T cell trials depend on the expression of cloned T cell receptors (TCR) with targeting affinity. This TCR will recognize either intracellular or extracellular antigen in the context of major histocompatibility complex (MHC). T-Cell Receptors (TCR) and Chimeric Antigen Receptors (CAR) are the most advanced ones in the development of adoptive T-cell therapy.
Both receptors use the T-cells to target the tumor, but CAR T-cells (CAR-T) are limited to cell surface antigens binding, while TCR T-cells (TCR-T) recognize peptides (obtained from intracellular proteins) presented on the cell surface by MHC class I.
TCR cell therapy was improved with the Dominant TCR technology to give a more effective treatment for patients with solid tumors who otherwise are having an inferior prognosis.
Adoptive transfer of T cells gene-engineered with T cell receptors (TCRs) has demonstrated its feasibility and therapeutic potential in the treatment of malignant tumors.
The first approved CD19-specific CAR-Ts are advised for hematologic malignancies, but they were less successful against solid tumors.
Work with TCR-engineered T cells started more than two decades ago, with multiple preclinical studies predicting that such cells could mediate tumor lysis and eradication. The success of these trials has given the foundation for clinical trials that include recent clinical achievements of using TCR-engineered T cells to target New York esophageal squamous cell carcinoma (NY-ESO-1).
The success of these demonstrated the potential of this approach to treat cancer. Most of the clinical TCRs tested so far are HLA-A2-restricted and directed towards either melanoma-associated antigen recognized by T cells 1 (MART-1), carcinoembryonic antigen (CEA), glycoprotein (GP) 100, melanoma-associated antigen (MAGE-)A3, p53 or New York esophageal squamous cell carcinoma antigen (NY- ESO)1.
Another TCR that was tested clinically was HLA-A1-restricted. Collectively, these trials have demonstrated the feasibility and signiﬁcant clinical responses in patients with metastatic melanoma, synovial sarcoma, and colorectal carcinoma.
To add to the further clinical development of TCR gene therapy, it should be necessary to select absolute TCRs that produce antigen-selective responses that are restricted to the tumor cells and, along with it has to include strategies that restore or enhance the entry, migration and local accumulation of T cells in tumor tissues.
TCR-engineered T cells therapy is highly potent but its reactivity outside the tumor needs to be minimized, and T cell trafficking inside tumor tissues needs to be maximized.
Treatment-related toxicity has shown evident from studies with TCRs, selectively those of high-afﬁnity, directed against antigens are over-expressed on tumors and also expressed on healthy cells.
Toxicity was caused by cross-reactivity with related and unrelated peptides making the development of much more sophisticated specificity screening systems.
Strategies that are aiming to prevent or limit toxicities, as well as tumor recurrences, have already been advanced, some of them need further preclinical testing, and some of them are already implemented in clinical trials.
These strategies are categorized along with three renewed challenges of choice of the target antigen, ﬁtness of T cells and sensitization of micromilieu for T cell therapy. We present and will argue that optimizations along with each or combinations of these challenges will signiﬁcantly contribute to the advancement of clinical TCR gene therapy.
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