T cells play a key role in the immune response of humans as they can directly recognize and eliminate diseased cells such as cells infected with viruses. This mechanism is mediated via T cell receptors (TCRs) expressed on the surface of the T cells.
TCRs can also detect cancer cells and initiate their elimination. However, many tumor antigens are auto-antigens that are aberrantly or over-expressed in cancer cells. T cells of high reactivity to such auto-antigens are usually eliminated in the thymus as part of the body’s tolerance mechanism.
Therefore, one of the most promising approaches is the use of patient-derived T cells that have been genetically engineered outside the body to express tumor-specific TCRs and to escape elimination by the thymus. These cells can be generated in large quantities in the lab.
NEXT-GENERATION T CELL RECEPTORS: HuTCR
To generate TCRs with optimum affinity and safety, T-knife has developed a robust platform for an efficient priming and TCR selection by using proprietary transgenic mice (HuTCR mice) carrying the entire human TCRαβ gene loci. The T cells of these HuTCR mice express a remarkably diverse human TCR repertoire.
The HLA-restricted TCRs from HuTCR mice are of a higher affinity for human tumor antigens as compared to TCRs isolated from human donors, while having an improved specificity over TCRs which have been artificially affinity-matured.
Therefore, T-knife’s HuTCR mice are ideally suited to identify TCRs that are involved in human diseases, e.g. in infections, autoimmune diseases, and cancer.
The HuTCR platform is based on a technology developed by the research group of its Co-founder Prof. Dr. Thomas Blankenstein at the Max-Delbrück-Center for Molecular Medicine (MDC) in Berlin, Germany.
To derive TCRs with superior efficacy against tumors, HuTCR mice are vaccinated with human tumor antigens. Subsequently, they generate a strong immune response mediated by high-affinity T cells. The reactivity of these T cells is directed by high-affinity human TCRs that can be selected and further investigated. The gene sequences of the most promising TCRs are then transferred to T cells of healthy human donors and further characterized in terms of affinity to the target and off-target reactivity to unrelated antigens, healthy tissue and allo-HLAs. TCR candidates with the optimal efficacy/toxicity profile are selected for clinical development.
For cancer T-cell therapy, the selected TCRs are transferred to activated autologous patient T cells via a viral vector. These genetically engineered T cells are then expanded and readministered into the cancer patient.
T-knife has validated the vaccination approach in HuTCR mice for over 90 antigen epitopes and characterized functional TCRs for more than 40 antigens along with filing the respective IP.
T-knife has also achieved pre-clinical proof-of-concept for its TCRs from studies in syngeneic mouse tumor models.