CAR-T Cell Therapy: Current Limitations and Potential Strategies

Chimeric antigen receptor (CAR)-T cell therapy is a new treatment option for certain cancers whose use in clinical practice presents novel challenges and opportunities. Here we highlight a review outlining some limitations and potential strategies to overcome the limitations of CAR-T cell therapy.

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CAR-T cell interacting with cancer cell.

Chimeric antigen receptor (CAR)-T cells are an exciting new treatment option for certain cancers. Their FDA approval helped to cement the reality of cellular therapies having a practical role in clinical medicine. This effort took decades worth of time and the countless effort of many researchers and clinicians. While their introduction into the clinic has been a true accomplishment, there remain many more paths to blaze forward to continue to progress to make these products safer, more effective, and more accessible to more patients. There are challenges ahead, but these also can translate into engaging areas of research whose results could have dramatic clinical impact.

T cells are one of the body’s natural defenses against cancer. However, successfully activating these T cells to perform their desired functions in the context of the cancer microenvironment can be challenging. CAR-T cells are T cells that are engineered to express a synthetic receptor that targets a cancer surface antigen. These receptors consist of an antigen-binding domain (an antibody fragment), a structural hinge region, a domain that spans the T cell membrane, and intracellular signaling domains, which allows for the recognition of a cancer surface antigen and subsequent T cell activation with less steps and without the need for MHC to present the antigen as in standard T cell activation. CAR-T cells have mainly been used to successfully treat certain types of B cell leukemias or lymphomas. They have been limited in their efficacy with other types of hematological malignancies and solid tumors. Some of the obstacles that must be overcome to expand their usefulness include finding strategies to limit the sometimes severe, potentially life threatening toxicities associated with the treatment; sometimes low anti-tumor activity; antigen escape; trafficking restrictions; and low tumor infiltration. The ability of CAR-T cells to produce their desired effects is critically dependent on their interactions with the host and tumor microenvironments. This new field will require the development of a complex workforce to continue to discover and implement new treatment options in the discipline. Our review discusses the current limitations of CAR-T cell therapy and potential strategies to overcome them.

 

Robert C. Sterner is an M.D.-Ph.D. candidate in the University of Wisconsin-Madison Medical Scientist Training Program. He was supported by T32GM008692. Rosalie M. Sterner, M.D., Ph.D. studies immunology and immunotherapies at Mayo Clinic. R.M.S. is an inventor on patents related to CAR-T cell therapy licensed to Humanigen through Mayo Clinic. This work was supported through Regenerative Medicine Minnesota RMM 012819 EPC 003 (R.M.S.). R.C.S. and R.M.S. designed, wrote, edited, and approved the final version of the work. R.M.S. supervised the work.

Rosalie M. Sterner

MD, PhD, Mayo Clinic