Planegg/Martinsried, April 8, 2024. Medigene AG (Medigene or the “Company”, FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, today presents superior recombinant T cell receptor (rTCR) engineered T cell functionality as well as a favorable safety profile when rTCR-T cells are armored and enhanced with the PD1-41BB costimulatory switch protein (CSP) at the American Association for Cancer Research (AACR) Annual Meeting 2024 taking place April 5-10, 2024, in San Diego, USA.
The poster presentation with the title “TCR-gated control of costimulatory switch protein (CSP) activation in rTCR-T cells expressing PD1-41BB” is available on Medigene’s website at https://medigene.com/science/abstracts/
Targeting solid tumors with TCR-T therapies still faces significant challenges. Impaired T cell functionality and T cell exhaustion are driven by several factors within the hostile solid tumor microenvironment (TME). Programmed cell death ligand-1 (PD-L1), expressed by tumor cells in the TME engages the programmed cell death protein-1 (PD-1) expressed by activated T cells and induces T cell exhaustion and facilitates tumor immune escape. This is one major factor that allows cancer cells to proliferate and metastasize without being recognized by the host immune system. To counteract this inhibitory mechanism, a PD1-41BB CSP can be co-expressed in rTCR-T cells, turning an inhibitory signal mediated via the PD-1-PD-L1 axis into a costimulatory signal that improves TCR-T cell functionality.
“Medigene’s End-to-End Platform provides differentiated approaches to address the key challenges, including the immunosuppressive TME of solid tumors, in developing effective, safe and durable TCR-T therapies. The PD1-41BB CSP is our proprietary armoring and enhancement technology that improves immune function and persistence of TCR-T cells in the TME, resulting in better efficacy and sustained anti-cancer immune responses,” said Dolores Schendel, Chief Scientific Officer of Medigene. “This latest data from our lead program MDG1015, a first-in-class, 3rd generation TCR-T therapy targeting NY-ESO-1/ LAGE-1a, armored and enhanced with our PD1-41BB CSP, shows the gating of the PD1-41BB effects through prior cancer antigen engagement with our 3S TCR. It represents a safe and effective approach to improve clinical outcomes in hard-to-treat solid tumor indications such as gastric cancer, ovarian cancer, myxoid/round cell liposarcoma, and synovial sarcoma. Based on our positive interactions for MDG1015 with regulatory authorities, we look forward to progressing our package for IND / CTA submission and expect to receive IND/CTA approval in the second half of 2024.”
The data presented in the poster demonstrated that the CSP-mediated costimulatory signal is TCR-gated, such that costimulation only takes place when a specific peptide-human leukocyte antigen (pHLA) complex is present on a tumor cell and triggers a signal through the rTCR expressed by the TCR-T cells. Enhanced, gated T cell functionality of CSP-armored rTCR-T cells increased secretion of interferon-γ (IFNγ) only when tumor cells simultaneously expressed the pHLA target antigen and PD-L1. In addition, CSP-armored rTCR-T cells showed high sensitivity in recognition of diverse tumor cell lines of different tissue origin, such as melanoma, sarcoma, and gastric cancer which varied in levels of pHLA and PD-L1 in vitro. Rapid and sustained killing of 3D tumor cell-derived spheroids only occurred when PD-L1-positive tumor cells simultaneously expressed the specific pHLA target antigen.
Importantly, no recognition of healthy cells occurred if they lacked the pHLA target antigen, irrespective of PD-L1 expression, underpinning the safety of combining the CSP with a rTCR to generate rTCR-T cells that displayed no signs of toxicity for diverse healthy tissues in vitro.
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About Medigene AG
Medigene AG (FSE: MDG1) is an immuno-oncology platform company dedicated to developing differentiated T cell therapies for treatment of solid tumors. Its End-to-End Platform is built on multiple proprietary and exclusive technologies that enable the Company to generate optimal T cell receptors against both cancer testis antigens and neoantigens, armor and enhance these T cell receptor engineered (TCR) -T cells to create best-in-class, differentiated TCR-T therapies, and optimize the drug product composition for safety, efficacy and durability. The End-to-End Platform provides product candidates for both its own therapeutics pipeline and partnering. Medigene’s lead TCR-T program MDG1015 is expected to receive IND/CTA approval in the second half of 2024. For more information, please visit https://medigene.com/
About Medigene’s TCR-T Cells
T cells are at the center of Medigene’s therapeutic approaches. Medigene’s immunotherapies help activate the patient’s own defense mechanisms, and harness T cells in the battle against cancer. Medigene’s therapies arm the patient’s own T cells with tumor-specific T cell receptors (TCRs) creating TCR-modified T cells with enhanced potential to detect and efficiently kill cancer cells.
Medigene’s approach to immunotherapy is designed to overcome the patient’s tolerance of cancer cells and tumor-induced immunosuppression. By activating the patient’s T cells outside the body, genetically modifying them with tumor-specific TCRs and expanding the resultant activated TCR-T cells, patients can rapidly be given large numbers of tumor-specific T cells to fight their cancer.
About Medigene’s MDG1015 Program
MDG1015 is a first-in-class, 3rd generation T cell receptor engineered T cell (TCR-T) therapy targeting NY-ESO-1/ LAGE-1a, a well-recognized and validated cancer testis antigen, which is expressed in multiple tumor types. MDG1015 contains our optimal affinity 3S (sensitive, specific and safe) NY-ESO-1/LAGE-1a TCR combined with our proprietary PD1-41BB costimulatory switch protein that blocks the PD1/PD-L1 inhibitory axis while simultaneously activating the T cell through the well described -41BB pathway further enhancing the activity and persistence of the TCR-T in the hostile tumor microenvironment. MDG1015 is currently undergoing IND/CTA enabling studies with IND/CTA approval expected in the second half of 2024.
About Medigene’s PD1-41BB Costimulatory Switch Protein
Checkpoint inhibition via PD-1/PD-L1 pathway:
Cells of solid tumors are sensitive to killing by activated T cells but can escape this killing activity by producing inhibitory molecules known as ‘checkpoint proteins’, such as the Programmed Death Ligand 1 (PD-L1), on their surface. When this occurs, activated T cells which express PD-1, the natural receptor for PD-L1, are inactivated. The expression of PD-L1 is an adaptive immune resistance mechanism for tumors that can help them survive and grow.
The 4-1BB (CD137) costimulatory signaling pathway:
Effective T cell immune responses to antigens typically require both a primary antigenic stimulation via the T cell receptor (TCR) and costimulatory signals. The intracellular signaling domains of the 4-1BB protein offer a well-characterized pathway to costimulation and enhanced T cell responses.
Medigene’s PD1-41BB switch receptor turns the tumor’s attempted self-defense mechanism against the tumor by substituting the inhibitory signaling domain of PD-1 with the activating signaling domain of 4-1BB. Therefore, instead of inactivating T cells, the switch receptor delivers an activating signal to TCR-T cells. PD1-41BB-modified TCR-T cells proliferate strongly in the presence of PD-L1-positive tumor cells and kill more tumor cells upon repeated exposure. Additionally, switch receptor signals enable TCR-T cells to function better with low levels of glucose or high levels of TGFß, two conditions characteristic of strongly hostile tumor microenvironments.
This press release contains forward-looking statements representing the opinion of Medigene as of the date of this release. The actual results achieved by Medigene may differ significantly from the forward-looking statements made herein. Medigene is not bound to update any of these forward-looking statements. Medigene® is a registered trademark of Medigene AG. This trademark may be owned or licensed in select locations only.
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Pamela Keck
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