New Insights on CAR-T Design: Paving the Way for Broader Cancer Applications

The Cancer Research Institute (CRI) is excited to share the latest study from CRI Lloyd J. Old STAR, Yvonne Chen, PhD, from the University of California, Los Angeles. Published in Nature Metabolism, the study focuses on how different chimeric antigen receptors (CAR) molecules guide CAR-T cell metabolism to impact their functional activity.

CAR-T cell therapy has demonstrated remarkable success in treating various hematological malignancies such as multiple myeloma, B-cell lymphoma, and Acute Myeloid Leukemia (AML). This cutting-edge immunotherapy involves genetically engineered T-cells that express CARs that are designed to target specific molecules or antigens found in cancer cells, directing them to cancer cells where they can unleash their killing potential. CAR molecules are synthetic proteins consisting of different parts.  

Metabolism is an indispensable part of T-cell functional activity, including proliferation, activation, and exhaustion. How the expression of CAR molecules on T-cells affects their metabolism is not well understood. As different cancer targets require different CAR-T cells, Dr. Chen and her colleagues asked whether the choice of CAR would affect T-cell metabolism and efficiency of CAR-T-cell therapy.

By investigating seven different CAR-T cells, the team discovered that certain CAR molecules can enhance the metabolic activity of CAR-T cells even in the absence of tumor cell antigens. This metabolic rewiring makes these T-cells hypermetabolic, causing them to secrete metabolites and nucleotides at a much faster rate than normal cells, which in turn may affect their rate of proliferation and ultimately the efficiency of CAR-T cell therapy.

Understanding how the CAR building blocks interact and affect T-cell metabolism is crucial for predicting their effectiveness. This study indicates that a non-signaling extracellular region of CAR is essential and sufficient to rewire the metabolic network in CAR-T cells.

Why is this research important?

CAR-T cell therapy is a revolutionary new “live” immunotherapy and has been approved by FDA for various hematological malignancies. However, CAR-T therapy doesn’t work for all cancers, and efforts to fine-tune CAR-T therapy are underway to design more effective cell therapies.

Dr. Chen’s work helps us understand how the building blocks of CAR proteins fit together to interact with and control T cell metabolism. This research could potentially aid in tweaking the CAR-T cells to design more effective CAR-T cell therapies for a wide range of cancers, including solid tumors.