Understanding the Mechanisms of Resistance in CAR T Immunotherapy for Lymphoma and Strategies to Overcome Them

In the past 5 years, the US Food and Drug Administration has approved 4 anti-CD19 chimeric antigen receptor T cell (CAR T19) products for relapsed/refractory B cell lymphomas and leukemia. However, we and others showed that only ~30-40% of patients maintain a durable complete remission at long term. Several interrelated factors contribute to the lack of response or relapse after CAR T19, including tumor cell-intrinsic factors, CAR T cell dysfunction, and an immunosuppressive tumor microenvironment (TME). Therefore, our goal is to develop next-generation immunotherapies that are characterized by enhanced cytotoxicity against lymphoma and leukemia cells in the complex dynamic of the immunosuppressive TME and with an acceptable safety profile.

 

We run a research program aimed to improve the outcome of patients with relapsed or refractory hematologic malignancies. We have acquired significant expertise in studying the mechanisms of relapse after targeted immunotherapies and developing successful chimeric antigen receptor T cells (CAR T) for patients with lymphoid malignancies. Several projects that we led have significantly contributed to the advancement of the field by providing: i. a better understanding of the mechanisms of resistance in patients treated with CAR T19 (role of apoptosis; epitope-masking; antigen-negative escape); ii. first-in-human innovative clinical trials (CAR T19+ibrutinib, anti-CD19/CD22 CAR T).

 

Our lab uses a combination of next-generation techniques (scRNA sequencing, spatial transcriptomic, etc.) to characterize mechanisms of resistance, perform pre-clinical studies, and develop new CAR T products. Our ultimate research objective is to improve CAR T therapy for cancer by studying tumor evasion mechanisms and rationally designing novel CAR T approaches.

 

In this presentation, we'll describe some of our recent findings on resistance mechanisms to CAR T cells, focusing on cell-intrinsic factors and CAR T cell dysfunction. We'll also discuss other limitations of CAR T immunotherapy and propose possible strategies to overcome them.

 

 

Learning Objectives:

On November 7, we'll discuss these critical questions and take a deep dive into T-cell dysfunction, the tumor microenvironment, and tumor intrinsic resistance. We hope you can join us.