Development of a new platform for T cell immunotherapy: Avidity control of T-cell antigen receptor and adhesion receptors

Abstract

Immunotherapy with genetically engineered T cells expressing chimeric antigen receptors (CARs) has been recognized as an efficient strategy for the treatment of various cancers. However, despite many successful outcomes of CAR-modified T cells in patients with hematologic malignancies, this success is largely limited in solid tumors. T-cell antigen receptor (TCR)-engineered T cells have been recognized as another option for solid tumors as TCRs, unlike CARs, are able to recognize the intratumoral antigen peptides via HLA presentation. However, tumor cells not only express low levels of MHC to avoid immune surveillance, but also present a low affinity self-derived peptide for TCR. To overcome these limitations, attempts have been tried to target tumors by affinity engineering of TCR. However, a potential disadvantage of higher-affinity TCRs is that they can mediate greater self-reactivity against a wider range of structurally similar antigenic peptides. For this reason, both TCR affinity and target selectivity always have potential safety issues. In this presentation, thus, we propose two new approaches to overcome the current limitations of higher-affinity TCR strategy targeting for solid tumors. The first is the modification of TCR avidity rather than affinity through the lessoning how antigen-experienced T cells increases sensitivity in response to low antigen doses. The second is to increase the functional avidity of adhesion receptors by controlling the ‘inside-out’ signals rather than engineering the affinity of ectodomain. These two strategies may overcome the current limitations of T-cell therapies in solid tumors in which tumor antigens are low and immunity is suppressed.