Combinatorial Therapy of CDK9 Inhibitor with CD19 CAR-T to Reciprocally Overcome Therapy Resistance and Enhance Treatment Efficacies Against Aggressive B-Cell Lymphomas

Diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are subgroups of aggressive B-cell lymphoma associated with unacceptably high rates of refractoriness to intensive treatment and significantly shortened survival in this setting. In addition to standard therapies, modern lymphoma care has incorporated targeted agents including Bruton's tyrosine kinase inhibitors and BCL-2 antagonists. Despite achieving initial clinical responses, many patients eventually succumb to disease relapse following treatment with these novel agents. Meanwhile, chimeric-antigen receptor (CAR) T cell therapies have produced unprecedented initial responses in patients with relapsed or refractory DLBCL and MCL, yet at follow-up, only 40% of patients are able to sustain durable remissions. Thus, there is an urgent need to improve the duration of response and delay or prevent CAR-T therapy resistance. To this end, we previously performed mechanistic and translational studies aimed at developing CDK9 as a novel therapeutic target in DLBCL and MCL. This work involved the interrogation of gene expression and functional screening of a large panel of primary patient samples and lymphoma cell lines, ultimately revealing an essential transcription state characterized by increased RNA polymerase II-mediated transcription as the primary driver of therapy resistance evolution and fatal disease progression. Although clinical trials of CDK9 inhibitors (CDK9i) in B-cell lymphomas have shown promise in drug and CAR-T resistant lymphoma patients, mono-targeting of CDK9 has encountered clinical challenges, particularly the development of resistance in initial responders. Thus, understanding CDK9i resistance evolution mechanisms and identifying ways to target the key resistance-associated molecular determinants and subpopulation(s) of cells capable of giving rise to resistant disease holds great potential for advancing lymphoma therapy. Here, we extend our previous work with CDK9i to identify the underlying molecular determinants of CDK9i resistance and, ultimately, to design rational combination therapies to enhance and sustain CDK9i efficacy. In doing so, we are able to demonstrate that: 1) DLBCL and MCL are exquisitely sensitive to CDK9 inhibition (NVP2/AZD4573) regardless of genetic background or resistance status, 2) populations of CDK9i (NVP2/AZD4573) treatment-induced drug tolerant persister (DTP) cells are responsible for driving therapy resistance evolution, 3) CDK9i (NVP2/AZD4573) treatment induces an immunogenic response via activation of proinflammatory and IFN pathways ex vivo and in vivo, and 4) CDK9i and CD19 CAR-T therapies exhibit reciprocally enhanced efficacy in a manner that can overcome therapy resistance in DLBCL and MCL. The outcomes of this study have broad applicability across B-cell malignancies for eradicating both targeted and CAR-T therapy resistance, which we anticipate can be readily translated to the clinic and have immediate impact on DLBCL/MCL patient care.

Craig:Bayer: Consultancy, Other: Expert Testimony; BeiGene: Honoraria. Shah:Pepromene Bio: Other: DSMB; Jazz Pharmaceuticals, Kite-Gilead, Servier: Research Funding; Eli Lilly: Consultancy; Adaptive Biotechnologies: Consultancy; Bristol Myers Squibb: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Autolus, Beigene, Century Therapeutics, Deciphera, Jazz, Kite/Gilead, Pfizer, Precision Biosciences, Novartis, Takeda: Consultancy. Portell:Merck: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy; Prelude: Research Funding; SeaGen/Pfizer: Research Funding; Infinity: Research Funding; Genentech/Roche: Research Funding; Kite: Research Funding. Williams:AbbVie: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy; Janssen: Research Funding.