Ibrutinib exposure correlates with improved efficacy of CAR T cells in patients with mantle cell lymphoma.

The pivotal ZUMA-2 trial evaluated the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel) for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL), and ultimately led to the approval of brexu-cel for R/R MCL. Here we report a retrospective analysis of data and samples from ZUMA-2, analyzed by exposure to class of Bruton tyrosine kinase inhibitor (BTKi; first-generation ibrutinib vs second-generation acalabrutinib) in a treatment line before brexu-cel. We found that the ibrutinib-exposed group had significantly greater duration of progression-free survival, greater CAR T-cell expansion, and more CAR T-cell-related toxicity than the acalabrutinib-exposed group. Brexu-cel products from the ibrutinib-treated patients had increased frequencies of T helper 17 cells and transcriptional signatures associated with cytotoxic function. Seven days after infusion, peripheral blood CAR T cells from ibrutinib-exposed patients showed more pronounced effector memory differentiation, which independently correlated to clinical response to brexu-cel. In contrast, brexu-cel products from acalabrutinib-treated patients were enriched for central memory phenotypes and less effector differentiated at day 7 after infusion. Our findings revealed CAR T-cell phenotypic associations with previous BTKi use, and highlight BTKi exposure as a potentially important clinical variable in ZUMA-2 worthy of further study in efforts to improve CAR T-cell therapies. This trial was registered at www.ClinicalTrials.gov as NCT02601313.