On October 23, 2023 Medigene AG (Medigene, the "Company", FSE: MDG1, Prime Standard) an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, reported 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 (Free ESMO Whitepaper) Congress 2023 held October 20-24, 2023, in Madrid, Spain (Press release, MediGene, OCT 23, 2023, View Source [SID1234636273]).

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The poster with the title "Mitigation of Tumor Microenvironment-Mediated Immunosuppression Using a PD1-41BB Switch Protein with Optimal Affinity TCRs for First-In-Class, 3rd Generation TCR-T Therapies" will be available on Monday, October 23, 2023, following the conference presentation on Medigene’s website: View Source

"The immunosuppressive tumor microenvironment remains a major challenge for many T cells, including engineered T cells when applied against solid tumors. We are pleased to report encouraging pre-clinical data showing significantly enhanced T cell functionality by engaging our PD1-41BB CSP with different optimal affinity TCRs not only targeting CTAs like NY-ESO-1/LAGE-1a, but also against the neoantigen mKRAS G12V," said Prof. Dolores Schendel, Chief Scientific Officer at Medigene. "Armoring and enhancing our optimal affinity TCRs with the PD1-41BB costimulatory switch protein has the potential to overcome an immunosuppressive tumor microenvironment, leading to TCR-T therapies that improve safety, efficacy and durability outcomes for patients."

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 (IFNγ) 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) (Free SITC Whitepaper) 38th Annual Meeting held in San Diego, November 1 to 5, 2023.

SITC 2023 Presentation Details:

Title: A novel library of optimal affinity KRAS mutation-specific T cell receptors associated with multiple HLAs, in combination with a PD1-41BB armoring and enhancement costimulatory switch receptor

Authors: Dolores Schendel, Giulia Longinotti, Mario Catarinella, Melanie Salvermoser, Julia Bittmann, Kirsty Crame, Kathrin Davari

Presenter: Selwyn Ho

Abstract number: 388

Date/ time: Saturday, November 4, 2023; Poster lunch session (11:55 am to 1:25 pm) and poster reception (7:00 pm to 8:30 pm); poster will be on display from 9:00 am to 8:30 pm (all times PDT)

Location: Poster Hall, San Diego Convention Center

The abstract will be available on the SITC (Free SITC Whitepaper) website on October 31, 2023 at 9 am EDT, and the poster will be available on Medigene’s website following the presentation.