CAR T Cell Therapy: A Versatile Living Drug

Abstract

After seeing a dramatic increase in the development and use of immunotherapy and precision medicine over the past few decades, oncological care now embraces the start of the adoptive cell therapy (ACT) era. This impulse towards a new treatment paradigm has been led by chimeric antigen receptor (CAR) T cells, the only type of ACT medicinal product to be commercialized so far. Brought about by an ever-growing understanding of cellular engineering, CAR T cells are T lymphocytes genetically modified with an appropriate DNA construct, which endows them with expression of a CAR, a fusion protein between a ligand-specific recognition domain, often an antibody-like structure, and the activating signaling domain of the T cell receptor. Through this genetic enhancement, CAR T cells are engineered from a cancer patient's own lymphocytes to better target and kill their cancer cells, and the current amassed data on clinical outcomes point to a stream of bright developments in the near future. Herein, from concept design and present-day manufacturing techniques to pressing hurdles and bright discoveries around the corner, we review and thoroughly describe the state of the art in CAR T cell therapy.

Keywords: adoptive T cell transfer; chimeric antigen receptor; immunotherapy.

Figure 1

Schematics of T cell and CAR T cell killing mechanisms. (A) TCR recognition of a cancer cell’s TAA epitope presented on MHC-I induces killing of the target cell; (B) Downregulation of MHC-I by the cancer cell prevents T cell activation and subsequent target cell killing; (C) CAR recognition of the surface-expressed TAA triggers killing mechanisms despite MHC-I downregulation.

Figure 2

Chimeric antigen receptor designs, ordered by their corresponding conceptual generation.

Figure 3

Simplified visualization of the steps involved in an example manufacturing process for CAR T cells.

Figure 4

Visual representation of special CAR T engineering designs. Receptor endodomain regions are represented simplistically as a single straight line in the cytoplasmic part of the depicted membrane proteins. The plus (+) sign signifies full CAR T activation signaling, and the minus (−) sign signifies inhibition of CAR activation signaling.