Medigene Presents Enhanced Tumor Cell Killing Effects upon Addition of PD1-41BB Switch Receptor to TCR-T Therapies
Planegg/Martinsried, 22 June 2023. Medigene AG (Medigene, FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, today presents an overview on elevated activity of T cell receptor engineered T cell (TCR-T) therapies when combining Medigene´s PD1-41BB switch receptor with T cell receptors (TCRs) targeting different antigens at the Immuno-Oncology Summit Europe June 20-22, 2023 in London, UK.
The presentation with the title “PD1-41BB Switch Receptor Technology Added to TCR-Ts Further Enhances Antitumor Activity in vitro and in vivo compared to TCR alone” will be available after the conference on Medigene’s website: https://medigene.com/science/abstracts/
The data provides an overview on the enhanced activity of TCR-T therapy seen with the combination of the PD1-41BB switch receptor with TCRs specific for different target antigens. Irrespective of the target antigen specificity, TCRs combined with the PD1-41BB switch receptor displayed superior T cell functionality in vitro and increased T cell efficacy in vivo as compared to TCR-T cells without the switch receptor (“naked” TCR).
“The success of TCR-T therapy against solid tumors is dependent on a safe, sensitive and specific TCR. However, the immunosuppressive tumor microenvironment (TME) is a major challenge for many T cells, including engineered T cells. We are pleased to present compelling preclinical data that demonstrate enhanced T cell functionality by incorporating our PD1-41BB switch receptor into TCR-T cell therapy to overcome the TME,” said Prof. Dolores Schendel, Chief Scientific Officer at Medigene. “We believe that the integration of our PD1-441B switch receptor with adoptive cell therapies has the potential to overcome challenges such as high PD-L1 expression levels which typically hinder TCR-T cell functionality in the TME.”
The PD1-41BB costimulatory switch receptor is an highly innovative receptor that enhances TCR-T cell functionality, enabling it to mitigate against the immunosuppressive TME, improve efficacy as well as enable sustained immune responses. In the preclinical models, the expression of the PD1-41BB switch receptor led to enhanced cytotoxicity and proliferative capacity of TCR-T cells surpassing the capabilities of TCR-T cells expressing the TCR alone (“naked” TCR).
Cancer cell lines exposed to the combination of TCR+PD1-41BB displayed elevated interferon-gamma (IFNγ) release as a surrogate parameter of superior TCR-T cell functionality when compared to the naked TCR. The observed effect was restricted to cell lines expressing both the appropriate antigen and PD-L1, underpinning the specificity of the TCR in combination with the PD1-41BB switch receptor. In presence of the PD1-41BB switch receptor, enhanced TCR-T cell proliferation and elevated killing ability of 3D tumor spheroids was detected as compared to the naked TCR. Also, a stem cell-like and central memory T cells were were maintanted in presence of the combination of TCR+PD1-41BB and were comparable to the levels observed for the naked TCR.
The killing efficacy of TCR-T cells in vivo was dependent on the antigen expression on tumor cells. In presence of high levels of antigen, the naked TCR prolonged survival in vivo and attenuated tumor growth compared to cancer cells expression with low levels of antigen. Exposure to TCR-T cells co-expressing the combination of TCR+PD1-41BB restored the anti-tumor effects in cancer cells with low antigen levels. The combination of TCR+PD1-41BB exhibited remarkable clinical efficacy in these preclinical in vivo xenograft models, also in cancer cells displaying low levels of targetable antigen.
The TME is subject to metabolic alterations limiting the benefit of immune responses. In vitro data showed that the combination of the PD1-41BB switch receptor with TCRs can bypass this barrier as enhanced cytotoxicity and proliferative capacity was observed even under low glucose.
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Medigene AG (FSE: MDG1) is an immuno-oncology platform company dedicated to developing T cell therapies to effectively eliminate cancer. Its end-to-end technology platform, built on multiple proprietary and exclusive product development and product enhancement technologies, allows Medigene to create best-in-class differentiated, T cell receptor engineered T cell (TCR-T) therapies for multiple solid tumor indications that are optimized for both safety and efficacy. This platform provides product candidates for both its in-house therapeutics pipeline and partnering. For more information, please visit www.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 significant numbers of tumor-specific T cells to fight their cancer.
About PD1-41BB Costimulatory Switch Receptor
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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