Strategies to genetically engineer T cells for cancer immunotherapy

Abstract

Immunotherapy is one of the most promising and innovative approaches to treat cancer, viral infections, and other immune-modulated diseases. Adoptive immunotherapy using gene-modified T cells is an exciting and rapidly evolving field. Exploiting knowledge of basic T cell biology and immune cell receptor function has fostered innovative approaches to modify immune cell function. Highly translatable clinical technologies have been developed to redirect T cell specificity by introducing designed receptors. The ability to engineer T cells to manifest desired phenotypes and functions is now a thrilling reality. In this review, we focus on outlining different varieties of genetically engineered T cells, their respective advantages and disadvantages as tools for immunotherapy, and their promise and drawbacks in the clinic.

Keywords: Adoptive cell therapy; Chimeric antigen receptor (CAR); Gene-modified T cells; T cell; T cell receptor (TCR); Tumor immunity.

Fig. 1

CAR-mediated target cell recognition. a Structure of a second-generation CAR interacting with tumor cell. A CAR consists of a single-chain variable fragment (scFv) composed of variable light (V _L) and heavy (V _H) chains linked via hinge, transmembrane domains, and intracellular signaling domains containing at least the γ chain of the FcR or the ζ chain of the TCR/CD3 complex. Identity of the scFv region dictates MHC-independent recognition of a surface antigen. ITAMs of CD3ζ are denoted in blue octagons; b comparison of costimulatory domains included in first, second, or third generation of CARs. ITAMs are denoted as colored octagons

Fig. 2

TCR-mediated target cell recognition. Depicted is the structure of an MHC class I-restricted TCR interacting with tumor or virus-infected cell. TCR α and β chains are specific to both MHC and presented antigenic peptide. The TCR complexes with various CD3 components on the cell surface, and the CD8 coreceptor stabilizes the TCR–pMHC interaction while recruiting lck to facilitate TCR signaling. ITAMs are denoted as colored octagons. Lck = lymphocyte-specific protein tyrosine kinase; Zap70 = zeta-chain-associated protein kinase 70

Fig. 3

TCR modifications to limit mispairing and improve cell surface expression and function. Modifications of wild-type TCR structure (far left) include codon optimization, introduction of a disulfide bridge, addition of leucine zipper, modification of glycosylated residues, substitution with murine constant regions, or use of single-chain Vα–Vβ–Cβ with a Cα chain