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تسجيل

CAR-T Combination with Immunomodulatory Agents: Ibrutinib

المؤلف:  Armin Ghobadi & John F. DiPersio

المصدر:  Gene and Cellular Immunotherapy for Cancer

الجزء والصفحة:  p75-76

2026-09-08

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Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) that is currently being used for the treatment of several types of B-cell lymphoma, Waldenstrom’s macroglobulinemia, and chronic graft versus host disease. Several reports have demonstrated the immune-modulatory properties of ibrutinib on CAR-T cells. It was noted that patients with chronic lymphocytic leukemia (CLL) who were receiving ibrutinib for more than 1 year at the time of apheresis to generate CD19- targeted CAR-T cells (CAR-T19) had improved CAR-T expansion ex vivo and enhanced engraftment and positive clinical response following treatment. This also correlated with decreased expression of exhaustion markers such as PD-1 and CD200. These results were also verified in xenograft mouse models of acute lymphoblastic leukemia (ALL) in which concurrent therapy with ibrutinib and CAR-T19 resulted in enhanced T cell expansion and decreased tumor burden. Similar results were obtained in vitro and in in vivo mouse models of MCL. This combination has been hypothesized to induce complete remission in patients with high- risk CLL with TP53 aberrations that failed prior Bcl-2 inhibitor therapy, and to act as an excellent bridge for hematopoietic stem cell transplantation. Given the promising results of these preclinical experiments, the first clinical trial assessing the safety and feasibility of administering ibrutinib concurrently with CAR-T19 in patients with CLL was completed and published in 2020. Out of the 19 patients enrolled, 15 patients responded, with 11 patients achieving undetectable minimal residual disease in bone marrow. Although CRS severity was lower with the addition of ibrutinib, progression-free survival was unchanged. Furthermore, ibrutinib has recently been shown to improve CAR-T19 production from patients with CLL, with increased cell viability and expansion, and enrichment in less- differentiated naïve-like CAR-T cells (CD45RA + CCR7+) with decreased expression of exhaustion markers such as PD-1, TIM-3 and LAG-3. Finally, emerging evidence suggest that this combination can be applied to other types of B-cell lymphomas. It remains unclear how or when ibrutinib should be used to enhance CAR-T cell therapy. One study treated patients with CAR-T19 after they achieved partial or minimal residual disease positive response with ibrutinib while another study used CAR-T19 in patients progressing/failing ibrutinib.