IRW-News: Medigene AG: Medigene AG: Medigene presents convincing in vivo data on the use of PD1-41BB-enhanced TCR T cells against solid tumors | message
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IRW-PRESS: Medigene AG: Medigene AG: Medigene presents convincing in vivo data on the use of PD1-41BB-enhanced TCR T cells against solid tumors
Symposium talk and poster presentation at the TCR-based Therapies Summit, 8.-10. June 2021
Planegg / Martinsried (June 9th, 2021) – Medigene AG (Medigene, FWB: MDG1, Prime Standard), an immuno-oncology company with clinical projects focused on the development of T-cell-directed cancer therapies, presents convincing new preclinical data on its leading T. Cell receptor (T cell receptor, TCR) candidate “TCR-4”. This TCR targets solid tumors and, in combination with the PD1-41BB switch receptor, overcomes the highly immunosuppressive microenvironment of solid tumors. The data support Medigene’s decision to advance TCR-4 against PRAME-positive cancer.
The presentations will be held as part of the TCR-based Therapies Summit, a Digital Event, which will take place June 8-10, 2021. Both the presentation and the poster can be found on the Medigene website: https://www.medigene.de/technologien/abstracts
TCR-4, which specifically recognizes the PRAME cancer antigen in connection with HLA-A2, was combined with Medigene’s lead functional T-cell enhancer, the PD1-41BB switch receptor. This combination has been tested in preclinical experiments under demanding conditions to determine its safety and effectiveness.
The safety of TCR-T cells that carry both TCR-4 and PD1-41BB has been demonstrated in vitro. There was no unspecific toxicity: cells from normal healthy tissue (such as lungs, bones, heart and kidneys, among others) that did not express the target antigen PRAME were not killed. In addition, no toxicity against HLA-A2 negative cells was observed.
TCR-T cells that carry both TCR-4 and PD1-41BB have shown better effectiveness against cancer both in vitro and in vivo. In vitro, they were functionally more active against tumor cells expressing the target antigen PRAME. They produced increased amounts of important cytokines (messenger substances) and were better able to kill tumor cells several times in a row. The improved performance has also been demonstrated in vivo. We had previously shown that TCR-T cells with TCR-4 alone are sufficient to eliminate PD-L1-negative melanoma tumors in vivo (AACR 2021). The new data come from a more sophisticated in vivo model of aggressively growing, PD-L1 positive melanoma and show that only TCR-T cells that carry the combination of both TCR-4 and PD1-41BB are associated with tumors were able to eliminate these strong immunosuppressive properties.
Prof. Dolores Schendel, CEO and Chief Scientific Officer at Medigene: “Tumors that express PD-L1 are highly immunosuppressive, which makes them the most difficult to treat solid cancers in medicine. The results we have presented show the outstanding specificity and convincing Functionality of our improved TCR-T cells, which carry both TCR-4 and the PD1-41BB switch receptor, against aggressively growing PRAME and PD-L1 positive solid tumor cells to select this impressive product candidate for further development towards clinical trials. “
— End of press release —
Medigene AG (FWB: MDG1, ISIN DE000A1X3W00, Prime Standard) is a listed biotechnology company with headquarters in Planegg, Martinsried near Munich. With scientific expertise, Medigene is working on the development of innovative immunotherapies to increase T-cell activity against solid cancers in areas with a high unmet medical need. The first product candidates are in clinical development.
Medigene pursues the strategy of advancing its own therapeutic approaches through to clinical proof of concept. In addition, the company offers selected partners opportunities to discover and develop therapeutic approaches based on its proprietary technology platforms. In return, Medigene expects upfront and milestone payments as well as reimbursement of research and development costs and future royalties.
Further information at https://www.medigene.de
About Medigenes TCR-Ts
Medigene’s therapeutic approaches focus on T cells. With the help of Medigenes immune therapies, the patient’s own defense mechanisms are to be activated and T cells are made ready for the fight against tumor cells. Medigene’s therapies aim to equip the patient’s own T cells with tumor-specific T cell receptors (T cell receptors, TCRs). The resulting TCR-Ts should be able to recognize tumor cells and destroy them efficiently.
This immunotherapeutic approach tries to overcome the existing tolerance towards cancer cells and the tumor-induced suppression of an immune response in the patient. For this, the patient’s T cells are activated outside the body, genetically modified with tumor-specific TCRs and then multiplied. In this way, a large number of specific T cells that can fight the tumor can be made available to patients within a short time.
Via Medigenes PD1-41BB switch receptor
Checkpoint inhibition via the PD1-PDL1 signaling pathway: It is known that solid tumor cells can be killed specifically by activated T cells. The tumor cells can escape these attacks by expressing inhibiting molecules on their surface, so-called “checkpoint proteins” such as “Programmed Death Ligand 1” (PD-L1). In this case, T cells that express PD-1, the natural receptor for PD-L1, are inactivated. The expression of PD-L1 by tumors thus represents an adaptive immune resistance mechanism that can lead to tumor survival and growth.
The co-stimulatory signal pathway via 4-1BB: An effective immune reaction of T cells to antigens typically requires that, in addition to the primary stimulation by the antigen via the T cell receptor (TCR), costimulatory signals are also received. The intracellular signal 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 T cells to PD-L1 on tumors. In the switch receptor, the inhibitory signal domain of PD-1 was replaced by the activating signal domain of 4-1BB. As a result, the switch receptor transmits an activating signal to the TCR T cells via PD-1 instead of the normally inhibiting signal. As a result, the PD1-41BB-modified TCR-T cells can multiply strongly in the presence of PD-L1-positive tumor cells and, with repeated exposure, induce greater killing of the tumor cells. In addition, the signals transmitted by the switch receptor also improve the metabolic fitness of TCR T cells and enable them to function better despite low glucose levels or high amounts of the immunosuppressive factor TGF – both characteristics that are typical of a highly hostile environment around the tumor are around.
PRAME (PReferentially expressed antigen in MElanoma) is a tumor antigen from the cancer testis antigens family that is overexpressed in various solid tumors. Expression in healthy tissue is restricted to the testis, which is itself an immune-privileged tissue that cannot normally be attacked by the body’s own immune cells. This makes PRAME very suitable as a target antigen for TCR-T therapies.
This release contains certain forward-looking statements. These reflect the opinion of Medigene as of the date of this announcement. The results actually achieved by Medigene may differ materially from the statements made in the forward-looking statements. Medigene is not obliged to update forward-looking statements. Medigene is a trademark of Medigene AG. This trademark may be owned or licensed in selected countries.
Dr. Gary Waanders, Dr. Anna Niedl
Tel .: +49 89 2000 3333 01
Sender: Medigene AG
Address: Lochhamer Strae 11, 82152 Planegg / Martinsried
Contact person: Medigene PR / IR
Tel .: +49 89 2000 3333 01
ISIN (s): DE000A1X3W00 (share)
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