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

Rawan Faramand, Michael Jain, Verena Staedtke, Hiroshi Kotani, Renyuan Bai, Kayla Reid, Sae Bom Lee, Kristen Spitler, Xuefeng Wang, Biwei Cao, Javier Pinilla, Aleksander Lazaryan, Farhad Khimani, Bijal Shah, Julio C. Chavez, Taiga Nishihori, Asmita Mishra, John Mullinax, Ricardo Gonzalez, Mohammad HussainiMarian Dam, Brigett D. Brandjes, Christina A. Bachmeier, Claudio Anasetti, Frederick L. Locke, Marco L. Davila

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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). Experimental Design: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)4823-4831
Number of pages9
JournalClinical Cancer Research
Volume26
Issue number18
DOIs
StatePublished - Sep 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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