CAR T-cell therapy for solid tumours

Chimeric Antigen Receptor T Cells: Toxicity and Management Considerations

Association of Bridging Therapy Utilization with Clinical Outcomes in Patients Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapy

Demographic Characteristics, Incidence and Outcomes of Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome in Patients Undergoing CAR T-Cell Therapy: An Analysis of the National Inpatient Sample (NIS) - 2021

Managing CAR T-Cell Toxicity: Impact of Steroid Prophylaxis on Toxicity and Outcomes

Age defining immune effector cell associated neurotoxicity syndromes in aggressive large B cell lymphoma patients treated with axicabtagene ciloleucel.

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

e18891 Background: CAR-T therapy represents the most significant advancement in the treatment of HM in the past 5 years. Life-threatening complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may occur leading to significant morbidity and mortality. We aimed to describes the frequency of CRS and ICANS and the time to onset of each post CAR-T therapy administration in real-world, U.S. patients. Methods: Patients (pts) with HM who received any FDA-approved CAR-T therapy were identified from a U.S. EMR database containing de-identified healthcare data for > 40M patients from > 500 hospitals and 30 healthcare systems (including academic centers). Confirmation of CAR-t treatment was based on ≥1 procedure code for general administration of CAR-T therapy (e.g., XW033C3, introduction of engineered autologous chimeric antigen receptor t-cell immunotherapy into peripheral vein) or a specific approved CAR-T (I.e., XW033K7, introduction of idecabtagene vicleucel immunotherapy into peripheral vein) between 2017 and 2022. Diagnosis of CRS or any ICAN was based ≥1 related ICD-10 diagnosis code (e.g., CRS = D89.83X). Frequency of occurrence of CRS, symptoms of CRS, ICANS symptoms, and severity of CRS or ICANS is described (severity based on validated clinical algorithm). Time to CRS and ICANS was calculated as the interval from CAR-T administration to first reported diagnosis, respectively. Results: 212 pts met the study criteria including 77 b-cell lymphoma, 64 multiple myeloma, 47 follicular lymphoma, 13 mantle cell lymphoma and 11 acute lymphoblastic leukemia pts. The majority were male (54.7%); median age was 60 years. Overall, 100 (47.2%) pts were diagnosed with CRS (any grade) while 82 (38.7%) pts experienced any ICAN symptoms. The top three CRS symptoms were fever (57.5%), hypotension (31.1%) and tachycardia (21.2%). The top three ICANS symptoms were obtundation (18.4%), confusion (12.7%), and delirium (12.7%). Of CRS pts, 25.0% experienced severe symptoms, including renal insufficiency (10.0%), atrial fibrillation (9.0%), ventricular tachycardia (7.0%), and cardiac failure (2.0%). The median time to development of CRS was 2 days (range 0-23 days). Of pts. experiencing ICANS, 72.0% experienced any mild symptom and 53.7% experienced any severe symptom, including obtundation (47.6%), aphasia (13.4%), and seizures (1.2%). The median time to development of ICANS post CAR-T therapy was 6 days (range 0-26 days). Conclusions: Our study is the first real-world, U.S. evaluation of the frequency and time to toxicities associated with CAR-t therapy across multiple hematologic malignancies. While well-described in RCTs these data highlight the need for the continued development of clinical and therapeutic approaches to minimize their impact on the effectiveness of CAR-T.

Chimeric Antigen Receptor T-Cell Therapy Associated Cerebral Glucose Hypometabolism (CART-CGHM): A Novel Cerebral Metabolic Complication

Introduction: The efficacy of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (LBCL) is limited by acute toxic events, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Identification of biomarkers of toxicities can allow for selection of high-risk patients and elucidate targetable mechanisms for mitigation. Previous biomarker studies have been constrained by relatively narrow panels of potential mediators and limited time points. Here, we employed NULISA, a novel ultrasensitive assay capable of simultaneously quantifying 204 inflammatory proteins from a single sample, to identify temporal proteome associations with acute toxicities in anti-CD19 CAR T-cell treated patients. Methods: Baseline and post-treatment peripheral blood samples from 80 patients with LBCL who underwent anti-CD19 CAR-T cell therapy were collected within specific time intervals. Plasma samples (n=480) were analyzed with NULISA. CRS and ICANS were graded according to ASTCT consensus criteria. Patients were grouped according to their maximum CRS and ICANS scores. Differential protein abundance across the toxicity groups was assessed using linear mixed effects models fit for each protein, including a time by toxicity group interaction. Proteins showing significant associations were subjected to pathway enrichment and network analysis. Results: Severe CRS and ICANS patient groups showed proteome upregulation beginning on day 1-2 and peaking at day 6-9, followed by extensive downregulation on day 11-16. The strongest upregulated pathway associations of severe CRS and ICANS were inflammatory response, IL-17 signaling, non-genomic action of vitamin D3, regulation of leukocyte proliferation, and cellular extravasation. Downregulated pathways included anti-microbial humoral response and TNFs binding to receptors. In addition to the previously identified inflammatory proteins IL-6, IFNγ, sIL-2Rα, CXCL8, CCL2, our analysis revealed significant association of several novel immune regulators and mediators. These included upregulated Th2 cytokines, IL-17A, IL-22, GZMB, CTLA4, IFNA1;IFNA13, and downregulated S100A12, IL-12B, CCL22, BDNF and TNFSFs, revealing exquisite temporal orchestration of lymphoid and myeloid activities during CRS and ICANS development. Conclusions: This study represents the most comprehensive characterization of immune response to CAR T-cell therapy to date. Using the novel NULISA technology, we identified new proteins and functional pathways associated with CAR T-cell-induced toxicity, implicating them as potential biomarkers. These previously unidentified factors also provide a platform to further investigate the causative immune mechanisms of acute toxicities in CAR-T cell therapy. Citation Format: Riley Kirkpatrick, Joanne Beer, Manishkumar S. Patel, Akansha Jalota, Agrima Mian, Ishara S. Ariyapala, Qinyu Hao, Wei Feng, Xiao-Jun Ma, Yuling Luo, Brian T. Hill, Neetu Gupta. Identification of novel biomarkers of immune toxicity from CAR T-cell therapy using ultrasensitive NULISA™ proteome technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3867.

Feasibility of outpatient administration of axicabtagene ciloleucel and brexucabtagene autoleucel using telemedicine tools: The Vanderbilt experience.

Efficacy and Safety of Intravenous Chimeric Antigen Receptor T-Cell Therapy in Adults with Primary Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis

BMS-986393 (CC-95266), a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from a Phase 1 Study

An Endothelial Activation and Stress Index (EASIX) Based Predictive Model for Neurotoxicity and Cytokine Release Syndrome (CRS) after B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Multiple Myeloma (RRMM)

Shortening the ex vivo culture of CD19-specific CAR T-cells retains potent efficacy against acute lymphoblastic leukemia without CAR T-cell-related encephalopathy syndrome or severe cytokine release syndrome.

Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a groundbreaking modality in cancer immunotherapy, offering remarkable clinical benefits, particularly in hematologic malignancies. By genetically reprogramming autologous T-cells to express synthetic receptors targeting tumor-specific antigens, CAR T-cells can mediate robust antitumor responses. This review provides a comprehensive overview of CAR T-cell immunotherapy, including its historical development, structural design, mechanism of action, and preclinical and clinical evolution. We highlight the intricacies of the tumor immune microenvironment, immune evasion mechanisms employed by cancer cells, and how CAR T-cells address these barriers. FDA-approved CAR T-cell therapies for B-cell malignancies and the current landscape of clinical trials for both liquid and solid tumors are critically analyzed. Furthermore, we explore novel targets, combination strategies, and technological innovations aimed at enhancing CAR T-cell efficacy and overcoming challenges related to antigen heterogeneity, toxicity, and resistance. Issues surrounding cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and tumor antigen escape are also discussed. The review delves into ongoing efforts in preclinical models, translational advancements, and emerging approaches such as dual-targeting CARs, armored CARs, and alternative co-stimulatory domains. Finally, the ethical, economic, and logistical challenges associated with CAR T-cell therapy are examined, including access disparities, manufacturing constraints, and the need for value-based pricing models. By synthesizing current insights and future directions, this review emphasizes transformative role of CAR T-cell therapy in oncology and the imperative for continued innovation to extend its benefits to broader patient populations.