T cells play a key role in the immune response of humans because 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 self-antigens that are aberrantly or over-expressed in cancer cells. T cells of high reactivity to such self-antigens are usually eliminated in the thymus as part of the body’s natural tolerance mechanism.
In order to escape elimination by the thymus, a promising approach is to genetically engineer patient-derived T cells outside the body to express tumor-specific TCRs. 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.
T-knife’s HuTCR mice are ideally suited to identify TCRs that are involved in human diseases, including infections, autoimmune diseases and cancer.
THE PROCESS
To derive TCRs with superior efficacy against solid 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.