Chimeric Antigen Receptor- and TCR-Modified T Cells Enter Main Street and Wall Street

Abstract

The field of adoptive cell transfer (ACT) is currently comprised of chimeric Ag receptor (CAR)- and TCR-engineered T cells and has emerged from principles of basic immunology to paradigm-shifting clinical immunotherapy. ACT of T cells engineered to express artificial receptors that target cells of choice is an exciting new approach for cancer, and it holds equal promise for chronic infection and autoimmunity. Using principles of synthetic biology, advances in immunology, and genetic engineering have made it possible to generate human T cells that display desired specificities and enhanced functionalities. Clinical trials in patients with advanced B cell leukemias and lymphomas treated with CD19-specific CAR T cells have induced durable remissions in adults and children. The prospects for the widespread availability of engineered T cells have changed dramatically given the recent entry of the pharmaceutical industry to this arena. In this overview, we discuss some of the challenges and opportunities that face the field of ACT.

Figure 1

Cellular therapy has several pathways to the patient. Normal donor cells can be modified to inactivate their alloreactivity while being armed with anti-tumor CARs or TCRs or a patient’s own cells can be modified with anti-tumor molecules. In the case of solid tumors, biopsy specimens can be used to isolate tumor infiltrating lymphocytes for expansion. In most cases the patient will require some amount of conditioning before receiving anti-tumor lymphocyte infusions, and careful management of toxicities emerging from these therapies is also required.

Figure 2

Design of CAR T cells. First generation CARs incorporated the CD3zeta chain, or similar signaling domains. Antibody based redirection of T cells was first described by Kuwana and refined by Eshhar. Margo Roberts and Helene Finney first described second generation CARs incorporating CD28 or CD137 signaling domains.