Medigene AG presented data showing significantly enhanced T cell activity when combining the PD1-41BB costimulatory switch protein (CSP) with recombinant T cell receptors (rTCR) not only when directed at the cancer-testis antigen (CTA) New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/L Antigen Family Member-1a (LAGE-1a), but also, presented here for the first time, against the neoantigen mutant Kirsten rat sarcoma virus (mKRAS) G12V at the ESMO Congress 2023 held October 20-24, 2023, in Madrid, Spain. Within the solid tumor microenvironment (TME) T cell functionality is strongly impaired by the expression of the programmed cell death 1 ligand 1 (PD-L1) on tumor cells. The engagement of PD-L1 on tumor cells with PD-1 on T cells prevents specific killing of tumor cells.

Moreover, PD-L1 signalling to T cells via the PD-1 receptor limits proliferation, cytokine secretion and cytotoxic response, while exhaustion is induced by repetitive TCR signalling in the absence of T cell costimulation. The presented data showed that by combining optimal affinity TCRs with a PD1-41BB CSP, not only is the PD-1/PD-L1 axis blocked, but also T cell proliferation, cytokine secretion and cytotoxic response are increased through positive 4-1BB signaling, resulting in mitigation of the immunosuppressive TME through enhanced T cell functionality. Robust expression of rTCR directed against NY-ESO-1/LAGE-1a and/or the neoantigen mKRAS G12V as well as the PD1-41BB CSP was demonstrated in TCR-T cells.

The combination of NY-ESO-1/LAGE-1a or mKRAS G12V-specific rTCRs with PD1-41BB CSP displayed elevated polyfunctionality by increased levels of effector, stimulatory and chemoattractive cytokines as compared to TCR-T cells without PD1-41BB CSP in melanoma and pancreatic tumor cell lines. Interferon-gamma (IFN?) release measured in several tumor cell lines of different origin was enhanced in TCR-T cells co-expressing the rTCR and PD1-41BB CSP as compared to TCR-T cells lacking PD1-41BB CSP. The co-stimulatory effects of PD1-41BB were highly dependent on the rTCR-mediated recognition of the specific tumor-antigen NY-ESO-1/LAGE-1a or mKRAS G12V, respectively, and on the expression of the inhibitory ligand PD-L1 on tumor cells.

Elevated and sustained killing of 3D tumor spheroids was observed with TCR-T cells co-expressing the rTCR targeting mKRAS G12V and PD1-41BB CSP compared to TCR-T cells without the PD1-41BB CSP. Additional data on Medigene?s library of KRAS mutation-specific TCRs will be presented at the Society of Immunotherapy of Cancer (SITC) 38th Annual Meeting held in San Diego, November 1 to 5, 2023.