Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 47 appraisals
Journal of hematology & oncology
Large language model-guided CAR-T in silico platform for cytokine optimization in liver cancer with low antigen density
CAR-T cell therapy has shown remarkable success in hematologic malignancies but remains limited in solid tumors such as liver cancer due to antigen heterogeneity, low target antigen density, and an immunosuppressive tumor microenvironment (TME). Cytokine engineering can enhance CAR-T persistence and effector function; however, the optimal cytokine payload may vary depending on tumor type, target antigen expression level, and microenvironmental context, making systematic experimental comparison time-consuming and labor-intensive. Here, we applied a large language model (LLM)-based CAR-T in silico platform to systematically evaluate cytokine engineering strategies, including IL-2, IL-7, IL-12, IL-15, and IL-18, in glypican-3 (GPC3)-targeted CAR-T cells for liver cancer. We used cytokine selection as a biologically grounded benchmark to test whether the platform could recover known CAR-T cell-relevant cytokine biology and support future novel predictions. Computational predictions identified IL-15 as the most effective enhancer, particularly against tumor cells with low GPC3 expression. Guided by these results, we generated cytokine-armored GPC3 CAR-T cells and performed in vitro and in vivo validation. IL-15-engineered CAR-T cells exhibited superior proliferation, persistence, and serial cytotoxicity against GPC3-low liver cancer cells. In human liver cancer xenograft models, IL-15-enhanced CAR-T cells achieved improved tumor control compared with conventional and other cytokine-engineered CAR-T cells. The recovery of IL-15 served as a positive benchmark supporting the validity of the LLM-guided CAR-T in silico workflow. Collectively, this study establishes an LLM-guided framework, schema-constrained for rational cytokine selection in CAR-T engineering and identifies IL-15 as a potent enhancer for targeting antigen-low liver cancers.
3 July 2026
Read appraisal →The Journal of dermatological treatment
Intralesional human papillomavirus vaccination for cutaneous verrucae: a systematic review and meta-analysis of therapeutic efficacy
OBJECTIVES: To evaluate the efficacy of intralesional human papillomavirus (HPV) vaccination in the management of cutaneous warts. METHODS: A comprehensive search of PubMed, MEDLINE, Embase, Scopus, and ClinicalTrials.gov was conducted in accordance with a registered PROSPERO protocol (CRD420251170324). Chronic or persistent warts were defined as lesions lasting more than six months or showing inadequate response to conventional therapies. The primary outcome was complete wart clearance, and pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Six studies were included. Intralesional HPV vaccination was associated with a significantly higher rate of complete clearance compared with intralesional normal saline (RR 18.54; 95% CI 6.59-52.18). Subgroup analyses demonstrated comparable efficacy between bivalent and quadrivalent vaccines. Reported adverse events were mild and localized. CONCLUSION: Intralesional HPV vaccination demonstrated significant therapeutic efficacy in the treatment of cutaneous warts and represents a promising immunotherapeutic option for patients with persistent or treatment-refractory disease.
30 June 2026
Read appraisal →Journal of chemical information and modeling
A Reproducible Hierarchical Virtual Screening Framework Integrating Scaffold-Aware Machine Learning, Ensemble Docking, and Molecular Dynamics: Application to IDO1
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme implicated in cancer immune escape and remains an attractive therapeutic target despite recent clinical setbacks. We report a fully reproducible hierarchical virtual screening framework integrating scaffold-aware machine learning, ensemble docking, consensus scoring, and molecular dynamics simulations for robust prioritization of IDO1 inhibitors. A curated ChEMBL data set of IDO1 inhibitors was subjected to strict standardization, duplicate removal, and activity binarization at pChEMBL ≥6. Models were trained using scaffold-based splitting and nested cross-validation to prevent chemical series leakage. An ensemble of Random Forest, XGBoost and SVM classifiers achieved balanced predictive performance (ROC-AUC ≈0.88-0.89) with applicability domain filtering to ensure reliability. Prospective screening of FDA-approved drugs yielded 39 compounds within the applicability domain predicted as active. These were further evaluated through ensemble docking against multiple IDO1 crystal structures using GNINA with CNN rescoring. Consensus strategies were systematically benchmarked, demonstrating that best-Z-score aggregation outperformed mean, rank-based, and weighted methods in enrichment factor (EF) metrics. Two top-ranked candidates were subjected to 300 ns molecular dynamics simulations, revealing stable binding modes and persistent interactions with key catalytic residues. This study demonstrates that hierarchical integration of scaffold-aware machine learning with structure-based ensemble strategies enhances robustness and reduces false positives in virtual screening campaigns. The proposed workflow is generalizable and supports reproducible candidate prioritization in computational drug discovery. The complete implementation, including data processing, model training, and analysis steps, is provided as a fully executable Jupyter notebook available at https://github.com/rocco-b/IDO1-inhibitors-ML-and-docking-data.
23 June 2026
Read appraisal →Science advances
PathTIGR: A pathway topology-informed graph representation learning framework for immunotherapy response prediction
Immunotherapy has revolutionized cancer treatment, yet substantial inter-patient response heterogeneity limits therapeutic benefit to specific patient subsets. Here, we present PathTIGR, a pathway topology-informed graph representation learning framework that systematically integrates biological pathway network topology knowledge with genome variation information for immunotherapy response prediction. PathTIGR uses a three-component design: (i) pathway graph encoder with multihead attention embeding pathway topology knowledge and cancer genomic variants to pathway representation, (ii) transformer module capturing pathway regulatory dependencies, and (iii) multilayer perceptron synthesizing pathway-level representations to predict immunotherapy response. This architecture enables PathTIGR to capture complex molecular interactions underlying immunotherapy response. Comprehensive validation across multiple independent immunotherapy cohorts demonstrates that PathTIGR achieves superior predictive performance compared to established biomarkers and state-of-the-art deep learning approaches while maintaining biological interpretability through identification of key signatures underlying response heterogeneity. PathTIGR represents an interpretable graph-based learning framework that enhances immunotherapy response prediction and elucidates molecular determinants of therapeutic efficacy, thereby facilitating the advancement of precision cancer immunotherapy.
14 June 2026
Read appraisal →Med (New York, N.Y.)
Neoadjuvant mFOLFOXIRI with or without cadonilimab versus mFOLFOX6 in locally advanced colorectal cancer: A randomized phase 2 trial (OPTICAL-2)
BACKGROUND: The efficacy of neoadjuvant chemotherapy combined with dual immune checkpoint blockade in proficient mismatch repair/microsatellite-stable (pMMR/MSS) locally advanced colorectal cancer (LACRC) remains uncertain. METHODS: In this open-label, randomized phase 2 trial (ClinicalTrials.gov: NCT05571644), eligible patients were randomly assigned (1:1:1) to receive 6 cycles of neoadjuvant mFOLFOXIRI plus cadonilimab, mFOLFOXIRI, or mFOLFOX6, followed by surgery and adjuvant chemotherapy. The primary endpoint was pathological complete response (pCR) in the intention-to-treat population. Secondary endpoints included major pathological response (MPR), safety, locoregional recurrence, disease-free survival, and overall survival. FINDINGS: Between July 2023 and August 2024, 123 patients were randomly assigned (41 per group). Neoadjuvant mFOLFOXIRI plus cadonilimab significantly improved pCR compared with mFOLFOX6 (26.8% versus 9.8%; odds ratio [OR], 3.4; 95% confidence interval [CI], 1.04 to 13.24; p = 0.046), whereas mFOLFOXIRI alone did not (14.6% versus 9.8%; OR, 1.6; 95% CI, 0.4 to 6.7; p = 0.50). MPR rates were 68.3%, 46.3%, and 43.9%, respectively, and were significantly higher with mFOLFOXIRI plus cadonilimab than with mFOLFOX6 (p = 0.026). Downstaging to ypStage 0-I occurred in 66%, 45%, and 41% of patients in the three groups, respectively, and was significantly higher in the mFOLFOXIRI plus cadonilimab group (p = 0.027). Grade ≥3 adverse events were manageable, with liver enzyme elevation and neutropenia being the most common. CONCLUSIONS: Neoadjuvant mFOLFOXIRI plus cadonilimab significantly improved pCR compared with mFOLFOX6 in LACRC, with a manageable safety profile, supporting further investigation. FUNDING: This work was funded by the National Science Fund for Distinguished Young Scholars (82425045) and the National Natural Science Foundation of China (82272800).
14 June 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Durvalumab in Combination With Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer: Long-Term Analysis From the GeparNuevo Trial
The phase II GeparNuevo trial investigated whether adding durvalumab to neoadjuvant chemotherapy (NACT) only in patients with early triple-negative breast cancer cT1b-cT4a-d would improve pathologic complete response (pCR) rate and patient survival. Hundred and seventy-four patients were randomly assigned to receive durvalumab or placebo concurrently with nab-paclitaxel once per week and followed by dose-dense epirubicin and cyclophosphamide. With 86.4 months of median follow-up compared with the previously reported 43.7 months, durvalumab showed sustained significant improvements in long-term outcomes as defined by STEEP compared with placebo regarding not only invasive disease-free survival (iDFS; hazard ratio [HR], 0.56 [95% CI, 0.32 to 0.99]; stratified log-rank P = .0431), but also distant disease-free survival (DDFS; HR, 0.41 [95% CI, 0.21 to 0.80]; P = .0069) and overall survival (OS; HR, 0.33 [95% CI, 0.14 to 0.79]; P = .0085). All analyses were stratified by stromal tumor-infiltrating lymphocytes (sTILs) at baseline (low [≤10%], intermediate [11%-59%], high [≥60%]). In exploratory subgroup analysis, patients with nodal involvement at baseline demonstrated a greater iDFS benefit (HR, 0.33 [95% CI, 0.144 to 0.771]; P = .01; Pinteraction = 0.045). sTILs in residual disease (RD) could be assessed in 39/71 patients without pCR. Post hoc analyses by sTILs high (>10%) versus low (≤10%) in RD showed estimated 7-year iDFS rates of 92.3% (95% CI, 56.6 to 98.9) and 51.4% (95% CI, 29.2 to 69.7), respectively. Hence, adding durvalumab to dose-dense NACT without adjuvant continuation of checkpoint inhibition improved long-term survival outcomes, irrespective of the extent of pathologic response. This underscores the necessity to re-evaluate the adjuvant continuation of checkpoint inhibition.
11 June 2026
Read appraisal →Blood advances
Phase 1 study of zanubrutinib plus lenalidomide for patients with relapsed/refractory diffuse large B-cell lymphoma
Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have a poor prognosis. In preclinical studies, lenalidomide and a Bruton tyrosine kinase (BTK) inhibitor demonstrated synergistic antitumor effects. Zanubrutinib, a next-generation BTK inhibitor, has greater selectivity to minimize off-target binding. BGB-3111-110 was a phase 1 multicenter dose-escalation/-expansion study. Patients with R/R DLBCL received zanubrutinib 160 mg twice daily plus lenalidomide (15, 20, or 25 mg once daily) until progression or unacceptable toxicity. Primary end points were safety, recommended phase 2 dose (RP2D), and overall response rate (ORR; Lugano 2014 criteria). Sixty-six patients were enrolled and treated. Patients had a median of 2 previous therapies, 83% had stage III/IV disease, and ∼67% had non-geminal center B-cell-like or activated B-cell-like DLBCL. No dose-limiting toxicities occurred; the lenalidomide RP2D was 25 mg once daily when combined with zanubrutinib 160 mg twice daily. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 74%; the most common (>20%) grade ≥3 TEAEs were decreased neutrophil count (58%) and decreased white blood cell count (29%). TEAEs led to 7 treatment discontinuations (11%) and 2 deaths (3%). At the RP2D, ORR and complete response rate were 58% and 42%, respectively; median time to response was 2.8 months. Median duration of response was 14.9 months. Median progression-free survival was 5.5 months (95% confidence interval [CI], 2.9-11.1); the 12-month event-free rate was 34% (95% CI, 21-48). Zanubrutinib plus lenalidomide demonstrated acceptable tolerability and antitumor activity in patients with R/R DLBCL. This trial was registered at www.clinicaltrials.gov as NCT04436107.
9 June 2026
Read appraisal →Science translational medicine
Efficacy and safety of durcabtagene autoleucel in a phase 1 trial for patients with relapsed/refractory multiple myeloma
Traditional manufacturing of B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapies is prolonged, leading to reduced patient access, T cell exhaustion, and consequently limiting therapeutic efficacy. To address this issue, we developed durcabtagene autoleucel, a BCMA-directed CAR T cell therapy manufactured using a rapid platform aimed at preserving T cell stemness. Here, we present the primary findings of part A of a phase 1 study (NCT04318327) of durcabtagene autoleucel in patients with relapsed/refractory multiple myeloma (r/r MM). The primary objective was safety; secondary objectives included response rates, cellular kinetics, immunogenicity, and manufacturing feasibility. Durcabtagene autoleucel was successfully manufactured for all 55 patients (median vein-to-vein time, 24 days) and given as a single infusion at one of four flat target doses (2.5 × 106 to 20 × 106 CAR T cells). Among all patients, the overall response rate was 98%, and the stringent complete response rate was 55%. Eighty percent of evaluable patients (35 of 44) achieved minimal residual disease negativity. There were no unexpected safety findings and no reports of delayed neurotoxicity. Immunophenotyping and transcriptomic analyses confirmed preservation of a stem-like phenotype in the manufactured final product. On the basis of the safety, efficacy, and cellular expansion results from the phase 1 trial, a phase 2 trial (NCT05172596) was initiated to further explore the efficacy and safety of durcabtagene autoleucel in heavily pretreated patients with aggressive r/r MM.
30 May 2026
Read appraisal →Indian journal of ophthalmology
Immune checkpoint inhibitor therapy for treatment of periocular Merkel cell carcinoma: A systematic review of clinical outcomes and safety
Merkel cell carcinoma (MCC) is a rare, aggressive neurocutaneous malignancy associated with ultraviolet damage, immunosuppression, and Merkel cell polyoma virus infection. Periocular MCC is uncommon but has high rates of local recurrence and metastasis and presents unique therapeutic challenges due to functional and cosmetic considerations. Immune checkpoint inhibitor (ICI) therapy has shown efficacy in systemic MCC; however, evidence for periocular use is limited to small case series and reports without consolidated evidence or consensus. Thus, this study summarizes and evaluates the effectiveness and safety of ICIs for periocular MCC. A systematic literature search across PubMed, Embase, and Web of Science was conducted according to PRISMA guidelines. Randomized and nonrandomized studies, case series, and case reports in English describing ICI use for periocular MCC were included. Non-human studies, non-periocular MCC, and reports without ICI treatment were excluded. Extracted data included patient demographics, tumor characteristics, treatment regimen, and patient outcomes. Seven studies reporting ten patients were included. Treatment regimens consisted of pembrolizumab (n = 6) and avelumab (n = 3), or both medications (n = 1). At a mean follow-up of 11.4 ± 9.0 months, nine patients had complete response (90%); only one patient developed subsequent distant progression despite local response. Patients with both localized periocular disease and metastatic involvement demonstrated favorable responses to ICI. Adverse effects were infrequent and typically mild; only one patient discontinued therapy due to adverse effects. ICIs may be an effective and well-tolerated treatment for local and advanced periocular MCC; however, larger, prospective studies are needed.
28 May 2026
Read appraisal →Journal of gastrointestinal cancer
Optimal First-line Immune-related Therapy Selection for Advanced Gastric Cancer: A Systematic Review and Network Meta-analysis
PURPOSE: Although immune checkpoint inhibitors combined with chemotherapy improve survival in advanced gastric cancer (AGC), comparative evidence across first-line regimens remains insufficient. This study aimed to systematically evaluate their relative efficacy and safety. METHODS: PubMed, Embase, the Cochrane Library, Web of Science, and major conferences were searched up to February 28, 2025. Eligible RCTs comparing ICI-related regimens as first-line AGC treatment were included. Primary outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS: Eleven RCTs involving 8,999 patients, six integrated strategies, and twelve specific regimens were included. Dual-target ICI-chemo and single ICI-chemo showed significant survival benefits over chemotherapy, whereas dual ICIs±chemo and single ICI alone did not. Dual-target ICI-chemo was associated with significantly better survival than both dual ICIs±chemo and single ICI±chemo. Among the specific regimens, cadon-chemo achieved the most favorable OS and PFS. No significant OS differences were observed among the single ICI-chemo regimens. In PD-L1-positive subgroups, both dual-target ICI-chemo and single ICI-chemo significantly improved survival compared with chemotherapy, with cadon-chemo being most effective in CPS ≥ 10 and CPS ≥ 1, and SHR1701-chemo in CPS ≥ 5. In the CPS < 5 subgroup, dual-target ICI-chemo significantly improved OS, while single ICI-chemo showed a trend toward benefit. However, no ICI-based strategy demonstrated benefit in CPS < 1. CONCLUSIONS: Dual-target ICI-chemo appears to be the most effective first-line strategy for AGC based on current indirect evidence, surpassing single ICI-chemo and dual ICI-based regimens. These findings support personalized therapy selection but await confirmation by head‑to‑head trials. Future studies should address CPS < 1 and explore optimized combinations to enhance outcomes.
25 May 2026
Read appraisal →BMC cancer
Efficacy and risk analysis of monotherapy and dual immunotherapy in dMMR/MSI-H metastatic colorectal cancer: a meta-analysis based on randomized controlled trials
BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for metastatic colorectal cancer (mCRC) exhibiting DNA mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). However, the comparative efficacy and safety of monotherapy versus dual immunotherapy remain inadequately quantified. This meta-analysis aims to evaluate the benefits and risks of these strategies by quantitatively synthesizing data from randomized controlled trials (RCTs) to inform clinical decision-making. DESIGN: We systematically searched major databases (PubMed, Web of Science, Cochrane, Embase) from inception to September 2025 for relevant RCTs. Outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and adverse events. Statistical analyses were performed using RevMan 5.3 and Stata 18.0. RESULTS: Six RCTs (1,460 patients) were included. Pooled analysis showed that PD-1/PD-L1 monotherapy significantly improved ORR compared with chemotherapy (OR = 1.52, 95% CI: 1.02-2.27, P = 0.04), based on two RCTs (n = 429), and demonstrated a significantly lower incidence of grade ≥ 3 adverse events (OR = 0.14, 95% CI: 0.08-0.23, P < 0.00001; 2 studies). Dual immunotherapy with nivolumab plus ipilimumab significantly improved ORR versus monotherapy (OR = 1.77, 95% CI: 1.25-2.49, P = 0.001), based on one RCT (n = 582), with a significantly increased toxicity risk (OR = 1.73, 95% CI: 1.22-2.44, P = 0.002). For PFS, KEYNOTE-177 (HR = 0.59, 95% CI: 0.45-0.79) and CheckMate 8HW (HR = 0.62, 95% CI: 0.48-0.81) showed significant benefits, while SAMCO-PRODIGE 54 and CheckMate 9 × 8 did not demonstrate statistically significant PFS improvement. OS hazard ratios across four studies ranged from 0.74 to 1.03, with all 95% confidence intervals crossing 1.0, indicating no statistically significant survival benefit in any individual study. DOR was consistently longer with immunotherapy, with median not reached for pembrolizumab versus 10.6 months for chemotherapy in KEYNOTE-177. CONCLUSIONS: Effect estimates for PFS, OS, and DOR generally favored immunotherapy; however, confidence intervals were wide and statistical significance was not consistently observed across trials. PD-1/PD-L1 monotherapy demonstrated a favorable safety profile and a statistically significant improvement in ORR compared with chemotherapy (OR = 1.52, 95% CI: 1.02-2.27, P = 0.04). Dual immunotherapy significantly improved ORR compared with monotherapy (OR = 1.77, 95% CI: 1.25-2.49, P = 0.001), but this benefit was accompanied by significantly increased toxicity (OR = 1.73, 95% CI: 1.22-2.44, P = 0.002) and did not consistently translate into statistically significant PFS or OS benefits across trials. These findings highlight the need for personalized risk-benefit assessment. Future research should focus on biomarker-driven patient selection and strategies to overcome resistance.
23 May 2026
Read appraisal →Cell reports methods
A lightweight TcrLM model predicts T cell receptor and epitope binding specificity.
Immune responses depend on specific interactions between T cell receptors (TCRs) and peptides presented by antigen-presenting cells (APCs). The vast diversity of the TCR repertoire makes accurate prediction of TCR-antigen binding specificity highly challenging. Here, we present a lightweight, masked language model, tcrLM, to address this problem. We pretrain tcrLM on a large-scale TCR CDR3 sequence dataset and use the pretrained encoder to extract informative features for pTCR binding prediction. tcrLM achieves competitive performance on hold-out and external test sets and shows comparatively robust zero-shot generalization relative to several baselines on a large, unseen-COVID-19 peptide set. The model effectively captures biochemical properties and positional preferences of amino acids within TCR sequences. In an exploratory melanoma cohort, the predicted TCR-neoantigen binding scores correlate with immunotherapy response and clinical outcomes. These results highlight the potential of tcrLM for advancing immunotherapy and personalized medicine.
20 May 2026
Read appraisal →Cell reports methods
A network-based deep learning model integrating subclonal architecture for therapy response prediction in cancer
Predicting treatment response remains challenging in oncology, particularly given the growing diversity of therapeutic options. Despite efforts using gene expression signatures, or integrative multi-omics frameworks, robust and interpretable biomarkers remain limited. We present SubNetDL, a deep learning framework that integrates subclonal mutation profiles and protein-protein interaction networks via network propagation. Unlike condition-specific approaches, SubNetDL leverages somatic mutations alone and is applicable across diverse cancer types and treatment modalities. Applied to 10 TCGA cancer-drug combinations, SubNetDL achieved consistently strong performance (median area under the receiver operating characteristic curve [AUROC] = 0.74) and successfully generalized to two independent immunotherapy datasets (median AUROC = 0.77). Importantly, it identified candidate biomarker genes with treatment-specific relevance. SubNetDL prioritized genes that were not central in the network, highlighting its ability to capture context-specific patterns beyond traditional metrics. In conclusion, our approach offers a robust and interpretable framework for identifying predictive biomarkers and stratifying patients based on mutation profiles and network context.
20 May 2026
Read appraisal →Journal for immunotherapy of cancer
Clinical outcomes and spatial transcriptomic profiles of CD19/20 CAR-T therapy in relapsed or refractory B-cell non-Hodgkin's lymphoma
BACKGROUND: Relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma (B-NHL) remains a major therapeutic challenge despite CD19-directed chimeric antigen receptor (CAR) T-cell therapies, with treatment failure often driven by antigen escape and limited CAR-T persistence. Dual targeting of CD19 and CD20 may mitigate antigen loss. We conducted an expanded phase I/II study of bispecific CD19/20 CAR-T cells and incorporated spatially resolved single-cell transcriptomics to evaluate tumor-intrinsic and microenvironmental factors of clinical response. METHODS: Patients with R/R B-NHL received CD19/20 CAR-T cells following lymphodepletion. Efficacy, safety, CAR-T expansion/persistence, and B-cell reconstitution were assessed. Pretreatment tumor biopsies from five patients with divergent outcomes underwent spatial single-cell transcriptomic profiling. RESULTS: 32 patients were treated, including 24 with diffuse large B-cell lymphoma. Among 31 evaluable patients, the best overall response rate was 74%, including 58% achieving complete remission. Median progression-free and overall survival were 6.8 and 22.1 months, respectively. Response rates were higher in patients with normal lactate dehydrogenase. CAR-T expansion peaked on days 7-17, and persistence exceeded 500 days in long-term responders. Cytokine release syndrome occurred in 53% (12% grade ≥3) and immune effector cell-associated neurotoxicity syndrome in 9% (all grade 3), with no lasting deficits. Spatial profiling identified two dominant tumor architectures: (1) a B-cell-dominant phenotype, in which durable remission was associated with heightened apoptotic competence in malignant B cells, and (2) a fibroblast-enriched and monocyte/macrophage-enriched phenotype, in which response correlated with a chemokine-rich, T-cell-permissive microenvironment. CONCLUSIONS: Bispecific CD19/20 CAR-T therapy produced durable clinical activity with manageable toxicity. Spatial single-cell analysis reveals distinct tumor-intrinsic and microenvironmental features associated with CAR-T responsiveness, providing a spatially informed framework for understanding heterogeneous therapeutic outcomes. TRIAL REGISTRATION NUMBER: NCT04723914.
18 May 2026
Read appraisal →Signal transduction and targeted therapy
HILL: the efficacy and safety of hepatic arterial infusion chemotherapy with the FOLFOX regimen combined with lenvatinib and the PD-L1 inhibitor durvalumab in unresectable hepatocellular carcinoma: a prospective, single-arm, phase 2 clinical trial
Despite numerous available treatment options, the overall prognosis for patients with unresectable hepatocellular carcinoma (uHCC) remains poor. This study aimed to evaluate the efficacy and safety of combining hepatic arterial infusion chemotherapy with FOLFOX (FOLFOX-HAIC), lenvatinib, and the PD-L1 inhibitor durvalumab in this population, with all uHCC patients receiving the triple-combination regimen as initial therapy. The primary objective was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. From August 2021 to September 2023, 40 uHCC patients were enrolled, with a median follow-up of 23.1 months (95% confidence interval [CI], 19.0-23.8); 3 deaths and 12 disease progressions were recorded. The median PFS was 15.8 months (95% CI, 8.3-23.3) with a 6-month PFS rate of 77.5% (95% CI, 63-90%), and 1- and 2-year OS rates were 97.5% and 94.0%, respectively. Per modified RECIST criteria, ORR was 75.0% (9 CR/pCR, 21 PR) and DCR was 95.0% (8 SD); median time to response (TTR) was 2.2 months and median duration of response (DOR) was 10.4 months. Seven patients (17.5%) underwent R0 conversion surgery, 3 (42.9%) achieving pCR. Safety was favorable: 85.0% had grade 1-2 adverse events, with grade 3 elevated alanine aminotransferase and thrombocytopenia each occurring in 2 patients (5.0%). No grade 4 adverse events were observed. Collectively, the triple-combination therapy of FOLFOX-HAIC, lenvatinib, and durvalumab exhibits promising therapeutic efficacy, favorable disease control, and a well-tolerated safety profile, providing a potential new treatment option for patients with uHCC. Trial number: NCT04961918.
18 May 2026
Read appraisal →Clinical cancer research : an official journal of the American Association for Cancer Research
PET/CT-Guided Neoadjuvant Tislelizumab plus Chemotherapy/Chemoradiotherapy for Resectable Esophageal Squamous Cell Carcinoma: RATIONALE-213 Final Analysis
PURPOSE: The aim of this study is to assess positron emission tomography/computed tomography (PET/CT)-guided neoadjuvant treatment with tislelizumab plus chemotherapy/chemoradiotherapy in patients with resectable esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: RATIONALE-213, a multicenter, open-label, two-cohort phase II study, enrolled 70 patients with resectable ESCC. After one induction chemotherapy cycle, patients were categorized as PET responders (PET maximum standardized uptake value decrease ≥35%) or PET nonresponders (<35%). Subsequently, all patients received three cycles of tislelizumab 200 mg intravenously. In addition, PET responders received chemotherapy and PET nonresponders received chemoradiotherapy as neoadjuvant treatment followed by surgery. The primary endpoint was the pathologic complete response (pCR) rate. RESULTS: As of October 25, 2024 (median follow-up 25.5 months), pCR rates were 30% [95% confidence interval (CI), 11.9-54.3] in PET responders and 34.4% (95% CI, 18.6-53.2) in PET nonresponders. Higher pCR rates were associated with higher baseline programmed cell death ligand 1 tumor area positivity scores in both cohorts. One-year disease-free survival rates were 79% and 74.2%, and event-free survival rates were 87.1% and 67.8%, respectively. Any-grade and grade ≥3 treatment-related adverse events (TRAE) occurred in 93.3% and 50% of PET responders and 97.5% and 82.5% of PET nonresponders, with no new safety signals. The most common grade ≥3 TRAE was decreased neutrophil count (36.7% and 70%, respectively). CONCLUSIONS: Tislelizumab with chemotherapy/chemoradiotherapy as neoadjuvant treatment for resectable ESCC yielded promising pCR rates and favorable survival outcomes with a tolerable safety profile in both PET/CT-guided responders and PET nonresponders.
18 May 2026
Read appraisal →Journal of neuro-oncology
Should checkpoint inhibitors be reserved for biomarker-selected pediatric brain tumors?
PURPOSE: Pediatric brain tumors, including high-grade gliomas (HHG), medulloblastomas (MB), and ependymomas (EPN), are a leading cause of death in children. They are often immunologically "cold" with low tumor mutational burden (TMB) and very few tumor-infiltrating lymphocytes (TILs), which may limit the role of immune checkpoint inhibitors (ICI). METHODS: We performed a PRISMA‑guided systematic review of PubMed/MEDLINE, Embase, and Scopus from inception to September 17, 2025, for English-language studies of patients ≤ 21 years with primary CNS tumors treated with PD‑1/PD‑L1 or CTLA‑4 inhibitors. Eligible reports included prospective trials, retrospective series, and observational/case reports with extractable data on efficacy and/or toxicity. Of 479 records identified, 386 unique citations were screened, 127 underwent full‑text review, and 40 met inclusion criteria for qualitative synthesis. RESULTS: Prospective and institutional studies in biomarker-unselected diffuse midline glioma, high-grade glioma, medulloblastoma, and ependymoma showed low objective response rates (generally ≤ 6%), short median progression-free survival (1-3 months), and overall survival similar to historical controls, despite acceptable safety (grade ≥ 3 treatment-related adverse events ~ 15-25% with anti-PD-1 ± anti-CTLA-4). In contrast, across germline MMR-deficient and broader RRD/hypermutant cohorts, PD-1 blockade produced clinically meaningful and sometimes durable responses, including complete remissions in malignant glioma and approximate 2-year overall survival near 50%, often with delayed responses and pseudoprogression. Histology-specific profiling highlighted marked variation in immune contexture: pediatric gliomas segregate into immune "hot," "altered," and "cold" subtypes; medulloblastoma is largely PD-L1-low with prominent B7-H3 and myeloid programs; checkpoint expression is also observed in germ cell and selected sellar tumors. Evidence quality is limited by small, heterogeneous, predominantly non-comparative designs. CONCLUSION: ICIs show manageable safety but limited efficacy in unselected pediatric CNS tumors. Durable benefit is most evident in RRD/hypermutant biology and possibly PD-L1-high niches (e.g., some low-grade gliomas and CNS-GCT). Future trials should be biomarker-driven and pair ICIs with priming combinations (e.g., radiation, epigenetic modulators, metronomic chemotherapy) to convert "cold" tumors into responders.
18 May 2026
Read appraisal →Clinical cancer research : an official journal of the American Association for Cancer Research
Pembrolizumab Monotherapy in Sorafenib-Treated and Treatment-Naïve Advanced Hepatocellular Carcinoma: Long-Term Follow-up of the Open-Label, Phase II KEYNOTE-224 Study
PURPOSE: In the phase II KEYNOTE-224 study, pembrolizumab showed durable antitumor activity and manageable safety in participants with sorafenib-treated (cohort 1) or treatment-naïve (cohort 2) advanced hepatocellular carcinoma (HCC). We present data after a median follow-up of ∼7 years for cohort 1 and ∼5 years for cohort 2. PATIENTS AND METHODS: Adults with advanced HCC received pembrolizumab 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity for ≤35 cycles. The primary endpoint was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. RESULTS: Overall, 155 participants received ≥1 dose of pembrolizumab (cohort 1, n = 104; cohort 2, n = 51). The median follow-up was 83 months (range, 79.3-87.3) for cohort 1 and 58.8 months (range, 55.3-60.8) for cohort 2. The median OS was 13.2 months [95% confidence interval (CI), 9.7-15.3] and 16.9 months (95% CI, 8.3-23.1), respectively; 24- and 48-month OS rates were 31%/17% and 34%/20%, respectively. The median PFS was 4.9 months (95% CI, 3.5-7) and 4.3 months (95% CI, 2.1-7.8), respectively. Treatment-related adverse events occurred in 76 participants [73.1%; grade 3-5, 27 (26%)] in cohort 1 and 28 participants [54.9%; grade 3-5, 8 (15.7%)] in cohort 2. CONCLUSIONS: Pembrolizumab continued to show durable response and manageable safety in participants with advanced HCC with or without prior systemic therapy, with long-term effects on OS lasting beyond 48 months in some participants despite receiving study treatment for ≤2 years.
17 May 2026
Read appraisal →Clinical cancer research : an official journal of the American Association for Cancer Research
Allogeneic B7-H3-Targeted CAR Vδ1T-cell Therapy in Advanced Solid Tumors: A Phase I Study
PURPOSE: The aim of the study was to evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an "off-the-shelf" allogeneic B7-H3-targeted chimeric antigen receptor (CAR) Vδ1T-cell therapy, in patients with pretreated, advanced B7-H3-positive solid tumors. PATIENTS AND METHODS: In this first-in-human, phase I, dose-escalation study (NCT06372236), 10 patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5 × 108, 8 × 108, or 1 × 109 cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and antitumor efficacy. RESULTS: UTAA06 demonstrated a manageable safety profile; no GVHD was observed, and cytokine release syndrome was limited to two transient grade 1 events. A single dose-limiting toxicity (grade 3 pneumonitis) was reported in one patient at the 5 × 108 cell dose level. Although UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by RECIST v1.1 criteria was observed. Further analysis identified that the limited CAR T-cell persistence was likely driven by subclinical host-versus-graft rejection. CONCLUSIONS: This study provides clinical proof of concept for allogeneic B7-H3-targeted CAR-Vδ1T cells as a safe platform with low risk of GVHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.
17 May 2026
Read appraisal →Blood advances
Early mortality with bispecific antibody therapy in RRMM: an IMWG immunotherapy database real-world analysis
Recent therapeutic advances, including bispecific antibodies (bsAbs), have improved outcomes for patients with relapsed/refractory multiple myeloma (RRMM). However, early mortality (EM) remains a significant challenge, even in the era of novel immunotherapies. We conducted a multicenter, retrospective analysis of real-world patients with RRMM treated with commercial bsAbs to evaluate the incidence and causes of EM. Between May 2022 and June 2025, a total of 441 patients were treated across 7 countries. EM, defined as death within 12 months of therapy initiation, occurred in 148 patients (34%), with a median time from bsAb initiation to death of 2.87 months (interquartile range, 1.38-6.85). The leading cause of EM was progressive disease (72%), followed by infection (13%); regardless of the cause of death, 82% had active disease at the time of death. Our findings highlight that despite encouraging efficacy, EM remains high among real-world bsAb recipients, emphasizing the need for improved disease control strategies and supportive care interventions.
13 May 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
First-in-Human Study of IL15-Activated Cytokine-Induced Killer Cells After Allogeneic HCT Shows Durable Remission and Serotherapy-Associated Immune Reconstitution in Leukemia
PURPOSE: Patients with high-risk (HR) leukemia remain at substantial risk of early relapse, treatment-related toxicity, and poor survival, underscoring the need for effective relapse prevention therapies. To our knowledge, this first-in-human, disease burden-guided study evaluated the feasibility, safety, and efficacy of donor-derived allogeneic interleukin-15-activated cytokine-induced killer cells (IL15-CIK) combining T-cell and natural killer cell properties for post-transplant disease control. METHODS: In a prospective, multicenter phase I/II trial (EudraCT 2013-005446-11) and an identically designed pilot study, 53 adult and pediatric patients with HR leukemia received 56 courses of IL15-CIK monotherapy after human leukocyte antigen (HLA)-matched or HLA-mismatched transplantation. Treatment intent was categorized as consolidation (13%), preemptive (61%), or salvage (27%) with 169 infusions administered as a single dose (29%) or according to adaptable dose-escalation regimens (71%). RESULTS: Acute graft-versus-host disease (GVHD) grades 1-2 and grade 3 occurred in 27% and 4% of cases, respectively; no extensive chronic GVHD or treatment-related mortality was observed. IL15-CIK-associated adverse events were predominantly mild. Disease clearance, assessed by the cumulative incidence of complete molecular remission, peaked at day 700, reaching 74% in the preemptive and 13% in the salvage setting. The five-year progression-free survival was 50% overall and highest (69%) in pediatric acute myeloid leukemia. The five-year overall survival (OS) was 71% in the consolidation, 61% in the preemptive, and 20% in the salvage setting. Multivariable analysis demonstrated significantly lower relapse rates with Campath compared with ATG, superior OS in myeloid malignancies, and reduced IL15-CIK efficacy in advanced disease. The median follow-up was 7.3 years. CONCLUSION: IL15-CIK monotherapy is feasible and safe and demonstrates promising relapse-preventive activity after hematopoietic stem-cell transplantation. Clinical outcomes are strongly influenced by disease burden at treatment initiation and previous serotherapy, supporting optimized patient selection and timing in future post-transplant immunotherapeutic strategies.
13 May 2026
Read appraisal →Journal for immunotherapy of cancer
Safety and immunogenicity of a tri-antigen vaccine targeting IGFBP-2, HER2, and IGF-IR in participants with non-metastatic breast cancer
BACKGROUND: Ductal carcinoma in situ (DCIS) is a preinvasive form of breast cancer. Current treatment consists of surgery, radiation, and often systemic therapy exposing patients to unnecessary health risks. Vaccines targeting DCIS may be a way to intercept preinvasive lesions and prevent the development of invasive breast cancer. METHODS: We developed a Th1 selective multiantigen, polyepitope plasmid-DNA vaccine encoding segments of IGFBP-2, HER2, and IGF-IR, all antigens expressed in hormone receptor positive and negative DCIS. We then performed a Phase I study in participants with non-metastatic breast cancer with no evidence of disease. The primary objective was to assess the safety of 3 monthly intradermal doses (150, 300, or 600 µg) of the tri-antigen vaccine with granulocyte macrophage colony-stimulating factor as an adjuvant. 32 participants were enrolled, 10 per dose level. Toxicity evaluations occurred monthly with vaccination and at 1 and 6 months after the last vaccine. Blood was collected at baseline and at 1 and 6 months after the last immunization to assess cellular immune responses. Participants were followed annually for 5 years for long-term toxicity. RESULTS: There was no significant difference in adverse events (AEs) across dose levels and all related AEs were grades 1 or 2. All doses were immunogenic; responders included 70% of participants at the 150 µg dose level, 67% at the 300 µg dose, and 40% at the 600 µg dose level. All participants at the 300 µg dose retained significant Th1-antigen-specific immune response at 6 months after end of immunizations. T-cells derived from vaccine immunologic responders exhibited gene expression profiles that indicated an increased metabolic fitness as compared with immunologic non-responders. CONCLUSIONS: The tri-antigen vaccine appears safe and immunogenic. The intermediate dose (300 µg) was chosen as the Phase II dose due to the long-term persistence of immunity after vaccination. The vaccine will be studied in Phase II trials for the treatment of DCIS. TRIAL REGISTRATION NUMBER: NCT02780401.
11 May 2026
Read appraisal →Journal for immunotherapy of cancer
Phase II trial of combination radiation, hormone, and immunotherapy in grade group 5 prostate cancer
BACKGROUND: Grade group 5 (GG5) prostate cancer (PCa) carries a less favorable prognosis after standard-of-care (SOC) therapy, necessitating novel therapeutic approaches. High-dose rate brachytherapy (HDRBT) and androgen deprivation therapy (ADT) may modulate immune response in GG5 PCa, particularly in tumors with increased immune content. This study evaluated whether the addition of nivolumab to SOC was associated with improved disease control in patients with high-volume GG5 PCa, including those with oligometastatic disease. METHODS: In this non-randomized phase II trial, 31 patients with localized or oligometastatic GG5 PCa and >30% positive biopsy cores were evaluated between September 2018 and April 2021. Patients received four doses of nivolumab (240 mg every 2 weeks) beginning 4 weeks prior to HDRBT, alongside ADT, HDRBT, and external beam radiation. The primary endpoint was to evaluate whether the 2-year freedom from biochemical recurrence (FFBR) rate would exceed a prespecified historical control rate of 75%. RESULTS: Among the 31 patients, the median follow-up was 38.8 months (IQR 31.0-46.5 months). The addition of nivolumab to SOC RT with ADT was associated with a 2-year FFBR rate of 90.3% (95% CI 74.3% to 98.0%) (median FFBR not reached), exceeding the prespecified historical control rate of 75% (one-sided p value from binomial test=0.024). Definitive and probable nivolumab-related toxicity included 6.3% acute grade 2 and 6.3% acute grade 3 adverse events (AEs), with no grade 4+ AEs observed. A higher Decipher immunosuppression score at diagnosis correlated with early pathologic response (p=0.005) and was independently associated with time to metastatic failure (p=0.044). CONCLUSIONS: Nivolumab combined with SOC was associated with encouraging FFBR in this high-risk GG5 PCa population and may represent a promising therapeutic intensification strategy. The Decipher immunosuppression score may serve as a predictive biomarker for response. These findings warrant further investigation in randomized trials.
11 May 2026
Read appraisal →Signal transduction and targeted therapy
Total neoadjuvant chemotherapy combined with PD‑1 blockade and IL‑2 in MSS/pMMR locally advanced rectal cancer: short-term results of a prospective, single-arm phase II study
Neoadjuvant therapy has become a cornerstone in the management of locally advanced rectal cancer (LARC). In this single-arm, open-label phase II study, we evaluated the efficacy and safety of total neoadjuvant chemotherapy (TNT) using a CapOX regimen combined with a programmed cell death protein 1 (PD‑1) antibody (sintilimab) and interleukin‑2 (IL‑2) in patients with microsatellite stable (MSS)/defining proficient mismatch repair (pMMR) LARC. A total of 33 patients, aged 18-75 years, with rectal tumors located within 12 cm from the anal verge and staged as cT3/4N_anyM0 or cT_anyN⁺M0, were enrolled. Patients received a regimen consisting of oxaliplatin, sintilimab, capecitabine, and IL‑2 administered in a three‑week cycle, with response evaluations performed after every two cycles. Following six cycles of treatment, 33 patients underwent radical surgery, achieving a 100% R0 resection rate. The pathological complete response (pCR) rate was 42.4% (95% CI: 25.68-59.16%) while the remaining 19 patients (57.6%, 95% CI: 41.07-74.09%) were assessed as having a partial response. The tumor regression grades (TRG) were, TRG1: 3 cases (9.1%, 95% CI: 1.90-25.97%), TRG2: 14 cases (42.4%, 95% CI: 26.27-60.38%), and TRG3: 2 cases (6.1%, 95% CI: 0.73-20.37%), respectively. Surgical safety reported as no cases of grade B/C anastomotic leakage or bowel obstruction. Adverse events (AEs) were manageable, with a 21.2% incidence of grade 3 events and no grade IV/V events or treatment‑related deaths. With a median follow‑up of 25.5 weeks, no recurrences were observed. Analysis of blood and tissue samples from patients with different treatment outcomes revealed significant activation of CD8+ T cells, NK cells, and M1 macrophage subsets in the tumor microenvironment of patients achieving pCR. These compelling data demonstrate promising efficacy with a favorable safety profile in MSS/pMMR LARC. These findings warrant studies to validate this regimen as a novel treatment paradigm for rectal cancer. ClinicalTrials.gov registration: NCT06108596.
10 May 2026
Read appraisal →Journal for immunotherapy of cancer
Phase 2 trial of pTVG-HP ± pTVG-AR DNA vaccines and pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC)
BACKGROUND: We previously reported a trial using pembrolizumab with a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) in patients with metastatic castration-resistant prostate cancer (mCRPC). Favorable clinical outcomes were associated with T-cell activation, suggesting immune response to vaccination was critical. In the current trial, we evaluated whether immunization with two vaccines, to broaden the T-cell response to other cancer-associated antigens, would elicit greater anti-tumor efficacy. MATERIALS AND METHODS: 60 patients with mCRPC were treated with vaccine on days 1 and 8 of a 3 week cycle, with pembrolizumab given on day 1 of each cycle. Patients in Arm A (n=30) received pTVG-HP as the vaccine, and patients in Arm B (n=30) received pTVG-AR (encoding the ligand-binding domain of the androgen receptor) alternating with pTVG-HP every two cycles. After eight cycles (6 months), patients continued to receive pembrolizumab alone, with the option to receive further booster immunizations at prostate-specific antigen (PSA) progression. The primary objective was 6-month progression-free survival (PFS). Secondary objectives included safety, objective response rate, PSA response rate, overall survival (OS), and immunological evaluations. RESULTS: Overall median time to progression was 24 weeks (24 weeks Arm A, 24 weeks Arm B, p=0.80). The month 6 PFS rate was 51% in Arm A and 45% in Arm B. Median OS was 2.8 years (2.5 years Arm A, 3.7 years Arm B, p=0.16). 20% of patients in each arm experienced a PSA decline of >50%. 20 patients (n=8 Arm A, n=12 Arm B) had measurable disease, and 6/20 (30%) experienced a partial response. Eight patients received booster immunizations after 6 months, 3 of whom subsequently experienced a PSA decline. Three patients in Arm B experienced creatine kinase elevation with or without increased transaminases, which were not observed in Arm A. T cell immune responses to both antigens were detected in patients treated in Arm B. CONCLUSIONS: Treatment with DNA vaccines and pembrolizumab demonstrated anti-tumor activity in terms of PSA declines and objective responses. The addition of pTVG-AR did not significantly increase measures of clinical efficacy; however, it was associated with a slight increase in toxicity to tissues that also express AR. TRIAL REGISTRATION NUMBER: NCT04090528.
27 Apr 2026
Read appraisal →Cancer immunology, immunotherapy : CII
Envafolimab combined with lenvatinib and albumin-bound paclitaxel in previously treated advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma: a prospective, phase II, multi-cohort trial
BACKGROUND: This single-center, open-label, exploratory trial aimed to investigate the efficacy and safety of envafolimab combined with lenvatinib and chemotherapy in previous treated advanced G/GEJ adenocarcinoma. METHODS: Eligible patients with HER2-negative, microsatellite stable (MSS) advanced G/GEJ adenocarcinoma who had progressed after first-line treatment were enrolled in this phase II trial. Patients without previously receiving PD-1/PD-L1 inhibitors were enrolled in Group A, and those who progressed on the first-line PD-1 inhibitors were included in Group B. Patients in both groups received envafolimab (200 mg, subcutaneous injection (sc), days 1 and 15, Q4W) combined with lenvatinib and albumin-bound paclitaxel (100 mg/m2, IV, days 1, 8 and 15, Q4W, up to 6 cycles) until disease progression, unacceptable toxicity, or refusal of continuation. The primary endpoint was objective response rate (ORR). RESULTS: A total of 30 patients were included for safety and efficacy analysis. As of data cutoff (Sep 14, 2024), the median follow-up was 17.0 months (IQR: 8.0-18.8) in Group A. The ORR was 60.0%, and the DCR was 100.0%. The mPFS was 8.2 months (95% CI 6.1-10.4) with mOS of 14.8 months (95% CI 7.4-22.2). With a median follow-up of 9.0 months (IQR: 6.1-16.2) in Group B, the ORR was 46.7%, and the DCR was 100.0%. The mPFS was 5.9 months (95% CI 3.8-8.1), and the mOS was 11.5 months (95% CI 3.1-19.9). The overall incidence of adverse events (AEs) of any grade was 100%. While Group A showed numerically better outcomes than Group B, there was no statistically significant difference in PFS (P = 0.629) or OS (P = 0.873) between the two groups. CONCLUSIONS: Second-line envafolimab-based combination therapy demonstrated promising effects in previously treated advanced GC, particularly in those who have not previously received ICIs.
23 Apr 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Nivolumab ± Ipilimumab in Patients With Pretreated Advanced Neuroendocrine Carcinoma: The GCO-001 NIPINEC Randomized Phase II Trial
PURPOSE: There is no standard second-line therapy for gastroenteropancreatic (GEP) and lung large-cell neuroendocrine carcinoma (NEC) after the failure of platinum-based chemotherapy. This study aimed to investigate the efficacy of nivolumab ± ipilimumab. METHODS: The GCO-001-NIPINEC (ClinicalTrials.gov identifier: NCT03591731) trial was a noncomparative, open-label, phase II trial. The main inclusion criteria were age ≥18 years, performance status (PS) ≤2, advanced large- and small-cell GEP-NEC and large-cell lung NEC, and second- or third-line treatment for NECs refractory to platinum-based chemotherapy. Patients were randomly assigned (1:1) and stratified by age and PS to receive nivolumab (3 mg/kg/once every 2 weeks) ± ipilimumab (1 mg/kg/once every 6 weeks) for 2 years or until progression or unacceptable toxicity. The primary end point was objective response rate (ORR) at 8 weeks, assessed by investigators. RESULTS: A total of 185 patients (91 in the nivolumab arm and 94 in the nivolumab-ipilimumab arm) were enrolled between December 2018 and March 2021; 169 were analyzed (median age of 64.5 years, 71% male, 91% PS 0-1). The main primary tumor locations were lungs (50%), colorectal (15%), gastroesophageal (14%), and pancreatic (13%) regions. The ORR at 8 weeks was 7.2% (95% CI, 2.7 to 15.1]) in the nivolumab arm and 14.0% (95% CI, 7.4 to 23.1) in the nivolumab-ipilimumab arm. The best ORR was 9.6% and 20.9%, respectively, whereas the median progression-free and overall survival were approximately 2 months and 6 months in both arms. One treatment-related death occurred, in the nivolumab arm. The grade 3-4 adverse events (≥5%) were asthenia (13%), gamma-glutamyl transferase increase (10%), alkaline phosphatase increase (9%), dyspnea (7%), and anemia (6%) in the nivolumab-ipilimumab arm. CONCLUSION: Nivolumab-ipilimumab could be a second-/third-line treatment option for patients with NECs. However, given the limited magnitude of benefit, studies are warranted to evaluate its use earlier and/or associated with chemotherapy.
21 Apr 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
CALYPSO: Final Results of Savolitinib and Durvalumab Combination in Metastatic Papillary Renal Cancer
PURPOSE: The CALYPSO study demonstrated activity of savolitinib and durvalumab in MET-driven papillary renal cancer (PRC). We report final efficacy outcomes and exploratory circulating tumor DNA (ctDNA) biomarker analysis. METHODS: This single-arm phase II study evaluated savolitinib and durvalumab in treatment-naïve or pretreated PRC. End points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). FoundationOne CDx assessed DNA alterations and MET/PD-L1 or MET/tumor mutational burden (TMB) copositivity. ctDNA collected at baseline and on treatment was correlated with outcomes. RESULTS: At 41-months median follow-up, ORR was 34% (95% CI, 20.0 to 51.0) in the intention-to-treat (ITT) population (N = 41) and 53% (95% CI, 28.0 to 77.0) in MET-driven patients (n = 17). Median PFS was 6.5 (95% CI, 2.7 to 12.0) versus 13.9 months (95% CI, 2.9 to 23.8), and OS was 18.3 (95% CI, 7.3 to 30.7) versus 27.4 months (95% CI, 9.3 to 37.4), in the ITT population and the MET-driven population, respectively. PD-L1 (66% positive) and TMB (median 2.5 mut/Mb) status did not correlate with response. Baseline ctDNA positivity (10/21) correlated with shorter OS (median 7.3 v 33.3 months), while ctDNA clearance and mean variant allele frequency reduction correlated with improved OS (median 31.3 v 7.2 and 31.3 v 15.5 months, respectively). CONCLUSION: Savolitinib plus durvalumab shows OS in MET-driven PRC, supporting the ongoing SAMETA RIII trial (ClinicalTrials.gov identifier: NCT05043090). ctDNA may be a useful predictive biomarker.
21 Apr 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Efficacy and Safety of Ultra-Low-Dose Immunotherapy in Relapsed Refractory Solid Tumors: Phase III Superiority Randomized Trial (DELII)
PURPOSE: Immune checkpoint inhibitors (ICIs) achieve sufficient receptor occupancy at much lower than standard approved doses. We hypothesized that ultra-low-dose nivolumab would retain clinical efficacy. PATIENTS AND METHODS: In this phase III randomized superiority trial, patients with advanced solid tumors (Eastern Cooperative Oncology Group 0-1) and progression on ≥1 prior line of systemic therapy were randomly assigned 1:1 to ultra-low-dose nivolumab (20 mg intravenously once every 2 weeks) or standard chemotherapy (docetaxel or paclitaxel, as per tumor type). Treatment continued until progression or intolerable toxicity. The primary end point was overall survival (OS). RESULTS: From June 2020 to February 2024, we enrolled 500 patients: 250 per arm; 52% had head and neck and 36% lung cancers. The median number of prior lines of therapy was 1 (range, 1-8); 29% had received ≥2 prior lines. Median OS was significantly longer with ultra-low-dose nivolumab: 5.88 months (95% CI, 4.99 to 7.13) versus 4.70 months (95% CI, 3.91 to 5.65; hazard ratio [HR], 0.80 [95% CI, 0.66 to 0.97]; P = .022). One-year OS was 27.3% versus 16.9%. Median progression-free survival was similar: 2.04 months (95% CI, 2.00 to 2.10) with ultra-low-dose nivolumab and 2.09 months (95% CI, 2.04 to 2.17) with chemotherapy (HR, 1.03 [95% CI, 0.86 to 1.23]; P = .77). Grade ≥3 treatment-related adverse events were less frequent with ultra-low-dose nivolumab (42.5% v 60.8%; P < .001). Quality of life (QoL) was significantly better with ultra-low-dose nivolumab. CONCLUSION: Ultra-low-dose nivolumab significantly improves OS versus chemotherapy in pretreated solid tumors, with fewer severe toxicities and better QoL. These findings support re-evaluation of ICI dosing strategies and may enhance global access.
21 Apr 2026
Read appraisal →mAbs
Multi-modal feature learning to prioritize ADCs with favorable half-life in mice
Favorable pharmacokinetic (PK) properties of antibody-drug conjugates (ADCs) enable higher systemic exposure and are associated with improved clinical efficacy, yet ADC PK optimization remains largely empirical and resource-intensive. We developed an in silico framework to predict half-lives of monoclonal antibodies (mAbs) and ADCs in C57BL/6 mice using multi-modal feature learning. To address structural complexity of ADCs, each compound was deconvoluted into three components: (1) antibody features represented using sequence descriptors, AlphaFold-based structural properties, or protein language model (PLM) embeddings; (2) conjugation-related features, including drug-to-antibody ratio and conjugation sites; and (3) physicochemical properties of linker-payloads. XGBoost models were trained using experimental half-life data from 118 mAbs and ADCs. Structure-based and PLM approaches achieved strong cross-validation (Pearson's r = 0.76), outperforming sequence-only models. In temporal validation of 32 mAbs and ADCs, the structure-based models demonstrated robust generalization (r = 0.79). PLM embeddings achieved comparable rank ordering (Spearman's ρ up to 0.81 for ESM-2), but lower quantitative accuracy relative to structure-based models. Overall, our study presents a scalable machine learning framework for early PK screening of mAbs and ADCs prior to synthesis and in vivo testing.
19 Apr 2026
Read appraisal →Clinical cancer research : an official journal of the American Association for Cancer Research
Neoadjuvant Nivolumab with or without Ipilimumab for Cisplatin-Ineligible Patients with Muscle-Invasive Bladder Cancer
PURPOSE: Many patients with muscle-invasive bladder cancer (MIBC) are ineligible for cisplatin-based therapy. We conducted a phase II trial of neoadjuvant nivolumab ± ipilimumab for cisplatin-ineligible patients. PATIENTS AND METHODS: Patients with MIBC were enrolled in two consecutive cohorts: (i) nivolumab alone and (ii) ipilimumab/nivolumab. A third cohort with alternative dosing was planned. The primary endpoint was eligibility for cystectomy ≤60 days after last treatment. Correlative analyses were performed, with the PURE-01 trial used as an independent dataset. RESULTS: Fifteen patients enrolled onto each cohort. In cohorts 1 and 2, 12 of 15 and eight of 15 were eligible for cystectomy within 60 days, respectively. Due to cohort 2's failure to meet the primary endpoint, cohort 3 was not initiated. With nivolumab alone, four patients achieved <ypT2ypN0 (26%), with two pathologic complete responses (pCR; 13%). With ipilimumab/nivolumab, three achieved <ypT2ypN0 (20%), with one pCR (7%). One patient after nivolumab and two after ipilimumab/nivolumab had durable clinical complete responses (CR) without cystectomy. Twelve-month recurrence-free survival (RFS) was 79% with nivolumab [95% confidence interval (CI), 61-100] and 61% with ipilimumab/nivolumab (95% CI, 39-95). Sequencing analyses suggest that NCOR1 alterations may be associated with improved clinical outcomes. Gene expression profiling indicated a potential association between tumor-infiltrating immune cells and longer RFS (log-rank P = 0.18); this was also observed in PURE-01 (P = 0.022). CONCLUSIONS: Among cisplatin-ineligible patients with MIBC, nivolumab alone was well tolerated. Ipilimumab/nivolumab caused toxicity that delayed cystectomy. Cases of progression before cystectomy indicated insufficient efficacy of pure neoadjuvant immunotherapy for unselected patients. Despite low response rates, some patients experienced sustained clinical CR without cystectomy.
16 Apr 2026
Read appraisal →Cancer immunology, immunotherapy : CII
Hematological toxicities and thrombosis risk associated with immune checkpoint inhibitors: a pharmacovigilance study from 2014 to 2024
BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes in a wide range of cancers but may also induce hematological toxicities and thrombosis risk. This study comprehensively evaluated hematological and thrombotic adverse events (AEs) associated with ICIs in real-world settings using the FDA Adverse Event Reporting System (FAERS) database, aiming to characterize their clinical features. METHODS: Data were extracted from the FAERS database (Q1 2014 to Q4 2024) for disproportionality analysis. AEs were classified using the Medical Dictionary for Regulatory Activities (MedDRA). Associations between ICIs and hematological/thrombotic AEs were assessed via the reporting odds ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) methods. Clinical characteristics of affected patients were analyzed, and time-to-onset across ICI regimens was further evaluated. RESULTS: We identified 14,753 ICI-associated hematological toxicities and thrombotic events. Among reports with available sex information, a higher reporting frequency was observed in men (50.90%) than in women (40.11%). The most frequent AEs were anemia (2963 cases, 16.62%), thrombocytopenia (1961, 11.00%), febrile neutropenia (1935, 10.85%), neutropenia (1392, 7.81%), myelosuppression (979, 5.49%), pancytopenia (739, 4.14%), lymphadenopathy (475, 2.66%), disseminated intravascular coagulation (DIC; 468, 2.62%), leukopenia (468, 2.62%), and deep vein thrombosis (DVT; 213, 1.19%). The median time-to-onset for ICI monotherapy-associated AEs was 28 days (IQR 11-79), with 78.22% occurring within 3 months. Notably, DIC and DVT had the highest mortality proportion among the top 10 AEs. CONCLUSION: Hematological and thrombotic AEs associated with ICI therapy show notable reporting frequencies in FAERS. Combination regimens demonstrated stronger reporting signals for certain events. These AEs frequently showed early reporting and notable mortality proportions, highlighting the importance of clinical vigilance. Further studies are needed to confirm these findings.
16 Apr 2026
Read appraisal →Cancer cell
HS-20093, a B7-H3-targeted antibody-drug conjugate in lung cancer: Results from the ARTEMIS-001 phase 1a/b trial
This phase 1a/b study (NCT05276609) evaluated the safety, pharmacokinetics, and efficacy of B7-H3-targeted antibody-drug conjugate HS-20093 (GSK5764227) in 306 patients with previously treated advanced solid tumors. In phase 1a, 12.0 mg/kg was established as the maximum tolerated dose. Among 236 lung cancer patients who received 8.0 or 10.0 mg/kg HS-20093, the most frequent grade ≥3 treatment-related adverse events (AEs) included decreased neutrophil (25.5% vs. 50.5%) and white blood cell counts (19.7% vs. 42.4%), and anemia (16.8% vs. 34.3%), respectively. Treatment-related interstitial lung disease and AEs leading to death occurred in 3.4% and 3.8% of patients, respectively. Among response-evaluable patients, the confirmed objective response rate was 52.3% (95% CI: 39.5, 64.9) for extensive-stage SCLC (ES-SCLC, N = 65) and 22.4% (95% CI: 16.0, 29.8) for non-small cell lung cancer (NSCLC, N = 152) patients, with comparable rates between 8.0 mg/kg and 10.0 mg/kg dose cohorts across both groups. These results support further development of HS-20093, with 8.0 mg/kg selected for phase 3 trials.
16 Apr 2026
Read appraisal →Blood advances
Zamtocabtagene autoleucel in relapsed/refractory B-NHL: 5-year follow-up of a CD20/19 tandem CAR T-cell phase 1 trial
Emerging long-term data indicate relapse rates of >50% after CD19-redirected chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). To reduce selective pressure on the CD19 antigen, we conducted a first-in-human phase 1 clinical trial of zamtocabtagene autoleucel (zamto-cel), a noncryopreserved tandem CD20-CD19-directed CAR T-cell therapy. Two predefined dose levels (dose level 1 [DL1], 1 × 106 and DL2, 2.5 × 106 CAR+ T cells per kg bodyweight) were applied. The primary end point (EP) was the maximum tolerated dose (MTD). Secondary EPs included adverse events, best overall response (BOR), and biomarker assessments. A total of 12 patients, 6 patients per DL, were treated. No dose-limiting toxicity and no cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome of grade ≥3 were observed. Thus, MTD was not reached. The BOR by investigator assessment was 75%, with 5 of 12 patients (42%) achieving complete remission (CR) until month 12 with no relapse in clinical evaluation up to 5 years after infusion. CR was associated with a higher mean maximum observed concentration of zamto-cel and detection of zamto-cel beyond month 6. Additional product characterization revealed increased expression of CD27 and CD127 along with increased expansion of CAR+ central memory T cells in patients with CR, facilitating persistence and improved outcomes in R/R B-NHL treated with zamto-cel. Based on the promising risk-to-benefit ratio, evaluation of zamto-cel at DL2 is ongoing in pivotal phase 2 clinical trials for patients with R/R aggressive B-NHL. This trial was registered at www.ClinicalTrials.gov as NCT03870945.
15 Apr 2026
Read appraisal →Blood advances
Treatment and survival outcomes for patients with follicular lymphoma and POD24: a systematic review and meta-analysis
Follicular lymphoma with progression of disease within 24 months (POD24) is associated with poor prognosis and represents clinical challenges. Therefore, we performed a systematic review and pooled analysis of patients with POD24. Twenty-one trials involving 1242 participants were included, assessing the overall response rate (ORR), complete response (CR), duration of response, and progression-free survival. In some trials, we compared pooled response rates between POD24 and non-POD24 populations with the same treatment regimen. Four trials evaluated chimeric antigen receptor (CAR) T-cell therapy in patients with POD24. Pooled analysis showed an ORR of 91.2% (95% confidence interval [CI], 83.7-98.7) with significant heterogeneity (P = .0414; I2 = 68.61%) and a CR of 75.7% (95% CI, 55.1-96.4) with significant heterogeneity (P< .0001; I2 = 93.99%). The specific response rates for different bispecific antibodies in POD24 were pooled analysis, the ORR was 81.6% (95% CI, 75.9-87.3) with no heterogeneity (P = .6958; I2 = 0%), and the CR was 65.7% (95% CI, 57.1-74.3) with moderate heterogeneity (P = .2148; I2 = 34.99%). For anti-CD19 antibody-drug conjugates (ADCs)/monoclonal antibodies (mAbs), the ORR and CR rate for loncastuximab plus rituximab and tafasitamab plus R2 (lenalidomide + rituximab) were 100% and 79.3%, and 87.5% and 43.2%, respectively. Phosphatidylinositol 3-kinase inhibitors and anti-CD20 mAb-containing regimens were also analyzed in pooled analyses. Our results demonstrated that anti-CD19 CAR T-cell therapy achieved the highest CR rate. Additionally, bispecific antibodies, anti-CD19 ADCs/mAbs, and the combination of lenalidomide with obinutuzumab or rituximab also exhibited excellent efficacy. Notably, lenalidomide plus obinutuzumab showed superior efficacy compared with R2.
15 Apr 2026
Read appraisal →Vaccine
The safety and efficacy of in situ vaccine FOLactis for advanced hepatic malignancies.
BACKGROUND: Recent years have witnessed the emergence of a novel research direction in the field of tumor vaccines. An in situ vaccine known as FOLactis, comprised of genetically engineered Lactococcus lactis expressing a fusion protein of Fms-like tyrosine kinase 3 ligand (Flt3L) and co-stimulator OX40 ligand (OX40L), was developed by the Oncology Centre of Nanjing Drum Tower Hospital. The present study was designed to evaluate the efficacy and safety of combination therapy based on intratumoral injection of the in situ vaccine FOLactis and intravenous PD-1 monoclonal antibody in combination with immunoradiotherapy or low-dose chemotherapy in the treatment of advanced hepatic malignancies. METHODS: In this exploratory clinical study, patients with advanced hepatic malignancies were enrolled and randomly assigned to Group A and Group B, corresponding to different treatment regimens. The treatment regimen in Group A consisted of the in situ vaccine FOLactis combined with a PD-1 monoclonal antibody and immunoradiotherapy (5Gy/fraction×3fractions). In contrast, the regimen in Group B included the in situ vaccine FOLactis, a PD-1 monoclonal antibody, and low-dose chemotherapy (cisplatin plus vincristine). All treatments were given in 21-day cycles. The primary observation indicator of the study was the objective response rate (ORR) as defined by RECIST v1.1. Secondary observation indicators included the disease control rate (DCR) and the incidence of adverse events. RESULTS: A total of 18 eligible patients were included in the study. In Group A, the ORR and DCR for targeted lesions were 33.3%(95%CI:12.1-64.6%) and 77.8%(95%CI:45.3-96.1%), while the ORR and DCR for non-targeted lesions were 22.2%(95%CI:3.9-54.7%) and 66.7%(95%CI:35.4-87.9%), respectively. Targeted and non-targeted lesions in Group B did not reduce significantly, and their respective DCRs were 66.7%(95%CI:35.4-87.9%) and 22.2%(95%CI:3.9-54.7%). Patients in Group A experienced no significant adverse events. Patients in Group B experienced grade 1-2 hyperthermia as a side effect. CONCLUSIONS: The combination therapy based on the in situ vaccine FOLactis and intravenous PD-1 monoclonal antibody showed a certain degree of anti-tumor effect, and was safe and well tolerated in patients with advanced hepatic malignancies. TRIAL REGISTRATION: The Ethics Committee of Nanjing Drum Tower Hospital approved this study (approval number 2022-101-01). The associated trial is registered at ChiCTR.gov.cn (ChiCTR2200060660).
12 Apr 2026
Read appraisal →Cancer immunology, immunotherapy : CII
A phase I, single-arm, open-label, dose-escalation, multicenter study of SAR445419, an off-the-shelf, ex vivo expanded allogeneic natural killer cell product, in participants with relapsed or refractory acute myeloid leukemia
BACKGROUND: SAR445419 is an investigational, off-the-shelf, allogeneic NK cell therapy derived from donor peripheral blood mononuclear cells and expanded ex vivo using PM21 particles. METHODS: This multicenter, Phase 1, dose-escalation study (NCT05712278) evaluated optimal dose(s), safety, and tolerability of SAR445419 in adults (aged ≥ 18 years) with relapsed/refractory acute myeloid leukemia (R/R AML). Following lymphodepleting chemotherapy (fludarabine 30 mg/m2/day and cytarabine 2 g/m2/day for 5 days), participants received six intravenous SAR445419 (1 × 109 and 3 × 109 NK cells/dose) doses, starting with the lower dose. The primary endpoint was the incidence of dose-limiting toxicities (DLTs), and key secondary endpoints included adverse events (AEs), hematological recovery, hematopoietic stem cell transplantation, and response rate. RESULTS: Of the 12 planned participants, 7 patients were enrolled, of whom 6 received SAR445419 before sponsor decided early study termination for reasons unrelated to safety or efficacy. No DLTs were observed. All participants experienced treatment-emergent adverse events (TEAEs); six had grade ≥ 3 TEAEs; and four had serious adverse events (SAEs). Two SAR445419-related SAEs (infusion-related reactions: both grade 2) were managed with supportive care. All participants experienced grade 3 anemia and grade 4 thrombocytopenia and neutropenia. Five deaths were reported, all due to disease progression, none related to SAR445419. No clinical responses were observed. CONCLUSIONS: This study demonstrated the overall safety of off-the-shelf ex vivo expanded allogeneic NK cells in patients with R/R AML. The successful manufacturing and distribution support the feasibility of donor-derived off-the-shelf NK cells in a clinical setting. Further investigations are required to improve the clinical efficiency of NK cells.
12 Apr 2026
Read appraisal →Journal for immunotherapy of cancer
Anti-TIM-3 antibody TQB2618 in combination with penpulimab in relapsed or refractory classic Hodgkin lymphoma previously treated with PD-1/PD-L1 therapy: a multicenter, open-label, single-arm, phase Ib clinical trial
BACKGROUND: Immune checkpoint inhibitors achieve high response rates in relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL), but few treatment options are available for patients who experience failure after PD-1/PD-L1 blockade. T cell immunoglobulin and mucin-domain containing-3, a key mediator of immune escape from PD-1/PD-L1 inhibition, is targeted by TQB2618, a humanized IgG4 monoclonal antibody. This phase Ib study aimed to evaluate the safety and efficacy of TQB2618 in combination with the anti-PD-1 antibody penpulimab in patients with r/r cHL. METHODS: This multicenter phase 1b study was conducted from June 2022 to September 2024 at 12 sites in China (NCT05400876). The study included a dose-escalation phase in which patients with r/r lymphoma received TQB2618 (600 or 1200 mg, every 3 weeks, Q3W) plus penpulimab (200 mg, Q3W) to evaluate dose-limiting toxicities and determine the recommended phase II dose (RP2D). The subsequent dose-expansion phase enrolled patients with r/r cHL previously treated with PD-1/PD-L1 inhibitors to assess the objective response rate (ORR). RESULTS: 10 patients with r/r lymphoma were enrolled in the dose-escalation phase, and TQB2618 (600 mg, Q3W) plus penpulimab (200 mg, Q3W) was selected as the RP2D. In the dose-expansion phase, 18 additional patients with r/r cHL previously treated with PD-1/PD-L1 inhibitors were enrolled. Among the total 21 r/r cHL patients, the median age was 32 years (range, 22-65), and 12 (57%) were male. The ORR was 52%, including 1 complete response and 10 partial responses. Treatment-related adverse events (TRAEs) occurred in 18 patients (86%), with grade ≥3 TRAEs in 5 (24%). The most common TRAEs (≥20%) were platelet count decreased (24%), anemia (24%), and aspartate aminotransferase increased (24%). As of the data cut-off in December 2024, the median follow-up was 14.1 months, the median duration of response and the median overall survival had not yet been reached. CONCLUSIONS: TQB2618 in combination with penpulimab was well tolerated and demonstrated promising efficacy in patients with cHL who had failed prior anti-PD-1/PD-L1 therapy, supporting its potential as a therapeutic option for this difficult-to-treat population. TRIAL REGISTRATION NUMBER: NCT05400876.
12 Apr 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Development of a Classifier for Metabolic Subtypes of Nasopharyngeal Carcinoma to Guide Personalized Immunotherapy Strategies: Biomarker Analysis of the Phase III CONTINUUM and DIPPER Trials
PURPOSE: Personalized immunotherapy strategies are urgently needed for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We aim to identify biomarkers predictive of immunotherapy benefits, using data from the phase III CONTINUUM (ClinicalTrials.gov identifier: NCT03700476) and DIPPER (ClinicalTrials.gov identifier: NCT03427827) randomized clinical trials. PATIENTS AND METHODS: Tumor samples from 407 patients in the CONTINUUM (discovery cohort) and DIPPER (validation cohort) trials were subjected to RNA sequencing. In the discovery cohort, metabolic gene-based consensus clustering was performed to determine subtypes. A machine learning-based classifier was subsequently developed in the discovery cohort and then applied to the validation cohort to assign metabolic subtypes. Gene set enrichment analyses were used to characterize the biological features of each metabolic subtype. The clinical end point was event-free survival (EFS). RESULTS: In the discovery cohort, three metabolic subtypes were identified with distinct tumor-intrinsic and immune features as well as differential EFS benefits from adding anti-PD-1 to chemoradiotherapy (CRT). Specifically, the MS1 subtype exhibited a significant improvement in 3-year EFS in the anti-PD-1 plus CRT arm compared with the CRT-alone arm (3-year EFS, 90.2% v 69.6%; hazard ratio, 0.27 [95% CI, 0.11 to 0.67]), whereas MS2 (3-year EFS, 94.1% v 93.8%) and MS3 subtypes (3-year EFS, 75.0% v 75.0%) derived no significant survival benefit. The subtype features were preserved in the validation cohort, with consistent prognostic and predictive value. A pooled analysis of both cohorts demonstrated the significant interaction between metabolic subtypes and the treatment effect (Pinteraction = 0.0074). CONCLUSION: In this biomarker study, we defined metabolic subtypes of NPC that predicted the EFS benefit from immunotherapy. This novel molecular classification provides a promising predictive biomarker for personalized treatment decision for patients with locoregionally advanced NPC.
11 Apr 2026
Read appraisal →Journal for immunotherapy of cancer
Simlukafusp alfa (FAP-IL2v) plus atezolizumab with or without bevacizumab in unresectable, metastatic renal cell carcinoma: a randomized, open-label phase Ib study
BACKGROUND: Simlukafusp alfa (FAP-IL2v) was engineered to preferentially activate CD8+ T and natural killer (NK) cells in tumor microenvironments overexpressing fibroblast activation protein (FAP). Checkpoint inhibitors combined with antiangiogenic agents are standard therapy for metastatic renal cell carcinoma (mRCC), which overexpresses FAP. Here, we explored the efficacy, safety, and pharmacodynamic effects of FAP-IL2v in combination with atezolizumab with or without bevacizumab in patients with mRCC. METHODS: Patients with treatment-naïve or pretreated clear cell and/or sarcomatoid mRCC were eligible. Dose escalation explored FAP-IL2v every 2 weeks (Q2W) with atezolizumab Q2W (doublet, arm A), and with atezolizumab and bevacizumab Q2W (triplet, arm B) in patients treated with up to one prior systemic therapy. Dose extension explored in untreated patients the recommended FAP-IL2v dose administered Q2W (doublet, arm A; and triplet, arm B) or 3-weekly (doublet, arm C; and triplet, arm D). Primary objectives were the recommended FAP-IL2v dose and antitumor activity. Secondary objectives included safety, pharmacodynamics, and exploratory biomarkers in peripheral blood and paired biopsies. RESULTS: By the data cut-off date (31 August, 2021), 66 patients were enrolled. The median duration of treatment was 11.0 months. Objective response rates (ORRs) were 25% for the doublet and 47% for the triplet, and median progression-free survival was 6.3 and 18.3 months, respectively. Safety profiles were consistent with the individual drugs, including expected interleukin-2 (IL-2) class-specific adverse events (AEs). Two deaths were recorded caused by AEs related to study treatment (acute kidney injury, n=1; pancytopenia, n=1). Expansion and activation of NK and T cells, but not regulatory T cells, was observed in peripheral blood, leading to increased tumor infiltration and inflammation in paired biopsies. The addition of bevacizumab led to a reduced angiogenesis signature score and reduced vessel density. CONCLUSION: The combination of FAP-IL2v plus atezolizumab with or without bevacizumab was consistent with the known safety profile of the individual drugs. The maximum tolerated dose was not reached, with a recommended FAP-IL2v dose of 10 mg. ORR was higher among patients receiving the triplet therapy compared with the doublet. Pharmacodynamic results were consistent with the mechanism of action of IL-2, supporting further research in this field.
11 Apr 2026
Read appraisal →Journal for immunotherapy of cancer
Deep learning-driven recognition of panoramic tumor microenvironment features in H&E sections and its application
The tumor microenvironment (TME), composed of tumor cells together with stromal cells, immune cells, vascular networks, and other components, constitutes a complex ecosystem that plays a decisive role in tumor initiation, progression, metastasis and therapeutic response. Traditional pathological diagnosis mainly relies on pathologists manually examining H&E-stained tissue sections under the microscope, a method that not only suffers from substantial interobserver variability but also has relatively low analytical efficiency. With the rapid development of computational pathology, the integration of whole-slide imaging technology and deep learning algorithms has provided powerful tools for characterizing tumor microenvironment. These techniques enable automated characterization of cellular, spatial and molecular heterogeneity within the tumor microenvironment, providing integrated insights that advance precision diagnostics and improve prediction of therapeutic response and patient outcomes. Based on a comprehensive review of existing research, this paper highlights recent advances in deep learning-driven recognition of panoramic TME features from H&E slides and their clinical applications and further discusses both the translational potential and current limitations of this technology in oncology research and clinical applications.
11 Apr 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Phase II Study of BCMA Chimeric Antigen Receptor T-Cell Therapy in Patients With Newly Diagnosed Multiple Myeloma Ineligible for or Not Proceeding to Autologous Stem-Cell Transplantation (CAREMM-001)
PURPOSE: Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for or not proceeding to autologous stem-cell transplantation (ASCT)-often because of age or frailty-have limited opportunities to receive multiple effective lines of therapy, underscoring the need for novel frontline strategies. METHODS: In this phase II, open-label, single-arm trial (ClinicalTrials.gov identifier: NCT05860036), patients received 3-4 cycles of protocol-allowed induction, followed by B-cell maturation antigen (BCMA) CAR-T infusion, and subsequent consolidation and lenalidomide maintenance. The primary end point was the rate of minimal residual disease (MRD) negativity (10-5) at Month three postinfusion. RESULTS: Between April 4, 2023, and December 26, 2024, 43 patients were screened, 40 were enrolled, and 36 received infusion (median age, 68 years [46-75]). In the infused cohort, the MRD negativity rate at Month three postinfusion was 100% (36 of 36; 95% CI, 90.3 to 100.0). With a median follow-up of 15.8 months postinfusion (range, 4.3-26.0), no MRD recurrence was observed. The complete response rate (CRR) increased from 33.3% (12 of 36; 95% CI, 18.6 to 51.0) preinfusion to 69.4% (25 of 36; 95% CI, 51.9 to 83.7) at Month 3% and 94.4% (34 of 36; 95% CI, 81.3 to 99.3) at last follow-up. The most common grade 3 to 4 adverse events were transient cytopenia, including lymphopenia (100%), neutropenia (88.9%), leukopenia (80.6%), thrombocytopenia (19.4%), and anemia (8.3%). Cytokine release syndrome occurred in 52.8% of patients (all grade 1 to 2), immune effector cell-associated neurotoxicity in 5.6% (all grade 1), and infections in 30.6% (grade ≥3 in 19.4%). No deaths or disease progressions occurred by cutoff. CONCLUSION: Frontline BCMA CAR-T therapy induces deep, rapid, and durable remissions with a manageable safety profile in the NDMM population ineligible for or not proceeding to ASCT. These findings support its investigation as a potentially practice-changing strategy for this population.
11 Apr 2026
Read appraisal →Blood
Brentuximab vedotin and nivolumab in combination with chemotherapy for nonbulky, early-stage classical Hodgkin lymphoma
Most patients with early-stage classical Hodgkin lymphoma (cHL) are treated with doxorubicin, bleomycin, vinblastine, and dacarbazine with or without radiation therapy, although studies are now evaluating the incorporation of novel agents paired with abbreviated chemotherapy. We present the efficacy and safety of AN+AD (brentuximab vedotin [BV] and nivolumab in combination with doxorubicin and dacarbazine) in patients with early-stage cHL. In this phase 2 study, patients with nonbulky (<10 cm) Ann Arbor stage I or II cHL received 4 cycles of AN+AD. The primary end point was complete response (CR) rate at end of treatment (EOT) by investigator. At the time of this analysis, 154 patients received ≥1 dose of AN+AD. The objective response rate at EOT was 96% (95% confidence interval [CI], 91.7-98.6), and the CR rate was 92% (95% CI, 86.0-95.4). In the favorable (n = 56) and unfavorable (n = 97) subgroups, CR rates were 95% (95% CI, 85.1-98.9) and 91% (95% CI, 83.1-95.7), respectively. The proportion of patients with duration of CR of at least 2 years was 96% (95% CI, 90.9-98.4). At a median follow-up of 27.9 months, the estimated 2-year progression-free survival rate was 97% (95% CI, 92.0-98.8). Any-grade and grade ≥3 treatment-emergent adverse events occurred in 99% and 44% of patients, respectively; no events of febrile neutropenia were reported. Any-grade treatment-emergent immune-mediated adverse events occurred in 22% of patients. One disease-related death was reported after the safety reporting period. Results from this study support the use of BV and nivolumab in combination with limited chemotherapy for patients with nonbulky, early-stage cHL. This trial was registered at www.clinicaltrials.gov as NCT03646123.
10 Apr 2026
Read appraisal →Signal transduction and targeted therapy
Anti-PD-1 antibody penpulimab plus chemotherapy for recurrent or metastatic nasopharyngeal carcinoma: a randomized, double-blind phase 3 study
In this phase 3 trial, penpulimab combined with chemotherapy was assessed against a regimen of placebo plus chemotherapy for the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma (R/M NPC). 291 patients were randomised and allocated in a 1:1 ratio in order to receive penpulimab (n = 144; 200 mg) or placebo (n = 147; 200 mg), plus chemotherapy (cisplatin/carboplatin and gemcitabine) every 3 weeks. Patients followed by maintenance therapy with penpulimab or placebo after 6 cycles. The primary endpoint of this study was progression-free survival (PFS) according to RECIST v1.1, and a significantly longer median PFS in the penpulimab arm versus the placebo arm (9.63 versus 7.00 months; hazard ratio 0.45, 95% CI: 0.33-0.62, P < 0.0001) was demonstrated in this prespecified interim analysis. The key secondary endpoint was the overall survival (OS). However, the OS data were still immature, and the median OS was not achieved (hazard ratio, 0.94; 95% CI: 0.63-1.40). The occurrence of treatment-related adverse events (grade ≥ 3) was 89.0% and 85.9% in two arms, with the most common being reduced the quantity of neutrophil (56.2% vs. 62.0%), reduced the quantity of white blood cell (54.1% vs. 54.9%), and anemia (45.2% vs. 38.7%). In the penpulimab arm, 6 patients (4.1%) experienced immune-related adverse events (grade ≥ 3). Adding penpulimab to chemotherapy led to a notable enhancement in PFS for the first-line R/M NPC treatment, alongside a safety profile that was both manageable and tolerable. ClinicalTrials.gov identifier NCT04974398.
8 Apr 2026
Read appraisal →Medicine
Adverse events associated with the use of nivolumab in the middle-aged and older population (>45 years): A pharmacovigilance analysis based on the FAERS database.
The clinical use of nivolumab has significantly improved the prognosis for survival in patients with a wide range of advanced malignancies. Given the increased incidence of tumors, there is a need to gain insight into the true extent of adverse events (AEs) associated with the nivolumab drug in the middle-aged and elderly population. This pharmacovigilance study was based on an analysis of reports from the US Food and Drug Administration's adverse event reporting system for the period January 1, 2014 to December 31, 2024, and compared AEs of the drug nivolumab in the middle-aged and elderly populations using proportional reporting ratio, reporting odds ratio, BCPN, and multi-item gamma Poisson shrinker methods. The analyses showed the presence of AEs in a variety of systems, mainly involving several systems such as endocrine disorders, nervous system disorders, skin and subcutaneous tissue disorders. The immune-related AEs listed in the package insert were validated by us and their clinical significance warrants careful consideration to further guide clinical dosing, adjust therapeutic decision-making, and develop age-adapted dosing algorithms for population pharmacokinetic development in order to minimize potential risks to patients. With the exception of reports of an unspecified nature, a greater proportion of the sample was male (65.7%) than female (32.5%), indicating significant variations. The highest percentage of reports was observed in patients aged between 65 and 85 years and in patients with a body mass index ranging from 50 to 100 kg/m2. The primary indication was non-small cell lung cancer. The top 3 AE signals reported with nivolumab were malignant neoplasm progression, death, and pyrexia, with the majority of AE cases occurring within the first month following nivolumab initiation.
5 Apr 2026
Read appraisal →The New England journal of medicine
Perioperative Enfortumab Vedotin and Pembrolizumab in Bladder Cancer
BACKGROUND: Patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy proceed directly to radical cystectomy with pelvic lymph-node dissection. Perioperative therapy may improve outcomes in this population. METHODS: In this phase 3, open-label trial, participants with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy were randomly assigned to perioperative (neoadjuvant and adjuvant) enfortumab vedotin, an antibody-drug conjugate directed at nectin-4, plus pembrolizumab and surgery (9 total cycles of enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] plus 17 total cycles of pembrolizumab [200 mg on day 1 every 3 weeks], with surgery after 3 cycles) or surgery alone (control). The primary end point was event-free survival. Key secondary end points were overall survival and pathological complete response (absence of viable tumor after surgical resection). Other secondary end points included safety. RESULTS: A total of 344 participants underwent randomization (170 in the enfortumab vedotin-pembrolizumab group and 174 in the control group). At data cutoff, median follow-up was 25.6 months (range, 11.8 to 53.7). Surgery was performed in 87.6% of participants in the enfortumab vedotin-pembrolizumab group and in 89.7% in the control group. At 2 years, estimated event-free survival was 74.7% in the enfortumab vedotin-pembrolizumab group and 39.4% in the control group (hazard ratio for an event or death, 0.40; 95% confidence interval [CI], 0.28 to 0.57; two-sided P<0.001); estimated overall survival was 79.7% and 63.1% (hazard ratio for death, 0.50; 95% CI, 0.33 to 0.74; two-sided P<0.001). A pathological complete response had occurred in 57.1% and 8.6% of the participants (estimated difference, 48.3 percentage points; 95% CI, 39.5 to 56.5; two-sided P<0.001). Adverse events occurred in all participants in the enfortumab vedotin-pembrolizumab group (grade ≥3, 71.3%; grade ≥3 drug-related, 45.5%) and in 64.8% in the control group (grade ≥3, 45.9%). CONCLUSIONS: Perioperative enfortumab vedotin plus pembrolizumab and surgery led to significantly better event-free and overall survival outcomes and a greater percentage of participants with pathological complete response than surgery alone in a predominantly cisplatin-ineligible population with muscle-invasive bladder cancer. Safety was also assessed. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-905 ClinicalTrials.gov number, NCT03924895.).
4 Apr 2026
Read appraisal →The Journal of investigative dermatology
A Metabolism-Driven Prognostic Model and PSMD14-SP1-GYS1 Axis Reveal Therapeutic Vulnerabilities in Melanoma
Melanoma is a highly aggressive cutaneous malignancy characterized by a strong propensity for metastasis and therapy resistance, with its progression being closely linked to metabolic reprogramming. This study integrated multiomics data (The Cancer Genome Atlas, Gene Expression Omnibus, European Nucleotide Archive) and advanced machine learning to develop prognostic and immunotherapy prediction models for melanoma, focusing on 114 metabolism-related pathways. Cox regression identified 70 genes linked to survival, with functional enrichment revealing key metabolic pathway alterations. A metabolism-related prognostic model (MRPM) was constructed using 101 combinations of machine learning algorithms, demonstrating superior predictive accuracy across 4 cohorts. High-risk patients showed worse survival and immunotherapy response in melanoma and other cancers. Tumor microenvironment analysis revealed MRPM's negative correlation with immune infiltration and positive association with tumor purity. Single-cell sequencing highlighted MRPM gene enrichment in melanocytes. Mechanistically, GYS1 (the key gene in MRPM) emerged as a pivotal prognostic gene that promotes melanoma proliferation and metastasis. Regulatory studies uncovered SP1's transcriptional control of GYS1- and PSMD14-mediated stabilization of SP1 through K48-linked ubiquitination removal. In vivo validation confirmed that PSMD14 knockdown suppressed tumor growth through SP1-GYS1 axis disruption. This work establishes MRPM as a robust predictive tool and elucidates the PSMD14-SP1-GYS1 regulatory network as a potential therapeutic target in melanoma metabolism.
4 Apr 2026
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