Empowering T cells with tumor-specific T cell receptors (TCRs)
Patient-derived T cells are modified for adoptive T cell therapy with selected and pre-clinically tested T cell receptors (TCRs). TCRs for any selected tumor antigen are generated using Medigene’s TCR platform, based on knowledge obtained in more than 30 years of research. Medigene’s growing portfolio of different TCRs have the potential to treat broad patient populations suffering from various types of cancer.
Medigene’s TCR platform offers unique advantages:
- Originating from Medigene’s TCR platform, TCRs with selected specificities are isolated and characterized and subsequently assessed to potentially treat various types of blood cancers and solid tumors.
- Isolated TCRs are of natural origin and are chosen to have optimal affinities and hence the TCRs do not need mutational engineering to improve their capacity to find and bind tumor cells.
- The TCR platform can deliver TCRs recognizing a variety of different tumor antigens, representing either common antigens shared by tumors or patient-individual neoantigens.
- TCRs for both CD4+ and CD8+ T cells can be generated, which recognize peptide fragments presented by different MHC class I and MHC class II alleles, providing greater potential to for effective treatments to larger numbers of patients.
How adoptive T-cell therapy works
- The TCR is introduced into the patient T cells using a vector system.
- Modified T cells are expanded to large numbers in 10-15 days.
Structure and function of T cell receptors
T cells are distinguished from other lymphocytes by the presence of T cell receptors (TCRs) on the cell surface. TCRs allow T cells to identify cancer targets, e.g. tumor-targeted antigens presented on the surface of the tumor cells. Each T cell receptor is a heterodimeric protein complex composed of one TCR α chain and one TCR β chain. The TCR heterodimers consist of a variable and a constant region. The polypeptide chains are linked together. Each variable region provides a single antigen-binding site. The TCR is associated with a CD3 complex, which combines three transmembrane signaling molecules. TCRs recognize a peptide fragment of a TAA presented by a major histocompatibility complex (MHC) molecule on the target cell. The activation of the T cell to kill the cancer cell starts upon simultaneous binding of a T cell co-receptor complex (CD4+ or CD8+ complex with CD3) to activate the T cell.
Medigene’s TCR pipeline
Medigene’s TCR pipeline is being built to contain a collection of TCRs that recognize different antigens which are expressed by various types of tumor. Upon completion, Medigene’s TCR pipeline will enable individuals of diverse patient populations to be matched for the treatment with TCRs according to their MHC molecules and specificities for antigens expressed by tumor cells. The pipeline is built by natural TCRs with optimal affinities that can be expressed in CD4+ or CD8+ cells, selected by their specificities. Peptide fragments presented by different MHC molecules (both MHC class I and class II allotypes) can be targeted by TCRs to treat different types of tumor.
Clinical status of Medigene’s TCR therapies
Medigene’s first company-sponsored clinical trial with a proprietary TCR is planned to start in early 2018. In July 2017, Medigene has therfore submitted a clinical trial application to the German regulatory authority, Paul-Ehrlich-Institut (PEI). A GMP-compliant manufacturing process for adoptive T cell therapy using TCR-modified T cells was established together with EUFETS GmbH.
In addition, Medigene is collaborating with the Max-Delbrück-Center (MDC) and Charité Hospital in Berlin (Germany) to start an investigator initiated (IIT) TCR study in Germany for patients with relapsed or refractory multiple myeloma (MM). This IIT is funded by the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; BMBF) over the next years. Patients’ T cells will be equipped with TCRs recognizing the tumor-targeted antigen MAGE-A1. The Charité Hospital will conduct and sponsor the study. The MDC is responsible for GMP production and cellular analytics. Medigene provided regulatory support and consulting on validated analytics and GMP production.