Planegg/Martinsried – Medigene AG (Medigene, FSE: MDG1, Prime Standard), a clinical stage immuno-oncology company focusing on the development of T cell immunotherapies, today presents new data on components of its preclinical programs targeting the development of future T cell receptor-modified T cell (TCR-T) therapies against solid cancers at the 18th Annual Meeting of the Association for Cancer Immunotherapy (CIMT) taking place on 10-12 May 2021. The three eTalk presentations can be found on Medigene’s website: https://www.medigene.com/technologies/abstracts
Component 1: Proprietary new T cell receptors (TCRs) targeting novel tumor-specific antigens that are potential solid cancer TCR-T therapy target candidates
Identifying novel tumor-specific antigens (TSAs) as targets for T cells is a vital goal in the development of effective and safe cancer immunotherapies. As Medigene has recently disclosed, ten novel tumor-specific peptides stemming from non-coding regions of the genome of tumor cells have been identified that can be recognized by TCRs. These “immunogenic” peptides were present in tumors from several patients with solid cancers of different origin (including ovarian, breast, and lung cancer), but were not detected in healthy tissues in work performed in collaboration with the University of Montréal.
To date, Medigene has isolated more than 20 TCRs of T cell clones that recognize these novel TSAs and have the potential to become next-generation TCR-T therapy candidates. Their functional and safety characterization is ongoing, as presented in the current eTalk.
Component 2: Medigene’s inducible TCR (iM-TCR) – A fine control system to switch TCR-T cells on and off
The iM-TCR system could allow physicians to avoid unwanted side effects of TCR-T therapy or to fine-tune an ongoing immune reaction. This is part of Medigene’s work on the safety and functionality of engineered T cells for adoptive transfer into patients.
The iM-TCR system controls the level of expression of an introduced TCR on the surface of T cells, thereby governing the amount of functional activity of the TCR-T cells on the cell surface. In the presence of the appropriate drug the TCRs which contain the iM-TCR signature are brought onto the T cell surface; without the drug, they are down-regulated from the surface and new TCRs are only replaced upon new specific drug induction. The presence or absence of the drug therefore determines the level of activity of the TCR-T cells, potentially giving clinicians the possibility of switching on and switching off TCR-T activity as required.
Medigene’s scientists show in the eTalk that iM-TCR-expressing cells can be tightly controlled by the dose and timing of drug-induced expression, allowing fine control of TCR-T cell activity.
Component 3: TCR-4 + PD1-41BB switch receptor – Enhanced killing of solid tumor specimens
Solid tumors grow stealthily, hiding from the immune system and evading T cell attacks, using mechanisms such as the expression of the checkpoint molecule PD-L1 on their surface. Medigene has developed the PD1-41BB switch receptor, turning the tumors’ off-signal sent by PD-L1 into an activation signal for its TCR-T cells.
In the eTalk Medigene’s scientists illustrate that adding the PD1-41BB receptor to TCR-T cells enhances their metabolic fitness and their killing of tumor cells, as demonstrated using TCR-4, Medigene’s lead TCR candidate against solid tumors. TCR-4 is a non-mutated TCR isolated from a healthy donor that, in the context of HLA-A2, specifically recognizes a peptide stemming from the PRAME protein. TCR-T cells expressing only TCR-4 have already demonstrated potent preclinical in vitro and in vivo efficacy. Adding the PD1-41BB switch receptor further improves cell killing functions and metabolic fitness of the TCR-Ts without inducing off-target toxicities.
Prof. Dolores Schendel, Chief Executive Officer and Chief Scientific Officer at Medigene: “Our high-throughput functional T cell screening platform efficiently identifies T cells and their TCRs against a wide variety of potential target antigens. The identification of novel TSAs from non-coding regions of the genome adds to the range of cancer antigens that Medigene can use as targets for these immunotherapies. We can also limit the risk of off-tumor reactivity of tumor-specific TCR-T cells through tight control of TCR surface expression using our iM-TCR system. Importantly, we believe tools such as our PD1-41BB switch receptor will allow our TCR-T cells to overcome tumor evasion from immune attacks without giving rise to potential side effects as seen, for example, when using systemic PD-1/-L1 blocking agents.
We are excited that the phenomenal progress of our technology programs is advancing our TCR-T therapies towards solid cancer indications. Our approaches could improve clinical safety and efficacy in TCR-T therapies against Medigene’s unique tumor-specific targets.”
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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