins) effect on OS, in low-risk (LR) OSCC patients. PATIENTS AND METHODS: In a randomized, controlled Phase 3 trial, treatment-naïve locally advanced patients, with stage III/IVa OSCC and soft-palate cancer, had surgical tumor samples assessed for pre-defined thresholds of PD-L1 tumor proportion score (TPS). OS was analyzed using proportional hazard models for LI + CIZ + SOC vs SOC, in the intention-to-treat (ITT) population. RESULTS: OS was superior in low risk (LR) patients receiving LI + CIZ + SOC compared to SOC; OS advantage hazard ratio (HR) 0.64, p = 0.0569 (without selecting for N0, PD-L1 TPS < 10%), and the Kaplan-Meier (K-M) lifetable achieved significance (log rank p = 0.0340) favoring LI + CIZ + SOC vs SOC. Applying the selection criteria (cN0 and TPS < 10%) to ITT, OS reached HR 0.34p = 0.0012, Kaplan-Meier log rank p = 0.0015. The ITT LR cohort (cN0 and TPS < 10%) achieved a HR 0.26 (p = 0.0023), Kaplan-Meier log rank p = 0.0013, supported by progression free survival (PFS) HR 0.43, p = 0.0178, Kaplan-Meier log rank p = 0.0431, with 32% absolute survival advantage over control at 60 months. CONCLUSIONS: Significant OS prolongation was observed in ITT population for LI + CIZ + SOC vs SOC, in LR and in ITT LR cN0, PD-L1TPS < 10% cohort having locally advanced squamous cell carcinoma tumors in oral cavity/soft-palate. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01265849; EudraCT (Identifier: 2010-019952-35).

Humans↗

PubMed2017

Surface PD-L1, E-cadherin, CD24, and VEGFR2 as markers of epithelial cancer stem cells associated with rapid tumorigenesis.

Cancer cells require both migratory and tumorigenic property to establish metastatic tumors outside the primary microenvironment. Identifying the characteristic features of migratory cancer stem cells with tumorigenic property is important to predict patient prognosis and combat metastasis. Here we established one epithelial and two mesenchymal cell lines from ascites of a bladder cancer patient (i.e. cells already migrated outside primary tumor). Analyses of these cell lines demonstrated that the epithelial cells with surface expression of PD-L1, E-cadherin, CD24, and VEGFR2 rapidly formed tumors outside the primary tumor microenvironment in nude mice, exhibited signatures of immune evasion, increased stemness, increased calcium signaling, transformation, and novel E-cadherin-RalBP1 interaction. The mesenchymal cells on the other hand, exhibited constitutive TGF-β signaling and were less tumorigenic. Hence, targeting epithelial cancer stem cells with rapid tumorigenesis signatures in future might help to combat metastasis.

B7-H1 Antigen↗

PubMed2026

Conserved miRNA regulators of PD-1/PD-L1 in glioblastoma and colorectal cancer.

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have transformed cancer therapy, but their efficacy remains limited in glioblastoma (GBM) and heterogeneous in colorectal cancer (CRC). MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, including immune checkpoint molecules, yet conserved regulatory miRNA networks across distinct cancers remain poorly defined. Five conserved miRNAs (miR-106a-5p, miR-106b-5p, miR-20a-5p, miR-20b-5p, miR-138-5p) fulfilled the selection criteria and were consistently dysregulated in GBM and CRC. MiR-106a-5p and miR-106b-5p were upregulated in both cancers and showed favourable prognostic associations, with higher expression correlating with improved survival. miR-20a-5p and miR-20b-5p were preferentially expressed in microsatellite-stable (MSS) CRC and correlated with favourable outcomes in both cancers, whereas miR-138-5p was downregulated in both tumours compared to normal tissue, but showed opposite survival associations, with higher levels linked to worse prognosis. Correlation analysis revealed significant inverse associations between several miRNAs and checkpoint gene expression, including moderate inverse correlations for CD274-miR-106a-5p in GBM, CD274-miR-20a-5p in CRC and PDCD1LG2-miR-20a-5p in both cancers. Pan-cancer profiling demonstrated broad and heterogeneous dysregulation, with expression absent in ovarian cancer for four of the five miRNAs. Pathway enrichment implicated the TGF-β, Hippo, FoxO, and cell cycle pathways, consistent with their known roles in tumour immune evasion. We identified a conserved set of miRNAs that are dysregulated in both GBM and CRC, correlate with survival, and display inverse relationships with PD-1/PD-L1/PD-L2 expression. These miRNAs represent candidate regulators of the PD-1/PD-L1/PD-L2 axis and potential biomarkers of tumour biology that may influence immune checkpoint signalling.

Humans↗

PubMed2025

The assembly of cancer-specific ribosomes by the lncRNA LISRR suppresses melanoma anti-tumor immunity.

Gains of chromosome 12p11.21, encoding for the cancer-specific lncRNA LISRR, correlate with poor survival across different cancers. In melanoma, LISRR is upregulated in immunotherapy-resistant patients to contribute to the generation of drug-tolerant cells by activating an immune-suppressive translational program, affecting the synthesis of PD-L1 and of the glycocalyx. Accordingly, downregulation of LISRR initiates robust immune responses and resensitizes to immunotherapy ex vivo and in vivo. The use of glycans to evade immunity exhibits shared characteristics with the testis, where defects in the glycocalyx cause infertility. Mechanistically, we showed that LISRR affects the ribosome core composition and recruits deleted in azoospermia-associated protein 1 to polysomes to prime the integrated stress response. Our study reveals the contribution of lncRNAs to the generation of cancer-specific ribosomes and identifies an RNA-based strategy to overcome resistance to immune checkpoint blockade.

RNA, Long Noncoding↗

PubMed2025

Unveiling non-small cell lung cancer treatment effect heterogeneity: a comparative analysis of statistical methods.

BACKGROUND: For patients with advanced non-small cell lung cancer lacking targetable genomic alterations, the impact of clinicogenomic characteristics on the effectiveness of combining chemotherapy with immunotherapy is unclear. METHODS: We evaluated 4 statistical methods for detecting heterogeneous treatment effects related to clinical factors, including programmed death-ligand 1 expression, tumor mutation burden, and stage at diagnosis, using the American Association for Cancer Research Project Genomics Evidence Neoplasia Exchange BioPharma Collaborative dataset supplemented with institutional data collected under the same data curation model. A 2-sided P value of no more than .05 was used to denote statistical significance for all analyses. RESULTS: The mixture model revealed 2 latent subgroups: in one subgroup, there was no meaningful treatment effect, with average progression-free survival (PFS) only 5% longer with immunotherapy alone (95% confidence interval [CI] = -19% to 35%); in the second subgroup, immunotherapy alone was associated with a 35% decrease in average PFS (95% CI = -59% to 2%), corresponding to a ratio in treatment effects of 1.62 (95% CI = 1.02 to 2.57). There was a marginal association between lower tumor mutation burden levels and membership in the subgroup with improved PFS following receipt of chemoimmunotherapy. The causal survival forest highlighted the importance of tumor mutation burden (variable importance ranking: 1) and programmed death-ligand 1 (variable importance ranking: 3) when assessing heterogeneity. In contrast, the accelerated failure time and Cox proportional hazards models did not detect any statistically significant heterogeneous treatment effects. In simulations, the mixture model identified heterogeneous treatment effects more frequently than other methods, especially with weak covariate relationships, demonstrating its utility for informing personalized treatment approaches. CONCLUSIONS: The application of novel statistical methods to large scale clinico-genomic databases offers an opportunity to more accurately identify heterogeneous treatment effects in some settings as compared to traditional statistical methods. Applying such methods to the AACR Project GENIE BPC non-small cell lung cancer data indicated a potential association between decreasing tumor mutation burden and improved outcomes with chemoimmunotherapy as compared to immunotherapy alone.

Humans↗

PubMed2026

Genetically proxied circulating PD-1/PD-L1 levels and broadly defined myocarditis: A bidirectional Mendelian randomization study with exploratory lipidomic analyses.

Myocarditis is an inflammatory myocardial disease with potentially severe outcomes. Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) regulate immune tolerance, but the association between lifelong genetically proxied circulating PD-1/PD-L1 levels and broadly defined myocarditis remains uncertain. We investigated these associations and explored related plasma lipid species. We conducted bidirectional 2-sample Mendelian randomization using proteomic genome-wide association data from the UK Biobank Pharma Proteomics Project and INTERVAL. FinnGen Release 10 was the primary broadly defined myocarditis outcome, and an independent myocarditis genome-wide association study (GCST90018882) provided outcome-level validation. Complementary estimators, heterogeneity and pleiotropy diagnostics, influence analyses, MR-RAPS, and supportive meta-analyses were performed. Associations with 179 plasma lipid species were examined in exploratory analyses. Higher genetically proxied circulating PD-L1 was inversely associated with broadly defined myocarditis in UKB-PPP (odds ratio [OR] 0.834, 95% confidence interval [CI] 0.698-0.995; P = .0441), and the independent INTERVAL analysis yielded a concordant inverse estimate (OR 0.619, 95% CI: 0.434-0.883; P = .0083); no clear association was observed for PD-1. The MR-RAPS estimate retained the inverse direction; estimates against the independent broadly defined myocarditis dataset were also inverse, and supportive meta-analyses across protein and outcome sources yielded inverse pooled estimates. Reverse MR did not support effects of broadly defined myocarditis liability on circulating PD-1 or PD-L1. Exploratory lipid analyses identified nominal associations requiring confirmation. Higher genetically proxied circulating PD-L1 may be associated with a lower risk of broadly defined myocarditis, supporting further investigation of PD-L1-related immune regulation. These findings do not directly estimate the effects of pharmacologic PD-1/PD-L1 blockade. The lipid findings are hypothesis-generating.

Myocarditis↗

PubMed2026

FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia.

UNLABELLED: FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations are frequent in acute myeloid leukemia (AML) and are associated with a high risk of relapse. CKLF-like MARVEL transmembrane domain containing member 6 (CMTM6) stabilizes PD-L1 surface expression and modulates tumor immunity in solid cancer. In this study, we found a role for FLT3-induced CMTM6 in hematologic malignancies. FLT3 drove CMTM6 and PD-L1 expression in AML cells, whereas FLT3 inhibition reduced expression of CMTM6 and PD-L1. In three distinct allogeneic hematopoietic cell transplantation mouse models, transplantation of Cmtm6-deficient FLT3-ITD+ leukemia cells resulted in prolonged survival, reduced leukemia burden, enhanced T-cell effector function, and decreased expression of T-cell exhaustion markers compared with Cmtm6-proficient FLT3-ITD+ leukemia cells. Furthermore, combination therapy with anti-PD-L1 and tandutinib significantly improved survival, suppressed leukemia cell expansion, and augmented the anti-leukemia T-cell response in mice bearing FLT3-ITD+ leukemia. Mechanistically, protein-protein interaction of FLT3 and CMTM6 within their transmembrane domains, which was not phosphorylation dependent, enhanced CMTM6 stability in leukemia cells, whereas FLT3-ITD did not increase CMTM6 and PD-L1 expression at the RNA level. Furthermore, CMTM6 upregulation and protein interaction with FLT3 were validated in primary leukemia cells from two independent cohorts of patients with FLT3-ITD+ AML. Collectively, these findings uncover FLT3-mediated stabilization of CMTM6 in AML cells, which results in enhanced PD-L1 cell surface expression and leukemia immune escape. SIGNIFICANCE: Activation of the CMTM6/PD-L1 axis in FLT3-ITD-driven acute myeloid leukemia mediates immunosuppression, providing the basis for potential inhibition of this pathway to harness antitumor immunity.

Animals↗

PubMed2024

Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade.

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

Humans↗

PubMed2024

Soluble immune-checkpoint factors: a potential immunotherapy biomarker.

There is unmet need for additional biomarkers to better select patients with non-small cell lung cancer (NSCLC) that are likely to benefit from immunotherapy in order to improve patient outcomes, reduce patient toxicity, and relieve the growing burden of healthcare costs. In this issue of the JCI, Hayashi and colleagues evaluated soluble forms of the immune checkpoint molecules PD-L1, PD-1, and CTLA-4 in the plasma of patients with advanced NSCLC who had been treated with anti-PD-1/L1 therapy. The findings suggest that these soluble immune-checkpoint factors may provide a complementary biomarker to PD-L1 IHC, although application into the clinic may not be straightforward.

Humans↗

PubMed2026

Dual-dimensional profiling of host genomic variations and HPV integration in PD-L1-stratified cervical cancer via Oxford Nanopore Technology.

BACKGROUND: The integration of human papillomavirus (HPV) DNA into the host genome is a key step in the development of HPV-associated cervical cancer (CC). However, the genomic characteristics of host genomic variations and HPV integration within the context of programmed death-ligand 1 (PD-L1) expression stratification have not been systematically investigated. METHODS: Whole-genome sequencing was performed using Oxford Nanopore Technology (ONT) on six samples (three from the high PD-L1 expression group and three from the low PD-L1 expression group). The characteristics of host genomic variations under different PD-L1 expression stratifications were explored, including structural variations (SV), copy number variations (CNV), single nucleotide polymorphisms (SNP), and insertion-deletions (Indel). Subsequently, the distribution features of HPV integration sites were analyzed, different integration types were identified, and pathway analysis was conducted. RESULTS: Whole-genome SV analysis revealed that the total number of SVs and the composition of mutation types were similar between the high and low PD-L1 expression groups, with insertions (INS) and deletions (DEL) predominating in both. These variations were primarily enriched in intergenic regions and introns. In the low PD-L1 expression group, integration events were observed at multiple chromosomal loci, with the most frequent integration occurring in the KLF5 gene region on chromosome 13. No frequently integrated loci were identified in the high PD-L1 expression group. Additionally, four distinct HPV integration breakpoint patterns were preliminarily identified and analyzed. CONCLUSION: PD-L1 expression stratification did not significantly alter the overall genomic instability of the host. However, differences were observed in the distribution patterns of HPV integration sites. These findings provide new insights into the genomic heterogeneity of CC under different PD-L1 expression backgrounds and may lay the groundwork for future research exploring stratified immunotherapy based on HPV integration features.

Humans↗

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

Propionyl-CoA carboxylase subunit B regulates anti-tumor T cells in a pancreatic cancer mouse model.

Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca-/- KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.

Animals↗