Citations

Abstract Background: Clear cell renal cell carcinoma (ccRCC), metastatic castration-resistant prostate cancer (mCRPC), and glioblastoma (GBM) are highly treatment-refractory tumors characterized by elevated TGF-β1, a key suppressor of antitumor immunity and antigen presentation. Because CAR-T cells infiltrating these tumors experience persistent physiologic TGF-β exposure, assessing CAR-T functional resilience across increasing TGF-β concentrations is critical for determining therapeutic feasibility. Methylseleninic acid (MSA), a pharmacologic selenium compound, potently inhibits TGF-β1, PD-L1, and VEGF with minimal off-target toxicity. FN14, the TWEAK receptor and a metastasis driver, is selectively overexpressed in these malignancies, making it a high-specificity CAR target. Methods: We developed second-generation anti-FN14 CARs containing CD28 or 4-1BB costimulatory domains and a CD3ζ signaling motif, then lentivirally transduced into primary human CD4+ and CD8+ T cells. Cytotoxicity against FN14+ ccRCC, mCRPC, GBM lines and patient-derived cells was assessed using LDH release and xCELLigence assays. Effector function was evaluated through intracellular cytokine profiling, multiplex analysis, and phenotypic characterization by flow cytometry. CAR-T persistence in TGF-β-rich conditions was measured using CCK-8 proliferation assays, and Ki-67 and activation/exhaustion markers (PD-1, CXCR3) in the presence of 0-10 ng/mL TGF-β. MSA’s immunomodulatory and synergistic effects were tested at physiologically concentrations to measure impacts on CAR-T viability, metabolic activity, cytokine secretion, and tumor cell susceptibility. Results: Anti-FN14 CAR-T cells mediated rapid, antigen-specific lysis across all tumor types, achieving >50% specific killing at a 1:1 E:T ratio. MSA (2.5-5 µM) reduced tumor PD-L1 and TGF-β expression by >40% and enhanced CAR-T metabolic activity, IL-2, and IFN-γ secretion. CAR-T cells maintained comparable proliferation and activation in 0-5 ng/mL TGF-β, indicating that antigen-driven signaling counteracted low-to-moderate TGF-β-mediated suppression. Ex vivo CAR-T manufacturing with MSA (2.5 µM) improved cytotoxicity and persistence versus untreated CAR-T cells (p < 0.01). MSA’s effects were dose- and schedule-dependent and remained within human-relevant exposure ranges without detectable toxicity. Conclusion: MSA enhances anti-FN14 CAR-T cytotoxicity, metabolic fitness, and sustained effector activity by suppressing tumor-derived TGF-β1 and PD-L1 and by directly improving CAR-T functional capacity. Consistent with this mechanism, physiological TGF-β levels (0-5 ng/mL) did not significantly impair CAR-T proliferation or activation, demonstrating intrinsic resilience of FN14 CAR-T cells in TGF-β-rich environments. As a clinically relevant TGF-β1 inhibitor and active metabolite of seleno-L-methionine, MSA represents a readily translatable strategy to reduce CAR-T exhaustion and enhance efficacy in TGF-β-rich solid tumors including ccRCC, mCRPC, and GBM. Citation Format: Obed B. Amissah, Casey Ager, Yousef Zakharia, Youcef M. Rustum, Gloria B. Kim. Anti-FN14 CAR-T cells overcome TGF-β-mediated suppression, and their synergy with methylseleninic acid enhances cytotoxicity and effector function in kidney, prostate, and brain tumors [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C010.

Abstract The adoption of electronic health records (EHRs) has transformed health care, improving efficiency and chart accessibility. However, the widespread reliance on unstructured data entry and the lack of standardized documentation frameworks have resulted in significant data fragmentation across health care systems. The prevalence of unstructured data in EHRs limits their potential for clinical decision support, trial matching, real‐world evidence (RWE) generation, and quality measurement. Data fragmentation in health care triggers a cascade of challenges that ultimately compromise patient care. Clinicians face an excessive documentation burden and struggle to locate critical information buried in unstructured notes. Researchers encounter difficulties in extracting reliable clinical data. EHR vendors grapple with standardizing unstructured information for interoperability, and payers are unable to process unstructured clinical data efficiently to support value‐based care models. These challenges are particularly acute in oncology, where complex clinical elements like cancer staging, disease status, and treatment changes require precise, structured documentation. Emerging artificial intelligence (AI) technologies, such as large language models (LLMs) and ambient listening, offer a path to automate structured data generation while reducing the workload on providers. Here, the authors propose LLM‐based workflows that balance automation with clinician verification, streamlining data entry without compromising accuracy. Realizing these benefits requires coordinated efforts among clinicians, researchers, EHR vendors, payers, and policymakers to align regulatory frameworks with AI‐driven innovations. This article outlines a strategy to enhance structured data capture within EHRs, ultimately improving patient care, research, and health care efficiency.

Abstract Background: Despite the success treating hematologic malignancies, chimeric antigen receptor T-cell (CAR T) therapies face challenges in breast cancer and other solid tumors due to lack of targets that distinguish tumor from normal cells. Epithelial growth factor receptor (EGFR) plays a critical role in oncogenesis across several cancers and is often upregulated [1]. While monoclonal antibodies targeting EGFR have demonstrated efficacy, these approaches are often limited by on-target, off-tumor toxicities, such as skin and gastrointestinal toxicity, which constrains dose escalation and efficacy [2]. A2B395 is an allogeneic, logic-gated, EGFR-targeted, TmodTM CAR T therapy designed to address these limitations and provide a convenient and consistent off-the-shelf option. This therapy incorporates 2 CARs: an activator targeting EGFR and a blocker targeting human leukocyte antigen (HLA)-A*02. The activator recognizes EGFR on both tumor and normal cells, whereas the blocker inhibits CAR T activity against normal cells (with preserved HLA expression) while allowing activation against tumor cells (with HLA-A*02 loss of heterozygosity [LOH]). This approach is designed to avoid on-target, off-tumor toxicity, a significant limitation to CAR T treatment of solid tumors [3]. To address potential graft-vs-host response, a short-hairpin RNA expression module targeting beta-2 microglobulin is included in the Tmod construct, which significantly reduces major histocompatibility complex class I levels and subsequent host immune response [4]. Importantly, the Tmod system is modular and adaptable to multiple targets. Initial data on autologous Tmod CAR T therapy suggest reduced off-tumor toxicity and encouraging clinical efficacy [5]. A2B395 represents a novel approach for targeting EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity. Methods: DENALI-1 is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B395 in adults. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA loss of heterozygosity at any time in the course of their disease via next-generation sequencing. Key inclusion criteria include histologically confirmed recurrent, unresectable, locally advanced, or metastatic cancers associated with EGFR expression, including triple-negative breast, colorectal, non-small cell lung, squamous cell head and neck, and renal cell cancers. Patients must have received ≥1 line of prior therapy, such as a checkpoint inhibitor, molecular targeted therapy, or chemotherapy. The primary objective of the phase 1 portion is to evaluate safety, tolerability, and the recommended phase 2 dose (RP2D) using a Bayesian optimal interval design for dose escalation. The dose-expansion phase will confirm the RP2D and collect and analyze biomarker data. The Phase 2 portion will assess overall response rate per RECIST v1.1. As of 03 July 2025, the first patient dosed with A2B395, who has breast cancer, completed the 28-day safety review period. Dose-escalation is ongoing. Citation Format: J. M. Specht, S. R. Punekar, M. Ulrickson, D. J. Wong, J. R. Hecht, M. Maus, P. M. Grierson, J. B. Sunwoo, J. R. Molina, D. G. Maloney, K. Spencer, H. E. Fuentes Bayne, M. Davila, S. P. Patel, B. Creelan, D. B. Zhen, J. Niu, D. C. Prasad, R. L. Marar, N. A. Bagegni, G. Palluconi, J. Lee, A. Mardiros, W. Bretzlaff, W. J. Langeberg, J. S. Welch, E. Ng, W. Y. Go, K. Kirtane, R. A. Shatsky. Denali-1: a seamless phase 1/2 study of A2B395, a logic-gated, allogeneic, Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with triple-negative breast cancer and other EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity (LOH) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-03.

Abstract Glioblastomas exhibit low immunogenicity and a highly immunosuppressive tumor microenvironment (TME) mediated by both tumor cells and tumor associated microglia/macrophages (TAMs). However, biomarkers that allow for specific detection, monitoring and therapy response assessment of the TAM phenotype in glioblastoma are still lacking. To address this gap, we characterized the dynamics of TAM clusters in the TME of experimental SB28 glioblastoma using single-cell RNA sequencing, immunofluorescence, and molecular imaging and identified Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as a dynamic TAM-specific target. Consequently, we investigated a novel 64 Cu-labeled TREM2 radiotracer with a blood-brain barrier transport vehicle for translational mapping of TAMs in the TME of glioblastoma. We found strong and highly myeloid cell-specific PET signals that followed the trajectory of TREM2 gene expression from early- towards late-stage tumors. Transient myeloid cell depletion via CSF1R inhibition showed a reduction of TREM2 PET signals compared to placebo and prolonged survival in SB28 glioblastoma mice, while TREM2 stimulation led to increased TREM2 PET signals. Translation into a pilot cohort of patients with glioblastoma revealed strong TREM2 PET signals predominantly at lesion edges and high heterogeneity across individuals, matching with immunohistochemistry. In summary, TREM2 PET imaging has strong potential as an immune cell-specific biomarker for personalized assessment of the TAM phenotype in the TME of patients with glioblastoma.

Abstract The phase 1/2 Intergroup study E4412 investigated checkpoint blockade with nivolumab (Nivo) and ipilimumab (Ipi) combined with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) in relapsed/refractory classic Hodgkin lymphoma. A total of 147 patients aged ≥12 years were randomized between BV/Nivo and BV/Ipi/Nivo; 132 patients were included in the primary efficacy analysis. The complete response (CR) rate, was 64.7% (52.2, 75.9) for BV/Nivo and 70.3% (57.6, 81.1) for BV/Ipi/Nivo (1-sided P = .29). The median survival follow-up was 38.0 months (interquartile range, 32.6-48.1). Progression-free survival (PFS) did not significantly differ between the 2 arms (hazard ratio [HR], 0.78, confidence interval [CI], 0.39-1.57; 1-sided P = .24). Treatment-related grade 3+ toxicities in the adult cohort, excluding rash, were similar between both arms (38.5% BV/Nivo and 39.3% BV/Ipi/Nivo); there was a higher frequency of grade 3 rash with BV/Ipi/Nivo (24.6%) compared with BV/Nivo (9.2%). We compared PFS by stem cell transplantation (SCT) status in a planned before hoc comparison; 58 patients received SCT, and 36-month PFS (from SCT) was >90% for both arms. Sixty-six patients were progression free after the first scan and did not undergo SCT. The 36-month PFS was 73.0% (54.5, 85.0) for BV/Ipi/Nivo compared with 45.8% (26.3, 63.4) for BV/Nivo (HR, 0.45; CI, 0.19-1.08; 1-sided P = .03). The study did not meet its primary end point of superior CR rate for the triplet, but it supports the use of checkpoint antibody-drug conjugate induction prior to auto SCT, and there is an intriguing signal of disease control for patients wishing to defer or avoid SCT with the triplet of BV/Ipi/Nivo. This trial was registered at www.clinicaltrials.gov as NCT01896999.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vaginal Cancer outline the recommended diagnostic workup, staging considerations, and treatment options for this rare malignancy. Because vaginal cancer is uncommon and shares many biologic and clinical characteristics with cervical cancer, several management recommendations, particularly systemic therapy, are extrapolated from evidence and practices established for cervical cancer. This guideline excerpt summarizes key components of management, including diagnostic evaluation and workup, principles of staging, pathology considerations, radiation therapy principles, and primary treatment recommendations for both early-stage and advanced disease. It also details approaches to manage relapses, including locoregional recurrence and distant metastases, and provides an in-depth overview of systemic therapy recommendations for vaginal cancer.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate are intended to serve as a resource for health care providers to identify individuals who may benefit from cancer risk assessment and genetic counseling and testing; help guide decisions related to genetic testing; and facilitate a multidisciplinary approach in the comprehensive care of individuals at increased risk for hereditary breast, ovarian, pancreatic, and prostate cancer. The current guidelines focus primarily on assessment of pathogenic and likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants associated with increased risk of these cancers. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding screening for prostate cancer and pancreas cancer, as well as testing criteria for nonepithelial ovarian cancer.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hodgkin lymphoma provide expert, multidisciplinary recommendations for the diagnosis and treatment of Hodgkin lymphoma. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Hodgkin Lymphoma focuses on the management of newly diagnosed and relapsed/refractory classic Hodgkin lymphoma in adults aged 18 to 60 years.