T-cells are a subset of lymphocytes that play a large role in the immune response. The T-cell receptor (TCR) is a membrane-bound protein complex found on the surface of T cells. TCR will recognize fragments of antigens as peptides bound to major histocompatibility complex (MHC) molecules. The TCR is composed of two different molecule chains. In human, for 95% of the population of T cells, the TCR consists of an alpha chain and a beta (α/β) chain, whereas in 5% of the population of T cells the TCR consists of gamma and delta (γ/δ) chains.
When the TCR engages with antigen peptide and MHC (peptide/MHC), the T cell is activated through signal transduction. For clarity, TCRs can recognize tumor-specific proteins on the inside of cells, namely, intracellular tumor-specific antigens. When tumor-specific proteins are broken into fragments, they show up on the cell surface with MHC. TCRs can be engineered to recognize a tumor-specific protein fragment/MHC combination (see figure 1).
Figure 1. TCR recognizes tumor-specific antigen peptide/MHC
TCR vs CAR-T
TCR therapy is an attractive alternative to chimeric antigen receptor (CAR) T-cell (CAR-T) therapy. CAR-T recognizes tumor cells through tumor antigen on the surface of tumor cells. As therapy, it has generated encouraging clinical outcomes, thereby demonstrating their therapeutic potential in treating tumors. In the past 5 years, CAR-T therapy has received considerable attention from researchers. The landmark approval and clinical successes of Novartis’ Kymriah® and Gilead/Kite Pharma’s Yescarta® has prompted a surge of further research. However, this approach, which involves isolating cells from a patient, bioengineering them to express CARs that identify and attach to tumor cells, and subsequently injecting them back into the patient has several limitations. These limitations include cytokine release syndrome (CRS) and neurotoxicity, and are life-threatening adverse effects that need to be carefully treated. Additionally, compromised effects of anti-solid tumor have been recognized as well. The difficulty with CAR-T is that it cannot always penetrate and deliver an effect in solid tumors. TCR therapy, which utilizes the natural mechanisms that T cells use to recognize the antigen and therefore the cancer, is better suited to penetrate the tumor. This approach targets the TCR- peptide/major histocompatibility complex (MHC) interaction, which enables eradication of tumor cells. Intracellular tumor-related antigens can be presented as peptides in the MHC on the cell surface, which interact with the TCR on antigen-specific T cells to stimulate an anti-tumor response. Once these TCRs are injected, they have a direct kill activity and an immunostimulatory activity to other cells. This results in a more comprehensive killing effect on the tumor cells. This approach is scientifically appealing and could bring value to a large array of solid tumors.
TCRs cover a wide range of potential target antigens, giving the likelihood that T cells are a promising treatment for cancer because they can express native or transgenic αβ-T cell receptors (TCRs). Native TCR specificities have successfully been exploited for adoptive T cell therapy with tumor infiltrating lymphocytes (TILs) for melanoma and other tumors, or with virus-specific T cells for viral-associated malignancies. Transgenic TCR therapy allows the genetic modification of T cells in a highly specific and reproducible manner, and has obtained promising results in melanoma and several solid tumors, multiple myeloma, viral-associated malignancies and acute myeloid leukemia.
To date, about 20 clinical trials with TCR transgenic T cells have been evaluated for safety and anti-tumor function of T cells against different antigens in melanoma, myeloid malignancies, colorectal cancer, and a number of other solid tumors. The majority of these TCRs were HLA class I – restricted, and the only class II – restricted TCR was directed against antigen MAGE-A3.
A main challenge for the TCR T cells is to efficiently deploy their full therapeutic potential. The administration of lymphodepleting chemotherapy and high-dose IL-2 after TCR infusion proved beneficial to achieving positive responses. In contrast, in the absence of lymphodepletion, stable disease was the best response obtained. TCRs targeting differentiation antigens, such as MART-1, tyrosinase/gp100, and CEA, were mostly limited by on-target, off-tumor toxicities to healthy tissues that share antigen expression with the tumor. Therefore, TCRs that target antigens more restricted to tumor cells may be better tolerated by the patients. Cancer testis antigen (CTA) NY-ESO-1-specific TCRs T cell was very well tolerated and produced promising overall response rates (ORR) in refractory synovial sarcoma patients across several studies. For example, an overall response rate of 61% (11/18) was reported in patients with synovial sarcoma, and 55% (11/20) in patients with melanoma, but most responses lasted less than 1 year. Another trial assessed safety and efficacy of allogeneic WT-1 TCR-specific, an Epstein Barr Virus-specific CD8+ T cells (EBVSTs) derived from the allogeneic stem cell donor. TCR+ EBVSTs were safely infused to high-risk Acute Myeloid Leukemia (AML) patients with no evidence of disease after allogeneic hematopoietic stem cell transplantation (HSCT), followed by low dose IL-2 and a second infusion in 7 of 12 patients. Toxicities were manageable, and at a median follow up of 44 months, all 12 patients remained relapse-free. In a matched control cohort of 88 patients treated at the same institution, relapse-free survival was 54%. These results indicate that transgenic TCR T cell therapy is highly promising for high-risk AML patients, when given in the post-transplant setting and undetectable disease state.
These clinical results indicate that several factors are crucial for the success of TCR gene therapy: 1) the selection of the targeted antigen, 2) the specific features of the TCR used, 3) the biology of the T cell in which the TCR is expressed, 4) the disease status of the patient, 5) the administration of lymphodepleting chemotherapy and in vivo cytokine support of the infused cells, 6) the in vivo persistence, 7) the homing to and infiltration of the tumor, and 8) the impact of the tumor microenvironment on T cells that successfully reached the tumor microenvironment, and the overall safety of the approach.
Rath JA and Arber C. Engineering strategies to enhance TCR-based adoptive T cell therapy. Cells 2020, 9, 1485; doi:10.3390/cells9061485
Zhao L and Cao YJ. Engineered T cell therapy for cancer in the clinic. Frontiers in Immunology, 2019, doi: 10.3389/fimmu.2019.02250