Influence of antigen receptor avidity, affinity, and specificity on genetically engineered T cells

Abstract

Affinity of a T cell receptor (TCR) refers to the strength of binding between a single TCR and a peptide/MHC (pMHC) complex while avidity of a TCR refers to the overall strength of binding between multiple cell-bound receptors and their ligands. Affinity of a TCR plays a role in thymic T cell selection and the generation of the TCR repertoire. In the absence of sensitivity to strong or weak antigen receptor signals, the homeostasis of the immune system is compromised and the risk of autoimmunity and/or infection ensues. Over the past few decades, T cells which have been genetically modified to target tumor antigens have been used to treat cancer patients. Antibody-based chimeric antigen receptors (CAR) were the first molecules used to redirect the specificity of normal T cells. CAR gene modified T cells can direct tumor rejection in mice and humans. Another class of receptors used to redirect the specificity of T cells is the T cell receptor (TCR). TCR gene modified T cells can also direct tumor rejection in mice and humans. CAR and TCR engineered T cells reactive against tumors have emerged as a promising advance in tumor immunotherapy. The rationale of this chapter is to study how CAR and TCR gene modified T cells modulate tumor immunity.