Automated in vitro testing could reveal better neoantigens that activate more effective killer T cell responses –

Two “Nature” publications show general need for better prediction and testing as performed by Medigene

PLANEGG, Germany I August 28, 2017 I Medigene AG (FSE: MDG1, Prime Standard, TecDAX), will demonstrate the use of its automated high throughput screening (HTS) platform, combined with in silico bioinformatic tools, to identify suitable and safe neoantigens for patient-individualized immunotherapies in a presentation at the Immuno-Oncology Summit from 28 August – 1 September in Boston, USA.

Prof. Dolores Schendel, Medigene’s CEO and CSO, will discuss how Medigene’s recent investments into novel technologies for discovering and developing therapeutics based on TCR-modified T cells and dendritic cell vaccines also offer avenues for developing therapeutics targeting neoantigens. She will summarize Medigene’s latest findings on achieving improved selection of better and safer neoantigens for use in immunotherapy during her oral presentation on 1 September at 11.30 AM on the topic: “High-Throughput Functional Screening of Neoantigens for Vaccines and TCR-Based Adoptive T Cell Therapies”.

Neoantigens are newly created tumor antigens that arise as a result of mutations that occur within a developing tumor. Some such mutations can be excellent targets for antitumor immune responses since they are unique to tumor cells and not present in healthy tissues. Medigene has invested substantially over the past two years in an automated HTS platform for antigen identification and T cell receptor (TCR) discovery for its clinical programs in immunotherapy. These well-developed HTS approaches are now also applied to assess computer-algorithm-predicted neoantigens for their actual functional capacity to activate living T cells in vitro. Furthermore, Medigene utilizes its growing in silico bioinformatic tool-box to preclude potential dangerous cross-reactivity of neoantigen-specific immune responses towards partial-matched epitopes present in healthy tissues. This provides an extra measure of safety in the choice of neoantigens for use in vaccine and TCR development. This approach could potentially be developed either for vaccines alone or as part of a two-pronged approach in combination with TCR-modified T cells for adoptive cell transfer.

The relevance of Medigene’s approach is underpinned by two recent publications in “Nature” from Ott et al. (1) and Sahin et al. (2) that show the power of neoantigens to induce strong immune responses with associated clinical efficacy in melanoma patients with advanced disease. In both studies, the neoantigens used for vaccination against the patients’ own tumors were chosen by computer-based algorithms that predict mutant peptides that may allow activation of CD4- and/or CD8-mediated T cell responses. Immune monitoring of the actual CD4 and CD8 T cell responses that developed in patients following neoantigen-based vaccination showed that 50-60% of predicted CD4 responses were detected against the selected vaccine neoantigens but only 16-29% of the predicted CD8 T cell responses were observed.

These findings underline general observations that selection of neoantigens that bind to MHC class II molecules and activate CD4 T cells is more successful than algorithm-based selection of peptides that are presented by MHC class I molecules and lead to CD8 T cell activation.
Medigene’s HTS approach that allows rapid in vitro analysis of CD8 activation by selected neoantigens, followed by in silico assessment of potential cross-reactivity aid the selection of better and safer neoantigens that should more effectively activate CD8 killer T cell responses through patient-individualized neoantigen-based vaccines and by use of adoptive T cell transfer of T cells expressing neoantigen-specific TCRs.

Medigene is currently focusing its efforts on the development of its proprietary T cell based immunotherapies and has no ongoing pre-clinical development efforts underway in the neoantigen field. However, neoantigen-specific immunotherapies have the potential to play an important role in the future treatment of cancer and Medigene has now valuable tools available in this field.

About Medigene’s TCR technology: Medigene’s TCR technology for adoptive T-cell therapy is one of the company’s three highly innovative and complementary immunotherapy platforms in immuno-oncology.

The TCR technology aims at arming the patient’s own T cells with tumor-specific T-cell receptors (TCRs). The receptor-modified T cells are then able to detect and efficiently kill tumor cells. This immunotherapy approach attempts to overcome the patient’s tolerance towards cancer cells and tumor-induced immunosuppression by activating and modifying the patient’s T cells outside the body (ex vivo).

TCR therapy is developed to utilize a higher number of potential tumor antigens than other T cell-based immunotherapies, such as chimeric antigen receptor T cell (CAR T) therapy. Medigene is preparing the clinical development of its first TCR candidates and is establishing a pipeline of recombinant T-cell receptors, and has established Good Manufacturing Practice (GMP)-compliant processes for their combination with patient-derived T cells.

Medigene’s first TCR immunotherapy “MDG1011” will be tested in a clinical Phase I/II trial intended to be started by the end of 2017.

Besides the planned company-sponsored TCR trial, Medigene is involved in the preparation of an investigator-initiated trial (IIT) with TCRs in multiple myeloma (MM) to be conducted by the Charité – Universitätsmedizin Berlin in cooperation with the Max Delbrück Centre (MDC), Berlin.

(1) Nature. 2017 Jul 13;547(7662):217-221. doi: 10.1038/nature22991. Epub 2017 Jul 5.
(2) Nature. 2017 Jul 13;547(7662):222-226. doi: 10.1038/nature23003. Epub 2017 Jul 5.

Medigene AG (FSE: MDG1, ISIN DE000A1X3W00, Prime Standard, TecDAX) 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 associated projects currently in preclinical and clinical development.

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SOURCE: Medigene