Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel

• Published in: Clinical cancer research 2020-09, Vol.26 (18), p.4823-4831
• Main Authors: Faramand, Rawan, Jain, Michael, Staedtke, Verena, Kotani, Hiroshi, Bai, Renyuan, Reid, Kayla, Lee, Sae Bom, Spitler, Kristen, Wang, Xuefeng, Cao, Biwei, Pinilla, Javier, Lazaryan, Aleksander, Khimani, Farhad, Shah, Bijal, Chavez, Julio C, Nishihori, Taiga, Mishra, Asmita, Mullinax, John, Gonzalez, Ricardo, Hussaini, Mohammad, Dam, Marian, Brandjes, Brigett D, Bachmeier, Christina A, Anasetti, Claudio, Locke, Frederick L, Davila, Marco L
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-1434

One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel). Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression. We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity. These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.