Medigene's PD1-41BB Switch Receptor Enhances TCR-T Cell Activity Towards Solid Tumors
MARTINSRIED, Germany and MUNICH, Germany, June 22, 2020 (GLOBE NEWSWIRE) -- Medigene AG (Medigene, FSE: MDG1), a clinical stage immuno-oncology company focusing on the development of T cell immunotherapies, presents insights from preclinical studies on its PD1-41BB switch receptor at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II taking place from 22 – 24 June 2020. The e-poster is available online today on the first day of the virtual conference as well as on Medigene’s website.
Medigene’s scientists demonstrated that the PD1-41BB switch receptor significantly improves the functional activity of T cell receptor-modified T cells (TCR-Ts) especially against solid tumor cells. Many solid tumors create a “hostile” microenvironment that suppresses immune cell attack, enabling tumors to survive and grow. To this end, tumor cells employ so-called “checkpoint mechanisms” to impede T cell activity. One prominent inhibitory axis exploited by tumors, the PD1-PDL1 pathway, is known to shut down T cell activity in tumors. Medigene’s PD1-41BB molecule is designed to convert the PD-1 "stop" signal induced by tumor cells to a "go" command by switching signals inside the T cells to activation, thereby overcoming the PD1-PDL1 inhibitory checkpoint blockade.
Prof. Dolores Schendel, Chief Executive Officer and Chief Scientific Officer of Medigene: “In preclinical studies we could show that the addition of the PD1-41BB switch receptor to our TCR-Ts strongly enhances the antigen-specific functions of the TCR-Ts against solid tumors.
“Based on these promising results, we believe that the PD1-41BB switch receptor will ultimately enable our TCR-Ts to be more active in patients with solid tumors which have previously been very difficult to treat due to multiple mechanisms of immunosuppression. Furthermore, exploiting the PD1-PDL1 pathway to increase TCR-T activity through our switch receptor can be done in a targeted, localized manner, thereby avoiding the challenges of systemic side-effects that accompany treatment with existing checkpoint inhibitors.”
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 usually 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 TGF-ß, two conditions that are characteristic of strongly hostile tumor microenvironments.
Medigene AG (FSE: MDG1, ISIN DE000A1X3W00, Prime Standard) is a publicly listed biotechnology company headquartered in Martinsried near Munich, Germany. The company is developing highly innovative immunotherapies to target various forms and stages of cancer. Medigene concentrates on the development of personalized T cell-based therapies, with a focus on T cell receptor-modified T cells (TCR-Ts) and associated projects currently in pre-clinical and clinical development.
For more information, please visit www.medigene.com
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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