Medigene Showcases Enhanced TCR-T Cell Function with Costimulatory Switch Protein

Planegg/Martinsried, May 2, 2024 – Medigene AG (Medigene) showcased significant advancements in T cell receptor engineered T (TCR-T) cell functionality at the 7th International Neoantigen Summit in Amsterdam. The company's focus is on the discovery and development of T cell immunotherapies targeting solid tumors. Their latest innovation combines optimal affinity 3S (sensitive, specific, and safe) TCRs with the PD1-41BB costimulatory switch protein (CSP).

The presentation, titled "KRAS Mutation-Specific TCR-T Cells are Empowered for Improved Multi-Functionality & Durability by Inclusion of a Costimulatory Switch Protein," addressed the challenge of overcoming the immunosuppressive solid tumor microenvironment (TME). Within these environments, the PD-1/PD-L1 axis hampers T cell activation, proliferation, survival, cytokine secretion, and cytotoxicity due to the presence of PD-L1 on tumor cells. Medigene’s PD1-41BB CSP counters this by replacing the inhibitory PD-1 signaling domain in TCR-T cells with the activating 4-1BB domain, thus enhancing TCR-T cell performance.

Dr. Selwyn Ho, CEO of Medigene, emphasized the innovative nature of their PD1-41BB CSP, a proprietary element of their End-to-End (E2E) Platform. This technology can pair with various optimal affinity 3S-TCRs, targeting cancer-testis antigens or neoantigens identified through their high-throughput TCR discovery process. Extensive in vitro experiments demonstrated the substantial benefits of integrating PD1-41BB CSP with 3S-TCRs, suggesting a significant potential to combat the immunosuppressive TME of solid tumors. This combination could enhance the efficacy and durability of TCR-T therapies for challenging solid tumors. The PD1-41BB CSP not only improves TCR-T therapies but also holds potential for other cell types and chimeric antigen receptor T cell therapies.

The data presented revealed the exceptional specificity and sensitivity of TCR-T cells co-expressing PD1-41BB CSP with three different 3S-TCRs that detect the mKRAS (mutant Kirsten rat sarcoma viral oncogene homologue) G12V neoantigen. This was evident from elevated interferon gamma (IFNγ) secretion, which occurred only after TCR-T cell stimulation with mKRAS G12V-positive tumor cells, not with wild-type KRAS proteins. Each 3S TCR exhibited high sensitivity to the mKRAS G12V neoantigen, getting activated by very low levels of mKRAS-G12V peptide. Co-expression of PD1-41BB CSP significantly improved TCR-T cell functionality, allowing sustained cytotoxicity against 3D tumor spheroids through multiple tumor exposure cycles, demonstrating potent anti-cancer activity.

Furthermore, all three 3S TCRs exhibited excellent safety profiles. TCR-T cells expressing each 3S TCR combined with PD1-41BB CSP were not activated to secrete IFNγ or mediate killing when exposed to healthy cells from major tissues or organs, confirming their selective cytotoxicity towards cancer cells without harming healthy tissue.

Medigene AG is an immuno-oncology platform company dedicated to developing differentiated T cell therapies for solid tumors. Their End-to-End Platform encompasses multiple proprietary technologies that enable the generation of optimal T cell receptors against both cancer testis antigens and neoantigens. These are then used to create best-in-class TCR-T therapies, optimizing safety, efficacy, and durability. Medigene's lead TCR-T program, MDG1015, is anticipated to receive regulatory approval in the second half of 2024.

The company’s approach centers on activating and modifying the patient’s T cells to effectively detect and eliminate cancer cells. This includes arming T cells with tumor-specific TCRs, expanding them, and reintroducing them into the patient for a robust anti-cancer response. By overcoming the patient’s immune tolerance and tumor-induced immunosuppression, Medigene’s therapies aim to provide a powerful weapon against solid tumors.

Medigene's PD1-41BB costimulatory switch protein enhances the immune response by turning the tumor's defense mechanism against itself, using the activating signaling domain of 4-1BB instead of the inhibitory PD-1 domain. This modification allows TCR-T cells to maintain functionality even in hostile tumor microenvironments, characterized by low glucose or high TGFß levels.

KRAS mutations, often found in fatal cancers like pancreatic, lung, and colorectal cancers, create neoantigens that drive unchecked cancer cell proliferation. These mutations are absent in healthy tissues, making KRAS an attractive target for TCR-T therapies. Unlike CAR-T cells, TCR-T cells can recognize intracellular proteins like neoantigens, making them particularly suitable for targeting KRAS mutations and other difficult neoantigens in solid tumors.