Journal for Immunotherapy of Cancer最新文献

The biological clock plays a central role in hematopoiesis and immune regulation, making circadian rhythms an increasingly important factor in immunotherapies and cellular therapies such as allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous work by Hou et al suggested that afternoon graft infusions were associated with a higher risk of acute graft-versus-host disease and worse survival, highlighting a potential role for infusion timing in shaping transplant outcomes.To further investigate this, we performed a retrospective analysis of 368 patients who underwent allo-HSCT at Geneva University Hospitals between 2015 and 2024. Observing that infusion timing patterns at our center differed from those reported by Hou et al, we applied a data-driven approach using receiver operating characteristic analysis, which identified 11:17 as the optimal cut-off for overall survival.Stratification using this threshold revealed that patients receiving grafts before 11:00 had significantly improved 2-year overall survival and lower non-relapse mortality compared with those infused later in the day, with no differences in relapse or engraftment rates.These findings suggest that infusion timing may be an important, under-recognized factor influencing allo-HSCT outcomes. Prospective clinical trials are needed to confirm these observations and explore their applicability across different clinical contexts.

Background: The CpG/α-OX40 in situ vaccine strategy has shown efficacy in immune-hot tumors but remains ineffective in immune-cold tumors possibly due to immunosuppressive microenvironments characterized by myeloid-derived suppressor cells (MDSCs) infiltration and T cell exclusion. This study aims to investigate the antitumor effect of non-α-biased IL-2 combined with CpG/α-OX40 in mice.

Methods: Using 4T1 breast cancer and CT26 colon cancer models, we evaluated the antitumor effects of combining CpG/α-OX40 with a non-α-biased IL-2 variant via both intratumoral and subcutaneous routes. Tumor growth, lung metastasis, immune profile, and in vitro function analysis were assessed through flow cytometry, transcriptomic analysis, and T cell suppression assays.

Results: The combination therapy significantly inhibited primary and distant tumor growth and reduced lung metastasis in 4T1 models. Subcutaneous administration induced complete tumor regression in 55% (5/9) of CT26-tumor-bearing mice and conferred durable tumor-specific memory. Mechanistically, the treatment enhanced CD8⁺ T cell activation, metabolic reprogramming, and IFN-γ production, while suppressing MDSC expansion and immunosuppressive function.

Conclusions: These findings demonstrate that non-α-biased IL-2 synergizes with CpG/α-OX40 to overcome microenvironmental immunosuppression and achieve systemic antitumor immunity via a subcutaneous route, offering a translatable combinatorial strategy for immune-cold tumors.

Casitas B lymphoma-b (Cbl-b) is an E3 ubiquitin ligase that serves as a critical brake on immune cell activations. It negatively fine-tunes immune responses through ubiquitination of signaling proteins. Cbl-b deficiency in mice leads to spontaneous tumor rejection and induces only mild, non-lethal autoimmunity, highlighting its potential as a promising immunotherapy target. NX-1607 is the first oral small molecule inhibitor of Cbl-b and it is currently in phase I clinical trial. A recent publication employed high-throughput drug combination screening to systematically elucidate the molecular pathways by which NX-1607 enhances T cell activation. The authors administered 81 well-characterized inhibitors to Jurkat T cells under CD3-stimulated and unstimulated conditions in the presence of NX-1607. Inhibitors of the MAPK/ERK pathway significantly attenuated NX-1607-enhanced T cell activation as indicated by CD69 markers. Proto-oncogene tyrosine-protein kinase Src (SRC) family kinase inhibitors also reduced both CD69 activation markers and the phosphorylation of PLCγ1 and HCLS1 which are upstream of MAPK/ERK pathways. These findings were validated in an immunocompetent B-cell lymphoma mouse model, where NX-1607 consistently upregulated PLCγ1 and ERK phosphorylation. Together, this work delineates a PLCγ1-MAPK/ERK axis through which Cbl-b inhibition unleashes T cell activation, providing critical insight for the development of NX-1607 based immunotherapy.

Background: Talimogene laherparepvec (T-VEC) is an oncolytic herpes simplex virus therapy approved for treatment of unresectable and metastatic melanoma. However, real-world use often occurs in heavily pretreated patients, where evidence of effectiveness remains limited. This study evaluates treatment responses and clinical factors influencing T-VEC outcomes in patients with diverse treatment histories.

Methods: We analyzed patients with metastatic melanoma treated with T-VEC between 2015 and 2024. Objective responses (OR), complete response (CR) and partial response were assessed using univariate and multivariate Cox regression models. Durability of responses, progression-free survival (PFS), and overall survival (OS) were evaluated using Kaplan-Meier estimates.

Results: Among 121 patients, 105 (87%) patients received ≥1 prior lines of systemic therapy; 48 (40%) had a current or prior history of distant metastatic disease, and 42 (35%) had both injectable and non-injectable disease at the T-VEC initiation. Median PFS was 12.2 months (95% CI 6.2 to 20.9), and median OS was 35.5 months (95% CI 25.8 to 63.9). Of 113 evaluable patients, 76 (67%, 95% CI 58% to 76%) achieved an OR, including 39 (35%, 95% CI 26% to 44%) CR. The probability OR by 6 months was 56% (95% CI 46% to 65%). Of the 39 patients achieving CR, 37 (95%) remained alive and progression-free at last follow-up (median 19.1 months). In multivariate analysis, the adjusted HR (aHR) for OR in patients with non-injectable distant metastases at T-VEC initiation relative to those without was 0.43 (95% CI 0.23 to 0.78; p=0.006). The aHR for OR among those immunosuppressed compared with those not immunosuppressed was 0.18 (95% CI 0.04 to 0.69; p=0.013), indicating a reduced likelihood of response for patients who were immunosuppressed. Unadjusted HRs for achieving an OR after 1, 2, and ≥3 prior therapies (vs none) were 1.20 (95% CI 0.57 to 2.52; p=0.627), 1.21 (95% CI 0.52 to 2.80; p=0.653), and 0.77 (95% CI 0.35 to 1.68; p=0.507), respectively.

Conclusions: This study demonstrates T-VEC's potential efficacy in achieving meaningful disease control and response durability in patients with unresectable and/or metastatic melanoma, including those with diverse prior-treatment histories and comorbidities.

Background: The biological sciences are producing increasingly larger datasets for biomarker discovery. While common data models have been developed for medical terms as they relate to patient health outcomes, a data model that supports longitudinal tracking of biospecimens and relating them against an individual patient experience is a large, unmet need.

Method: A structure and associated taxonomy were achieved through a six-tier build in Research Electronic Data CAPture (REDCap), which organizes the complexity of the therapeutic decisions, biospecimens, and outcomes that characterize a longitudinal patient experience. Modules were developed to support export of REDCap data into a Structured Query Language (SQL) format for merging with extended biomarker data, also housed in SQL.

Results: The resultant AstroID resource is a relational structure for clinical and biospecimen data that meets several desired goals: searchable, flexible, generic, Health Insurance Portability and Accountability Act-compliant, auditable, and easy-to-use. The essential elements forming the core of the six-tiered build are provided, so others can readily adopt this schema, as well as an example of an extended, customized build to support biomarker discovery for patients with melanoma. Two examples where this data structure was used to support biomarker discovery and development are described, and example queries of the database are also presented. To the extent possible, the data dictionary was aligned with large data models, such as those for the National Institutes of Health's Human Tumor Atlas Network. The structure can readily scale to accommodate thousands of patients, multimodality data, and spatial characterization of billions of cells. Radiologic imagery can also be included along with pathology imagery to support spatial studies, including artificial intelligence-driven analyses.

Conclusions: This effort provides a database model for investigators conducting research on large volumes of biospecimens with clinical annotation. We have now deployed this structure in our laboratories and have over 1B cells spatially mapped, each effectively tagged with the clinical information from longitudinal patient experiences. While the description uses the example of cancer biomarkers, this data structure could be used to characterize longitudinal biospecimens from any disease process. In the near future, automatic synchronization between the electronic medical record and one or more AstroID databases is anticipated.

Over the last decades, a growing number of distinct CD4+T helper cells has been identified and our understanding of CD4+T cell differentiation and function in various disease contexts has increased immensely. It has long been thought that the role of CD4+T cells in the tumor microenvironment (TME) was limited to coordinating the immune response by stimulating other immune cells and by secretion of cytokines with antitumor activity, while direct killing of tumor cells has been largely attributed to cytotoxic CD8+T cells. Notably, CD4+T cells with direct cytotoxic activity (CD4+CTLs) have been reported in the context of viral infections, autoimmune disorders, and more recently in patients with various cancer types. These cells have the ability to secrete cytotoxic molecules and kill target cells in a major histocompatibility complex (MHC) class II-dependent manner. In this review, we give an overview of phenotypical characteristics of CD4+CTLs in human cancers and the antitumor mechanisms employed by these cells. Further, we explore their role and clinical relevance in the context of cancer and describe how these cells may be used for the development of novel immunotherapeutic options to benefit patients with cancer with MHC class II-positive tumors.

Background: Patients with platinum-resistant/refractory ovarian cancer (PROC) experience suboptimal outcomes, highlighting an immediate need for novel therapies. This phase 1b study investigated the safety and efficacy of botensilimab (BOT), a fragment crystallizable (Fc)-enhanced anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody with differentiated mechanisms of action from first-generation CTLA-4 inhibitors, plus balstilimab (BAL; anti-programmed cell death protein 1 antibody), in an expanded cohort of patients with treatment-refractory ovarian cancer.

Methods: BOT was administered intravenously at 1 mg/kg or 2 mg/kg every 6 weeks in combination with BAL intravenously at 3 mg/kg every 2 weeks (up to 2 years). The primary objectives were to assess safety and tolerability. Efficacy end points included objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. Overall survival (OS) was an exploratory end point.

Results: Overall, 44 patients were evaluable for safety (with a median of 3 prior lines of therapy; median follow-up 9.6 months (range, 0.6-36.6)), and 35 for efficacy. The most common treatment-related adverse event was diarrhea/colitis (43%; 16% grade 3) with no treatment-related deaths. RECIST-confirmed ORR was 23% (8/35; 95% CI 10% to 40%; one complete (CR), seven partial responses (PRs)) and clinical benefit rate (CR, PR, or stable disease ≥24 weeks) was 31% (11/35; 95% CI 17% to 49%). Median DOR was 9.7 months (95% CI 2.8 to not reached (NR)), median PFS was 2.8 months (95% CI 1.4 to 5.5), median OS was 14.8 months (95% CI 12.1 to NR), and 12-month OS was 75% (95% CI 55% to 86%). Immune phenotypic analyses and biomarker data revealed significantly higher FcγRIIIA+CD11c+ cells and higher programmed death-ligand 1 expression in responding patients, a strong association between T-cell infiltrated tumors and clinical benefit, and differences in immune architecture across histologic subtypes.

Conclusion: The BOT/BAL combination demonstrated deep, durable responses and complete remissions in patients with treatment-refractory ovarian cancer where no standard treatments are currently available. RECIST under-represented clinical benefit with 11 patients achieving prolonged/clinically meaningful stable disease (or better) for ≥24 weeks. Toxicities were manageable and reversible. The encouraging clinical activity of BOT/BAL in heavily pretreated patients, as well as biomarker associations, warrants further investigation of this combination.

Introduction: Understanding the negative regulatory mechanisms of immune cell functions is essential for developing effective tumor immunotherapy strategies. Macrophages play a crucial role in antitumor immunity; however, the mechanisms that negatively regulate their antitumor functions remain incompletely understood. TIPE2 is known to be a critical regulator of various immune cells, but its role as a negative regulator of macrophage antitumor functions has not yet been established.

Objectives: This study aims to investigate whether TIPE2 negatively regulates the antitumor functions of macrophages and to elucidate the mechanisms involved.

Methods: We used a mouse model of hepatic tumor metastasis and a subcutaneous tumor model to evaluate the impact of TIPE2 on macrophage antitumor functions. In vitro experiments, including fluorescence microscopy and flow cytometry, were conducted to assess whether the TIPE2 deficiency enhances the phagocytic activity of macrophages against tumor cells. Additionally, we employed co-immunoprecipitation assays along with spleen tyrosine kinase (SYK) and Ras-related C3 botulinum toxin substrate 1 (RAC1) signaling blockade assays to investigate the molecular mechanisms through which TIPE2 exerts its negative regulatory effects.

Results: Our findings indicate that TIPE2 gene loss in myeloid cells inhibits hepatic tumor metastasis, which is dependent on macrophages in the liver. Furthermore, macrophages lacking TIPE2 demonstrated enhanced tumor growth inhibition in subcutaneous tumor models. In vitro, these macrophages exhibited increased phagocytic activity against tumor cells. Mechanistically, TIPE2 negatively regulates the activation of SYK and RAC1, thereby modulating the phagocytic capabilities of macrophages.

Conclusion: TIPE2 represents a negative regulatory mechanism for macrophage phagocytosis against tumor cells. In the future, TIPE2 may serve as a promising target to enhance the efficacy of tumor immunotherapy strategies based on macrophages.

Background: The immunomodulatory roles of cancer-associated fibroblasts (CAFs) in gastric cancer have been increasingly recognized. This study aimed to identify specific CAF subpopulations and to elucidate the mechanisms underlying their immunosuppressive effects.

Methods: We developed a single-cell RNA sequencing (scRNA-seq) protocol to enrich CAFs and matched normal fibroblasts (NFs) from stomach tissues. Bioinformatics analyses, along with in vitro and in vivo experiments, were performed to functionally validate a distinct CAF subset.

Results: We profiled 8,322 high-quality fibroblasts from nine patient-matched tumor and adjacent normal tissue pairs. A unique CAF subset, CD146⁺ CAFs, was identified. CD146⁺ CAFs were significantly enriched in the tumor microenvironment and associated with poor survival and M2-like macrophage infiltration. Tumor cells promoted CD146⁺ CAFs expansion via JAG1-NOTCH3 and LGALS3-CD146 signaling. Mechanistically, NOTCH3 acted as a master regulator in CD146⁺ CAFs. Tumor cell-derived JAG1 engaged NOTCH3 on CD146⁺ CAFs, which triggered PI3K/AKT-mediated CD146 transcription and enhanced COL4A1 secretion. Functionally, CD146⁺ CAF-derived COL4A1 bound macrophage CD44/IL7R to drive macrophage M2-like polarization, thereby suppressing CD8⁺ T-cell function. Therapeutic blockade of CD146 or COL4A1 in vivo impaired M2 polarization, reinvigorated CD8⁺ T-cell activity, and restrained tumor growth.

Conclusions: Our findings underscore the pivotal role of CD146⁺ CAFs in shaping an immunosuppressive microenvironment and highlight CD146⁺ CAFs and COL4A1 as promising candidates for targeted therapy in gastric cancer.

Background: The C-reactive protein (CRP) flare response, an indicator of early immune activation, has emerged as a promising and cost-effective biomarker for predicting response to immune checkpoint inhibitors (ICIs) across various tumor types. This study evaluates the utility of CRP dynamics as a tumor-agnostic biomarker and integrates systemic inflammatory markers with advanced multiparametric MRI metrics to uncover the biological mechanisms underlying the CRP flare phenomenon and its relationship with treatment response.

Methods: Patients were stratified into three groups based on CRP kinetics: (1) flare-responders, characterized by an initial doubling of baseline CRP followed by a decrease below baseline; (2) CRP responders, defined as patients with no flare increase but a CRP reduction of at least 30% below baseline and (3) CRP non-responders. Multiparametric MRI was performed at baseline, early (1-3 weeks), and intermediate (6-8 weeks) time points to assess tumor size and microstructural features, including cell density and vascularization. Clinical benefit and survival outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed using Kaplan-Meier curves and log-rank tests. Cox regression analyses were performed to identify independent predictors of clinical outcomes, while intergroup differences in MRI metrics were assessed using Wilcoxon rank-sum and Kruskal-Wallis tests.

Results: Among the 121 evaluable patients with solid tumors enrolled in the PREDICT trial, CRP flare-responders demonstrated significantly longer PFS (5.6 months) and OS (12.1 months) compared with responders (PFS: 3.4 months, OS: 8.0 months) and non-responders (PFS: 3.2 months, OS: 6.7 months; p=0.01 and p<0.01, respectively). Additionally, clinical benefit was achieved in 50% of flare-responders, compared with 13% of responders (p=0.05) and 23% of non-responders (p<0.01). Tumor growth was interrupted early after treatment initiation in CRP flare-responders, whereas non-responders exhibited marked increases in tumor size. In the pilot subset of 33 patients with MRI data, diffusion MRI revealed stable or increased apparent diffusion coefficient values in CRP flare-responders, indicative of reduced tumor cellularity just after 1-3 weeks of treatment.

Conclusions: This study highlights the potential of combining early CRP dynamics with non-invasive imaging metrics to identify ICI responders as early as 2 weeks after treatment initiation. By integrating systemic inflammatory biomarkers with MRI-derived insights into tumor size and microstructural changes, these findings optimize therapeutic strategies and advance understanding of immunotherapy-driven tumor dynamics.