On April 8, 2024 Medigene AG (Medigene or the "Company", FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, reported superior recombinant T cell receptor (rTCR) engineered T cell functionality as well as a favorable safety profile when rTCR-T cells are armored and enhanced with the PD1-41BB costimulatory switch protein (CSP) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 taking place April 5-10, 2024, in San Diego, USA (Press release, MediGene, APR 8, 2024, View Source [SID1234641844]).
The poster presentation with the title "TCR-gated control of costimulatory switch protein (CSP) activation in rTCR-T cells expressing PD1-41BB" is available on Medigene’s website at View Source
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
Targeting solid tumors with TCR-T therapies still faces significant challenges. Impaired T cell functionality and T cell exhaustion are driven by several factors within the hostile solid tumor microenvironment (TME). Programmed cell death ligand-1 (PD-L1), expressed by tumor cells in the TME engages the programmed cell death protein-1 (PD-1) expressed by activated T cells and induces T cell exhaustion and facilitates tumor immune escape. This is one major factor that allows cancer cells to proliferate and metastasize without being recognized by the host immune system. To counteract this inhibitory mechanism, a PD1-41BB CSP can be co-expressed in rTCR-T cells, turning an inhibitory signal mediated via the PD-1-PD-L1 axis into a costimulatory signal that improves TCR-T cell functionality.
"Medigene’s End-to-End Platform provides differentiated approaches to address the key challenges, including the immunosuppressive TME of solid tumors, in developing effective, safe and durable TCR-T therapies. The PD1-41BB CSP is our proprietary armoring and enhancement technology that improves immune function and persistence of TCR-T cells in the TME, resulting in better efficacy and sustained anti-cancer immune responses," said Dolores Schendel, Chief Scientific Officer of Medigene. "This latest data from our lead program MDG1015, a first-in-class, 3rd generation TCR-T therapy targeting NY-ESO-1/ LAGE-1a, armored and enhanced with our PD1-41BB CSP, shows the gating of the PD1-41BB effects through prior cancer antigen engagement with our 3S TCR. It represents a safe and effective approach to improve clinical outcomes in hard-to-treat solid tumor indications such as gastric cancer, ovarian cancer, myxoid/round cell liposarcoma, and synovial sarcoma. Based on our positive interactions for MDG1015 with regulatory authorities, we look forward to progressing our package for IND / CTA submission and expect to receive IND/CTA approval in the second half of 2024."
The data presented in the poster demonstrated that the CSP-mediated costimulatory signal is TCR-gated, such that costimulation only takes place when a specific peptide-human leukocyte antigen (pHLA) complex is present on a tumor cell and triggers a signal through the rTCR expressed by the TCR-T cells. Enhanced, gated T cell functionality of CSP-armored rTCR-T cells increased secretion of interferon-γ (IFNγ) only when tumor cells simultaneously expressed the pHLA target antigen and PD-L1. In addition, CSP-armored rTCR-T cells showed high sensitivity in recognition of diverse tumor cell lines of different tissue origin, such as melanoma, sarcoma, and gastric cancer which varied in levels of pHLA and PD-L1 in vitro. Rapid and sustained killing of 3D tumor cell-derived spheroids only occurred when PD-L1-positive tumor cells simultaneously expressed the specific pHLA target antigen.
Importantly, no recognition of healthy cells occurred if they lacked the pHLA target antigen, irrespective of PD-L1 expression, underpinning the safety of combining the CSP with a rTCR to generate rTCR-T cells that displayed no signs of toxicity for diverse healthy tissues in vitro.