DMG-54. Mapping Tumor Microenvironment and Treatment Response in Diffuse Midline Glioma Using Multiplexed Immunofluorescence Profiling

B-cell maturation antigen chimeric antigen receptor T-cell re-expansion in a patient with myeloma following salvage programmed cell death protein 1 inhibitor-based combination therapy.

Autoimmune Outcomes in Patients with Concurrent Autoimmune Disease Receiving CD19 CAR T-Cell Therapy for Lymphoma

Biomarker correlates of clinical outcomes from a global Phase 1b study of JNJ-90014496, CD20/CD19 bi-specific chimeric antigen receptor (CAR) T-cell therapy for patients with large B-cell lymphoma (LBCL)

Comparative safety profiles of bispecific T-cell engagers and CAR-T therapies: Real-world insights from the FDA adverse event reporting system database

Natural Killer-Cell Recovery in Patients Receiving CD19 CAR T-Cell Therapy: Dynamics and Clinical Significance

In patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) who are either refractory to first-line therapy or relapse within 12 months, chimeric antigen receptor (CAR) T-cell therapy is more effective than salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) as second-line therapy. Adoption of CAR T-cell therapy into routine clinical practice involves a period of adaptation and refinement of clinical processes. We aimed to document the evolution of clinical processes for CAR T-cell therapy during 2022 and 2023, and compare healthcare resource utilization (HCRU) associated with CAR T-cell and ASCT processes in routine clinical practice. ClipMedPPM software-based process modeling was used to assess HCRU for patients with R/R LBCL receiving CAR T-cell or ASCT therapy, mapping 991 and 1174 processes associated with CAR T-cell therapy in 2023 and 2022, respectively, and 1874 processes associated with ASCT over both years. Improvements in lymphodepletion therapy administration and assessment and management of CAR T-cell therapy-specific adverse events led to a 5-day (30%) reduction in hospitalization and a 15% decrease in total personnel time in the CAR T-cell therapy process from 2022 to 2023. HCRU for CAR T-cell therapy was almost half that of ASCT, with 77% less personnel time for therapy administration. Hospitalization for CAR T-cell therapy was 70%-75% shorter than for ASCT therapy (11–13 vs. 44 days). These patient-centered process efficiencies provide patients with reduced hospitalization time. Understanding this evolution is vital for addressing complexities of advanced treatments, enhancing patient care quality, and optimizing resource allocation.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00277-025-06564-y.

BACKGROUND Several recent studies have shown promising efficacy of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in central nervous system (CNS) lymphomas. Data regarding neurotoxicity were reassuring, with rates of severe acute neurotoxicity similar to those described in systemic lymphomas. However, recently published data from our group outlined the risk of prolonged neurologic deterioration in patients who experienced severe neurotoxicity, which is unusual in systemic lymphomas. The aim of this study was to evaluate mid-term neurocognitive outcomes in CNS lymphomas treated with CAR T-cells. MATERIAL AND METHODS Patients were retrospectively selected from the French LOC network database according to the following criteria: 1) CNS lymphoma treated with CAR T-cells at Pitié-Salpêtrière hospital; 2) Isolated CNS relapse at the time of leukapheresis; 3) Availability of neuropsychological follow-up. Neuropsychological assessment was performed as part of the usual care, before CAR T-cell infusion and, in the absence of tumoral progression, 6 weeks (W6), 6 months (M6) and 12 months (M12) after CAR T-cell therapy. RESULTS Of 38 CNS lymphomas who received CAR T-cells between May 2021 and March 2024, 30 patients (median age: 61 years (range: 30-82), 17 women, 14 primary, 16 secondary CNS lymphomas) benefited from repeated neuropsychological assessments. At the time of CAR T-cell infusion, 7 had stable or progressive disease, median Karnofsky Performance Status (KPS) was 75 and median Montreal Cognitive Assessment (MoCA) score was 23.5 (range: 11-29). Eleven patients received tisagenlecleucel, 17 axicabtagene ciloleucel and 2 brexucabtagene autoleucel. Nineteen patients experienced acute neurotoxicity, including 6 cases of grade 3-4 neurotoxicity. Twenty-two patients were assessed up to M12 (all other patients progressed). Clustering of these longitudinal data using a k-means approach revealed at W6 a subgroup of patients (n=22) with stable or improved cognitive functioning and a subgroup (n=8) with worsened cognitive functioning. Membership to these clusters was strongly associated with the occurrence and severity of an acute neurotoxicity (p=0.01). At M12, there was a statistically significant improvement of MoCA score (median 26 vs 23.5, p<0.001) compared to baseline. Scores addressing memory, executive functions, visuo-spatial functions and anxiety/depression also improved, although not significantly. Such improvements were already seen at M6, and applied both to the whole population and to the subgroup who experienced grade 3-4 neurotoxicity. CONCLUSION Mid-term neurocognition follow-up of patients with CNS lymphoma treated by CAR T-cells seems reassuring, with no significant cognitive worsening, even in patients who experienced severe acute neurotoxicity. These results should be confirmed with longer follow-up.

Chimeric antigen receptor (CAR) T-cell therapy is a promising and rapidly expanding therapeutic option for a wide range of human malignancies. Despite the ongoing progress of CAR T-cell therapy in hematologic malignancies, the application of this therapeutic strategy in solid tumors has encountered several challenges due to antigen heterogeneity, suboptimal CAR T-cell trafficking, and the immunosuppressive features of the tumor microenvironment (TME). Oncolytic virotherapy is a novel cancer therapy that employs competent or genetically modified oncolytic viruses (OVs) to preferentially proliferate in tumor cells. OVs in combination with CAR T-cells are promising candidates for overcoming the current drawbacks of CAR T-cell application in tumors through triggering immunogenic cell death (ICD) in cancer cells. ICD is a type of cellular death in which danger-associated molecular patterns (DAMPs) and tumor-specific antigens are released, leading to the stimulation of potent anti-cancer immunity. In the present review, we discuss the biological causes of ICD, different types of ICD, and the synergistic combination of OVs and CAR T-cells to reach potent tumor-specific immunity.

CAR-t cell therapy in TP53-mutated CNS lymphoma: Overcoming a high-risk genetic barrier

Impact of prior BCMA-targeted therapy on CAR-T expansion and host T-cell phenotypes in patients with Relapsed/Refractory multiple myeloma receiving BCMA CAR-T therapy

Despite the success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies, successful targeting of solid tumors with CAR T cells has been limited by a lack of durable responses and reports of toxicities. Our understanding of the limited therapeutic efficacy in solid tumors could be improved with quantitative tools that allow characterization of CAR T-targeted antigens in tumors and accurate monitoring of response. We used a radiolabeled FAP inhibitor (FAPI) [18F]AlF-FAPI-74 probe to complement ongoing efforts to develop and optimize FAP CAR T cells. The selectivity of the radiotracer for FAP was characterized in vitro, and its ability to monitor changes in FAP expression was evaluated using rodent models of lung cancer. [18F]AlF-FAPI-74 showed selective retention in FAP+ cells in vitro, with effective blocking of the uptake in presence of unlabeled FAPI. In vivo, [18F]AlF-FAPI-74 was able to detect FAP expression on tumor cells as well as FAP+ stromal cells in the tumor microenvironment with a high target-to-background ratio. We further demonstrated the utility of the tracer to monitor changes in FAP expression following FAP CAR T-cell therapy, and the PET imaging findings showed a robust correlation with ex vivo analyses. This noninvasive imaging approach to interrogate the tumor microenvironment represents an innovative pairing of a diagnostic PET probe with solid tumor CAR T-cell therapy and has the potential to serve as a predictive and pharmacodynamic response biomarker for FAP as well as other stroma-targeted therapies. A PET imaging approach targeting FAP expressed on activated fibroblasts of the tumor stroma has the potential to predict and monitor therapeutic response to FAP-targeted CAR T-cell therapy. See related commentary by Weber et al., p. 5241.

Simple SummaryChimeric antigen receptor (CAR) T-cell therapy has shown much promise in liquid tumors but often fails in solid tumors. This work uses a computational model to examine under what conditions this therapy might fail or be successful. The model includes interactions between cancer cells, CAR T-cells (treatment), and vascular cells (that feed and support tumor growth). From our results, we determined specific tumor conditions in which CAR T-cell therapy is predicted to fail and suggest a combination treatment that might improve the efficacy of the treatment. Chimeric antigen receptor (CAR) T-cell therapy has been successful in treating liquid tumors but has had limited success in solid tumors. This work examines unanswered questions regarding CAR T-cell therapy using computational modeling, such as, what percentage of the tumor must express cancer-associated antigens for treatment to be successful? The model includes cancer cell and vascular and CAR T-cell modules that interact with each other. We compare two different models of antigen expression on tumor cells, binary (in which cancer cells are either susceptible or are immune to CAR T-cell therapy) and gradated (where each cancer cell has a probability of being killed by a CAR T-cell). We vary the antigen expression levels within the tumor and determine how effective each treatment is for the two models. The simulations show that the gradated antigen model eliminates the tumor under more parameter values than the binary model. Under both models, shielding, in which the low/non-antigen-expressing cells protect high antigen-expressing cells, reduced the efficacy of CAR T-cell therapy. One prediction is that a combination of CAR T-cell therapies that targets the general population of cells as well as one that specifically targets cancer stem cells should increase its efficacy.

Chimeric Antigen Receptor T-cell (CAR-T) therapy is a revolutionary immunotherapy involving the genetic modification of T cells to express chimeric receptors targeting specific tumor antigens. Over the past decade, CAR-T therapy has significantly advanced with the development of five generations of CAR-T cells, each introducing modifications to enhance T cell efficacy, persistence, and the ability to overcome immune evasion mechanisms. The manufacturing of CAR-T cells has also evolved, employing techniques such as viral vector transduction or CRISPR-based gene editing, lipid nanoparticle, or transposon mediated approaches, to optimize their function. However, the development of CAR-T therapy for solid tumors faces significant challenges, primarily due to the hostile tumor microenvironment (TME), which traditional two-dimensional (2D) culture systems fail to accurately replicate. This review explores the potential of three-dimensional (3D) culture models, including spheroids and organoids, as tools for studying CAR-T cells in the context of solid tumors. Unlike 2D models, 3D systems offer a more physiologically relevant environment, better mimicking the TME, tumor heterogeneity, and immune interactions which CAR-T cells must encounter. We examine the advantages and limitations of 2D versus 3D models and discuss four key methods for generating spheroids/organoids: direct cell aggregation, scaffold-based, microfluidic, organs-on-chip and bioprinting, and patient-derived organotypic tumor approaches. Moreover, we explore the use of murine models in preclinical CAR-T research, highlighting their role in studying the dynamics of CAR-T cell trafficking, efficacy, and off-target effects. While CAR-T therapy has shown impressive success in some hematological malignancies, there is still a critical need for improved models to study CAR-T efficacy against solid tumors, particularly in relation to the TME. 2D models remain a valuable tool but should be combined with 3D models and in vivo murine studies for more accurate clinical outcome predictions. As we advance toward preclinical and clinical applications, ongoing efforts to develop and refine 3D culture systems are essential for overcoming the unique challenges of CAR-T therapy in solid tumors.

Relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma (r/r T-ALL/LBL) are frequently aggressive and associated with unfavorable prognoses. Pan-targeted Chimeric Antigen Receptor (CAR) T-cell therapy have shown promising results in clinical trials. In recent years, CD7 CAR T-cell and CD5 CAR T-cell demonstrate effectiveness in treating r/r T-ALL/LBL patients with bone marrow infiltration. However, nearly half of r/r T-ALL/T-LBL patients are accompanied by extramedullary disease (EMD), where comprehensive data on the efficacy and safety of CAR T-cell therapy remain limited. Additionally, CD7 CAR T-cell and CD5 CAR T-cell therapy can cause severe immunodeficiency and hematologic toxicity, complicating with difficult immune reconstitution. This review provides an in-depth analysis of the safety profile and adverse events associated with CAR T-cell therapy in r/r T-ALL/LBL, with a a particular emphasis on its impact in patients with EMD.

A Novel Method for Molecular Enumeration of Circulating Tisa-Cel and Axi-Cel in Lymphoma Patients