cells Review Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy Jan A. Rath and Caroline Arber * Department of oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, Lausanne University Hospital and University of Lausanne, 1015 Lausanne, Switzerland * Correspondence:
[email protected] Received: 18 May 2020; Accepted: 16 June 2020; Published: 18 June 2020 Abstract: T cell receptor (TCR)-based adoptive T cell therapies (ACT) hold great promise for the treatment of cancer, as TCRs can cover a broad range of target antigens. Here we summarize basic, translational and clinical results that provide insight into the challenges and opportunities of TCR-based ACT. We review the characteristics of target antigens and conventional αβ-TCRs, and provide a summary of published clinical trials with TCR-transgenic T cell therapies. We discuss how synthetic biology and innovative engineering strategies are poised to provide solutions for overcoming current limitations, that include functional avidity, MHC restriction, and most importantly, the tumor microenvironment. We also highlight the impact of precision genome editing on the next iteration of TCR-transgenic T cell therapies, and the discovery of novel immune engineering targets. We are convinced that some of these innovations will enable the field to move TCR gene therapy to the next level. Keywords: adoptive T cell therapy; transgenic TCR; engineered T cells; avidity; chimeric receptors; chimeric antigen receptor; cancer immunotherapy; CRISPR; gene editing; tumor microenvironment 1. Introduction Adoptive T cell therapy (ACT) with T cells expressing native or transgenic αβ-T cell receptors (TCRs) is a promising treatment for cancer, as TCRs cover a wide range of potential target antigens [1].