Pirtobrutinib and venetoclax combination overcomes resistance to targeted and chimeric antigen receptor T-cell therapy in aggressive mantle cell lymphoma
Yang Liu, Fangfang Yan, Changying Jiang, Yijing Li, Yuxuan Che, Joseph McIntosh, Alexa A Jordan, Ian Hou, Lei Nie, Jingling Jin, Wei Wang, Heng‐Huan Lee, Yixin Yao, Michael Wang
Abstract
Despite the remarkable success of targeted therapies for mantle cell lymphoma (MCL), including inhibitors of Bruton tyrosine kinase (BTK) and CD19-directed chimeric antigen receptor (CAR) T-cell therapy, resistance and disease relapse persist, so there is an urgent need to develop novel agents and combinatorial strategies against this deadly disease. 1,2 BTK is a key component of the B-cell receptor pathway, which regulates B-cell survival and proliferation. Ibrutinib, the first Food and Drug Administration-approved covalent BTK inhibitor, achieved overall response rates of 70-77% in patients with relapsed/refractory MCL, 3 which represented a major milestone in targeted MCL therapies. s a key regulator of apoptosis, BCL-2 is aberrantly expressed in MCL, and its inhibition with venetoclax (ABT-199) induces massive apoptosis in MCL cells. Notably, combinatorial ibrutinib and venetoclax yielded favorable complete response rates in MCL patients in a phase II study (71%) 6 and in the phase III SYMPATICO study (62%), Pirtobrutinib (LOXO-305) is a next-generation, highly selective, non-covalent BTK inhibitor. Compared to traditional covalent BTK inhibitors, pirtobrutinib achieves remarkable target coverage regardless of the intrinsically high rate of BTK turnover, and lacks the off-target inhibition of other kinases. In the phase I/II BRUIN study pirtobrutinib exhibited promising efficacy in heavily pretreated MCL patients irrespective of prior exposure to covalent BTK inhibitors. 9 Given the clinical success of combinatorial ibrutinib and venetoclax in MCL patients, we investigated and here report the antitumor effects of pirtobrutinib in combination with venetoclax in various MCL models in vitro and in vivo to provide proof of concept for further exploration in the clinic. The patients' apheresis samples used in this study were collected after obtaining