Engineering T cells for cancer: our synthetic future.

It is widely accepted that the immune system has evolved cellular and humoral mechanisms that can evoke natural immune responses to tumors (1). However, in most instances, vaccines fail to induce rejection of established tumors (2). Adoptive T-cell transfer, a term coined by Billingham, Brent, and Medawar (3), has the potential to overcome one of the significant limitations associated with vaccine-based strategies, and specifically the requirement to de novo activate and expand a tumor antigen-specific T-cell response in patients, who are often immune compromised. As recounted by Kalos et al. in this issue of Immunological Reviews (4), Mitchison et al. (e) first reported the targeting of cancer through the adoptive transfer of lymphocytes in rodent models over 50 years ago. Application of the emerging discipline of synthetic biology to cancer, which combines elements of genetic engineering and molecular biology to create new biological structures with enhanced functionalities (6), is the focus of this volume. In 1989, Eshhar and colleagues (7) reported the first synthetic receptor expressed in lymphocytes. Shortly thereafter, Irving and Weiss (8) reported that a chimeric antigen receptor (CAR) comprised of CD8 and the CD3ζ chain was sufficient to activate T cells. A coalescence of preclinical and clinical data supports the premise that the principles of gene transfer combined with adoptive cellular therapy are poised to overcome the fundamental limitations associated with central and peripheral tolerance and enable the potent and efficient at-will targeting of tumors. There are many mechanisms that prevent the immune system from eliminating tumors in most patients (9). One major issue is the relatively low affinity of T-cell receptors (TCRs) for self-antigens compared to foreign antigens. In humans, comparative analyses have revealed that the TCRs from T cells that recognize self-tumor antigens have a substantially lower affinity (approximately 1.5 logs) for cognate major histocompatibility complex (MHC):peptide complexes compared to their virus-specific TCRs (10). Adoptive transfer using engineered TCRs and CARs is a promising approach to overcome this obstacle (Fig. 1). The adoptive transfer of T cells with endogenous TCRs is an effective therapy for virally induced tumors. As reviewed by Rooney and colleagues in this issue of Immunological Reviews (11), the fraction of cancer caused known to be caused by tumor-associated viruses continues to increase. Because cytomegalovirus (CMV) appears to infect glioblastoma (12), clinical studies are using CMV-specific T cells as a potential therapy (13, 14). Fig. 1 T cells can be engineered to have retargeted specificity for tumors. Bispecific T cells are created by introduction of genes that encode T-cell receptors (TCRs) and chimeric antigen receptors (CARs) of desired specificity and affinities for tumors. CARs ... Reviews in this volume of Immunological Reviews discuss many of the issues currently facing the field to develop effective cancer therapy with retargeted T cells using synthetic receptors. The individual reviews provide in-depth discussion of the data and status of the various approaches that are currently being explored in preclinical and clinical trials. In this introduction, we summarize key elements in each review to achieve a comprehensive overall status of the field of synthetic biology with engineered TCRs.