Medigene AG presented superior T cell receptor engineered T (TCR-T) cell functionality upon combination of optimal affinity 3S (sensitive, specific and safe) TCRs with the PD1-41BB costimulatory switch protein (CSP) at the 7th International Neoantigen Summit held in Amsterdam, Netherlands from April 29 - May 1, 2024. Overcoming the immunosuppressive solid tumor microenvironment (TME) stands as a major hurdle for durable TCR-T therapies in patients. The PD-1/PD-L1 axis suppresses T cell activation, proliferation, survival, cytokine secretion and cytotoxicity in a TME with tumor cells that express PD-L1.

The Company´s PD1-41BB CSP effectively counters this tumor self-defense mechanism against T cell attack by replacing the inhibitory signaling domain of PD-1 expressed by TCR-T cells with the activating signaling domain of 4-1BB, thereby improving TCR-T cell functionality. The data presented displayed the exceptional specificity and sensitivity of TCR-T cells co-expressing the PD1-41BB CSP with three different 3S-TCRs that recognize the mKRAS (mutant Kirsten rat sarcoma viral oncogene homologue) G12V neoantigen. This was seen by elevated interferon gamma (IFN?) secretion, which was solely observed following TCR-T cell stimulation with mKRAS G12V-positive tumor cells but not by stimulation with any tumor or healthy cell type expressing naturally occurring wild-type KRAS protein.

Each of the three 3S TCRs displayed exceptionally high sensitivity for the mKRAS G12V neoantigen, as evidenced by their response to activation by exceedingly low levels of mKRAS-G12V peptide. Coexpression of the PD1-41BB CSP strongly enhanced TCR-T cell functionality and allowed sustained cytotoxicity to be directed against 3D tumor spheroids through multiple rounds of tumor exposure, underscoring the potent anti-cancer activity of the TCR-T cells. Finally, all three 3S TCRs exhibited excellent safety profiles.

TCR-T cells expressing each of the 3S TCRs, in combination with the PD1-41BB CSP, were not activated to secrete IFN? nor to mediate killing upon exposure to healthy cells from major tissues or organs, confirming their selective cytotoxicity towards cancer cells without toxicity for healthy tissue.