Antitumor Potency of an Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, Lisocabtagene Maraleucel in Combination With Ibrutinib or Acalabrutinib

Abstract

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.

Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia

“…Based on preclinical studies showing that ibrutinib could improve the anti-tumor efficacy of CAR T cells, a phase I clinical trial was conducted showing the safety and feasibility of ibrutinib administered in combination with anti-CD19 CAR T cells in relapsed and refractory CLL patients (171). In line with these results, recent preclinical data show that also the novel BTK inhibitor acalabrutinib can improve the in vitro and in vivo anti-tumor functions of CD19-directed CAR T cells (276).…”

CAR‐T TREK through the lymphoma universe, to boldly go where no other therapy has gone before

“…In one study, axi-cel is combined with the second-generation Bruton tyrosine kinase (BTK) inhibitor, acalabrutinib (NCT04257578). Of note, one report using liso-cel and acalabutinib in a B-ALL cell line xenograft model showed better tumour control with the combination, 32 while other reports seem to suggest that BTK-inhibition is necessary to specifically increase CART functions. [33][34][35] Given its ability to improve the overall anti-tumour activity of CD19 CART therapy, in the ZUMA-11 clinical trial (NCT03704298), axicel is administered in combination with utomilumab, an agonistic monoclonal antibody targeting 4-1BB, capable of enhancing T cell and natural killer cell functions against lymphoma.…”

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data

“…Finally, in r/r B-CLL, CD19 CAR-T cells have been tested but response rates were rather disappointing [54][55][56]. In these patients, combination strategies with, for example, ibrutinib, may be required to unlock the full therapeutic potential of CD19 CAR-T-cell therapies [62].…”