Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for 
patients with CD19 B-cell malignancies. Combination strategies that improve CAR 
T-cell potency, limit tumor environment-mediated immune dysfunction, and 
directly reduce tumor burden may increase the potential for durable clinical 
benefit of CAR T-cell therapy. Lisocabtagene maraleucel (liso-cel) is a product 
therapy candidate being tested in patients with relapsed/refractory non-Hodgkin 
lymphoma or chronic lymphocytic leukemia. This study assessed the in vitro and 
in vivo functionality of CAR T cells transduced to express the anti-CD19 CAR of 
liso-cel in combination with ibrutinib or acalabrutinib. In prolonged 
stimulation assays, the presence of ibrutinib or acalabrutinib improved the CAR 
T-cell effector function. RNA-Seq analysis and surface marker profiling of these 
CAR T cells treated with ibrutinib but not acalabrutinib revealed gene 
expression changes consistent with skewing toward a memory-like, type 1 
T-helper, Bruton tyrosine kinase phenotype. Ibrutinib or acalabrutinib improved 
CD19 tumor clearance and prolonged survival of tumor-bearing mice when used in 
combination with CAR T cells. A combination of the defined cell product therapy 
candidate, liso-cel, with ibrutinib or acalabrutinib is an attractive approach 
that may potentiate the promising clinical responses already achieved in CD19 
B-cell malignancies with each of these single agents.