Planegg/Martinsried – Medigene AG (Medigene, FSE: MDG1, Prime Standard), a clinical stage immuno-oncology company focusing on the development of T cell immunotherapies, presents compelling new pre-clinical data on its lead T cell receptor (TCR) candidate “TCR-4” targeting solid tumors combined with its PD1-41BB switch receptor to overcome the highly immunosuppressive solid tumor microenvironment. The data underpins Medigene’s decision to advance TCR-4 in PRAME-positive cancer.
The presentations are being made as part of the TCR-based Therapies Summit, a Digital Event being held 8-10 June 2021. Both the presentation and the poster can be found on Medigene’s website: https://www.medigene.com/technologies/abstracts
TCR-4 which specifically targets the PRAME cancer antigen in the context of HLA-A2 was combined with Medigene’s lead functional T cell enhancer, the PD1-41BB switch receptor, and evaluated pre-clinically against a set of key performance hurdles to determine safety and efficacy.
The safety of the TCR-T cells carrying both TCR-4 and PD1-41BB was demonstrated in vitro. There was no off-target toxicity: cells which did not express the target antigen PRAME, including a panel of normal healthy tissues (such as lung, bone, heart and kidney among others), were not killed. Furthermore, no toxicity was observed against HLA-A2 negative cells.
TCR-T cells carrying both TCR-4 and PD1-41BB demonstrated enhanced anti-cancer efficacy both in vitro and in vivo. In vitro, they were functionally more active against tumor cells expressing the PRAME target, producing increased levels of key cytokines (messenger molecules) and improving the sustainability of repeated killing activity. The improved performance was echoed in vivo. We had previously shown that TCR-T cells with TCR-4 alone were sufficient to eliminate PD-L1 negative melanoma tumors in vivo (AACR 2021). The new data come from a more challenging in vivo model of aggressively growing, PD-L1 positive melanoma and show that only TCR-T cells carrying the combination of both TCR-4 and PD1-41BB could eliminate tumors with these highly immunosuppressive characteristics.
Dolores Schendel, Chief Executive Officer and Chief Scientific Officer at Medigene: “Tumors expressing PD-L1 are highly immunosuppressive making them the most challenging solid cancers in medicine. The results we have presented show the exquisite specificity and compelling functional potency of our enhanced TCR-T cells carrying the TCR-4 plus PD1-41BB combination against aggressively growing PRAME positive, PD-L1 positive solid tumor cells. This data gives Medigene the critical evidence it needs to select this impressive product candidate for further development towards clinical trials.”
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Medigene AG (FSE: MDG1, ISIN DE000A1X3W00, Prime Standard) is a publicly listed biotechnology company headquartered in Planegg/Martinsried near Munich, Germany. With its scientific expertise, Medigene is working on the development of innovative immunotherapies to enhance T cell activity against solid cancers in fields of high unmet medical need. The first product candidates are in clinical development.
Medigene’s strategy is to develop its own therapies towards clinical proof-of-concept. In addition, the Company offers selected partners the opportunity to discover and develop therapies on the basis of its proprietary technology platforms. In return for such partnerships, Medigene expects to receive upfront and milestone payments as well as research and development funding and royalties on future product sales.
For more information, please visit https://www.medigene.com
About Medigene’s TCR-Ts
T cells are at the center of Medigene’s therapeutic approaches. With the aid of Medigene’s immunotherapies the patient’s own defense mechanisms are activated, and T cells harnessed in the battle against cancer. Medigene’s therapies arm the patient’s own T cells with tumor-specific T cell receptors (TCRs). The resulting TCR-Ts should thereby be able to detect and efficiently kill cancer cells.
This approach to immunotherapy aims to overcome the patient’s tolerance to cancer cells and tumor-induced immunosuppression by activating the patient’s T cells outside the body, genetically modifying them with tumor-specific TCRs and finally multiplying them. In this way, large numbers of specific T cells are made available to patients to fight the cancer within a short period of time.
About Medigene’s PD1-41BB switch receptor
Checkpoint inhibition via PD1-PDL1 pathway: Solid tumor cells are known to be sensitive to killing by activated T cells. Tumor cells can escape this killing activity by expressing inhibitory molecules, so-called ‘checkpoint proteins’, such as 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 by tumors represents an adaptive immune resistance mechanism that can lead to tumor survival and growth.
The 4-1BB co-stimulatory signaling pathway: Effective T cell immune responses to antigens typically require costimulatory signals to be received alongside the primary antigenic stimulation via the T cell receptor (TCR). The intracellular signaling domains of the 4-1BB protein offer a well-characterized pathway to positively enhance T cell responses.
Medigene’s PD1-41BB switch receptor takes advantage of the binding of PD-1 on the T cells to PD-L1 on tumors. In the switch receptor, the inhibitory signaling domain of PD-1 has been substituted with the activating signaling domain of 4-1BB. As a result, the switch receptor then delivers an activating signal to the TCR-T cells (not the usual inhibitory signal of PD-1). This enables the PD1-41BB-modified TCR-T cells to proliferate strongly in the presence of PD-L1-positive tumor cells and to mediate greater killing of tumor cells upon repeated exposure. Additionally, signals mediated through the switch receptor also enhance metabolic fitness of TCR-T cells, enabling better function in conditions of low levels of glucose or high levels of the immunosuppressive factor TGFß, two conditions that are characteristic of strongly hostile tumor microenvironments.
PRAME (PReferentially expressed Antigen in MElanoma) is a tumor antigen of the cancer-testis-antigen family which is over-expressed in various solid tumors. Expression in healthy tissue is limited to the testis, which itself is an immuno-privileged tissue that usually cannot be attacked by the body’s own immune cells. This makes PRAME very suitable as a target antigen for TCR-T therapies.
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.
Dr. Gary Waanders, Dr. Anna Niedl
Phone: +49 89 2000 3333 01
Phone: +44 7483 284 853