The Emerging World of TCR-T Cell Trials Against Cancer: A Systematic Review

Abstract

T-cell receptor-engineered T-cell therapy and chimeric antigen receptor T-cell therapy are 2 types of adoptive T-cell therapy that genetically modify natural T cells to treat cancers. Although chimeric antigen receptor T-cell therapy has yielded remarkable efficacy for hematological malignancies of the B-cell lineages, most solid tumors fail to respond significantly to chimeric antigen receptor T cells. T-cell receptor-engineered T-cell therapy, on the other hand, has shown unprecedented promise in treating solid tumors and has attracted growing interest. In order to create an unbiased, comprehensive, and scientific report for this fast-moving field, we carefully analyzed all 84 clinical trials using T-cell receptor-engineered T-cell therapy and downloaded from ClinicalTrials.gov updated by June 11, 2018. Informative features and trends were observed in these clinical trials. The number of trials initiated each year is increasing as expected, but an interesting pattern is observed. NY-ESO-1, as the most targeted antigen type, is the target of 31 clinical trials; melanoma is the most targeted cancer type and is the target of 33 clinical trials. Novel antigens and underrepresented cancers remain to be targeted in future studies and clinical trials. Unlike chimeric antigen receptor T-cell therapy, only about 16% of the 84 clinical trials target against hematological malignancies, consistent with T-cell receptor-engineered T-cell therapy's high potential for solid tumors. Six pharma/biotech companies with novel T-cell receptor-engineered T-cell ideas and products were examined in this review. Multiple approaches have been utilized in these companies to increase the T-cell receptor's affinity and efficiency and to minimize cross-reactivity. The major challenges in the development of the T-cell receptor-engineered T-cell therapy due to tumor microenvironment were also discussed here.

Keywords: TCR-T; adoptive T-cell therapy; clinical trial; tumor antigen; tumor immunotherapy.

Figure 1.

Diagrams of CAR-T and TCR-T-cell therapy. CAR-T cell, which normally targets only cell surface proteins, has had 4 generations and the latest generation is shown here. All generations of CAR-T cell contain an scFv consisting of an antibody’s variable light (VL) and variable heavy (VH) chain, a transmembrane domain and a CD3ζ chain with ITAM for T-cell activation. The fourth-generation CAR further includes a costimulatory molecule (CM1), such as CD28 and B7, and an interleukin-12 (IL-12) domain for enhanced T-cell effects. T-cell receptor-engineered T cell has 1 TCR consisting of an α chain and a β chain, each containing a variable domain (v) and a constant domain (c), as well as an unlabeled transmembrane domain and 6 CD3 chains for T-cell activation. Class I MHC protein consists of an α chain with 3 domains α1, α2, α3, and a β2-microglobulin, presenting peptides derived from proteolysis of intracellular proteins. CAR indicates chimeric antigen receptor; ITAM, immunoreceptor tyrosine-based activation motif; MHC, major histocompatibility complex; scFv, single-chain fragment variant; TCR, T-cell receptor.

Figure 2.

Major information and trend of 84 TCR-T clinical trials. (A) Figure 2A is the number of clinical trials started each year (bar chart, based on the right-hand side y-coordinate) and the number of clinical trials that have been completed since 2004 (line graph, based on the left-hand side y-coordinate). (B) Figure 2B is the number of clinical trials that was completed or will be completed each year. (C) Figure 2C is the respective proportions of trials not yet recruiting, active but not recruiting, recruiting, enrolling by invitation, withdrawn, terminated, completed and of unknown status. (D) Figure 2D is the respective proportions of different clinical stages in the 84 trials. (E) Figure 2E is the proportion of each type of antigen in the 84 trials.

Figure 3.

Proportion of each type of antigen and cancer targeted by 84 TCR-T clinical trials. (A) Figure 3A is the proportion of each particular antigen targeted in the 84 trials. (B) A total of 210 cancers are targeted in the 84 trials collected (many trials target more than one cancer, and many types of cancer are targeted by more than one trial). Figure 3B is the proportion of each type of cancer targeted in the 84 trials.