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.
Highlights
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].Native TCR specificities have successfully been exploited for ACT with tumor infiltrating lymphocytes (TILs) for melanoma [2] and other tumors [1], or with virus-specific T cells (VSTs) for viral-associated malignancies [3]
Transgenic TCR-based ACT allows the genetic redirection of T cell specificity in a highly specific and reproducible manner, and has produced promising results in melanoma and several solid tumors [4,5], multiple myeloma (MM) [6,7], viral-associated malignancies [8] and acute myeloid leukemia (AML) [9]
Clinical ACT trials with TCR transgenic T cells have so far evaluated the safety and anti-tumor function of T cells directed against differentiation antigens in melanoma [81,82,83] and colorectal cancer [84], CTAs (NY-ESO-1, MAGE) in a variety of solid tumors and multiple myeloma [4,5,6,7,77,79,85,86,87,88,89], the overexpressed self-antigen WT-1 in myeloid malignancies [9,90], and Human Papilloma Virus 16 (HPV-16)-associated antigen E6 in epithelial cancers [8]
Summary
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]. Transgenic TCR-based ACT allows the genetic redirection of T cell specificity in a highly specific and reproducible manner, and has produced promising results in melanoma and several solid tumors [4,5], multiple myeloma (MM) [6,7], viral-associated malignancies [8] and acute myeloid leukemia (AML) [9]. Even though clinical results are encouraging for both approaches, several major limitations have been identified and are being addressed by various engineering strategies Those challenges include: target antigen selection, TCR selection, human leukocyte antigen (HLA). Approaches that involve the combination of TCR-based ACT with drugs, peptides or dendritic cell vaccines, and the historical context of ACT, have been extensively reviewed elsewhere [12,13,14,15,16,17,18,19,20,21]
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