Understanding Resistance Mechanism to Enhance CAR-T Immunotherapy for MCL
Jianguo Tao
MD PhDUniversity of Virginia
Project Term: July 1, 2023 - June 30, 2027
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by resistance to standard treatments and short survival. For the 2023 LLS MCLII Synergistic Team Award, we have assembled a team of leaders in basic, translational, and clinical research in MCL to tackle the current significant obstacles in understanding and treating MCL. In the last decade, we investigated the therapy resistance mechanism of MCL, and pioneered clinical trials for targeted therapies (ibrutinib, lenalidomide) and chimeric antigen receptor T-cell (CAR-T) therapy. However, despite these dramatic advancements, resistance to these newer therapies, including targeted therapy and CAR-T cells, is seen in over 50% of patients. Thus, it remains an unmet need to better define the mechanisms of resistance and then develop rationally designed strategies to overcome resistance. The overall goal of this Synergistic Team Award is to develop improved curative therapies for patients with MCL at relapse. The goals will be addressed in three highly focused, independent but highly integrated projects that utilize state-of-the-art genomic technologies, patient-derived xenograft models, clinical data and primary MCL samples. With the joint effort of our laboratories, highly interactive and accomplished scientists, and physician researchers from multiple institutions with expertise in MCL and therapy, we are uniquely poised to develop improved next-generation of combination therapy for relapsed MCL patients.
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by resistance to standard treatments and short survival. For the 2023 LLS MCLII Synergistic Team Award, we have assembled a team of leaders in basic, translational, and clinical researchers in MCL to tackle the current significant obstacles in understanding and treating MCL. In the last decade, we have investigated MCL pathobiology and therapy resistance mechanisms, and pioneered clinical trials for targeted therapy (ibrutinib) and chimeric antigen receptor T-cell (CAR-T) therapy. However, despite these dramatic advancements, resistance to standard therapies, including small molecules and CAR-T cells, is seen in over 50% of patients. Thus, there is an unmet need to define the mechanisms of resistance and then develop rationally designed strategies to overcome resistance. The ultimate goal of this Synergistic Team Award is to develop improved therapies with curative intent for patients with MCL at relapse focusing primarily on enhancing CAR-T cell and targeted small molecules therapies. The objective of this proposal is to shift current treatment paradigms and clinical practice by introducing, developing, and applying new concepts and technologies to address relapsed MCL. The goal will be addressed in three highly focused, independent but highly integrated projects that utilize state-of-the-art genomic technologies, patient-derived xenograft models, clinical data, and primary MCL samples. With the joint effort of our laboratories, highly interactive and accomplished scientists, and physician researchers from multiple institutions with expertise in MCL and therapy, we are uniquely poised to develop improved next generation of combination therapy for relapsed MCL patients.
In such, Project 1 will continue 1) to determine the mechanism and major molecules of intrinsic tumor cell and extrinsic tumor microenvironmental cells that drive CAR-T resistance, and 2) to test the strategy that targeting the key molecule determinants to enhance anti-tumor immunity, overcome CAR-T therapy resistance and augment the effects of CAR-T therapy in MCL.
Project 2 focuses on developing and supporting that transcription kinase CDK9 (co-factor for RNA polymerase II) as the lead principle therapeutic vulnerability against MCL to overcome treatment resistance.
Project 3 will study the role of apoptosis in MCL cells and penetrating the tumor microenvironment to develop potent combinations of pro-apoptotic agents with CART therapy.