Empowering T cells with tumor-specific T cell receptors (TCR-Ts)
Patient-derived T cells are modified for adoptive T cell therapy with selected and pre-clinically tested T cell receptors (TCR-Ts). TCR-Ts for any selected tumor antigen are generated using Medigene’s TCR-T platform, based on knowledge obtained in more than 30 years of research. Medigene’s growing portfolio of different TCR-Ts have the potential to treat broad patient populations suffering from various types of cancer.
Medigene’s TCR-T platform offers unique advantages:
- Originating from Medigene’s TCR-T platform, TCR-Ts with selected specificities are isolated and characterized and subsequently assessed to potentially treat various types of blood cancers and solid tumors.
- Isolated TCR-Ts are of natural origin and are chosen to have optimal affinities and hence the TCR-Ts do not need mutational engineering to improve their capacity to find and bind tumor cells.
- The TCR-T platform can deliver TCR-Ts recognizing a variety of different tumor antigens, representing either common antigens shared by tumors or patient-individual neoantigens.
- TCR-Ts 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-T 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-T pipeline
Medigene’s TCR-T pipeline is being built to contain a collection of TCR-Ts that recognize different antigens which are expressed by various types of tumor. Upon completion, Medigene’s TCR-T pipeline will enable individuals of diverse patient populations to be matched for the treatment with TCR-Ts according to their MHC molecules and specificities for antigens expressed by tumor cells. The pipeline is built by natural TCR-Ts 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 TCR-Ts to treat different types of tumor.
Clinical status of Medigene’s TCR therapies
End of March 2018, Medigene announced the start of the Phase I/II clinical trial with TCR-T cell immunotherapy MDG1011 for the treatment of various types of blood cancer. MDG1011 is Medigene’s first clinical TCR-T immunotherapy product candidate and the trial with MDG1011 is the first clinical trial with a TCR-T therapy in Germany.
In Phase I of the trial, approximately 12 blood cancer patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or multiple myeloma (MM) are to be treated. In total (Phase I and Phase II) roughly 92 patients should be included in the trial. Patients are first tested for suitable Human Leukocyte Antigen (HLA) status and then whether their tumor cells are positive for the expression of the PRAME antigen. Only if these basic requirements are met, among other inclusion criteria, can the respective patient be enrolled into the clinical trial. As a first step, an apheresis is performed to isolate the patient’s own T cells. These are then equipped with Medigene’s specific PRAME TCRs and subsequently expanded. After comprehensive quality testing of the T cell therapy product the patient undergoes a preparative chemotherapy and a one-time infusion of MDG1011. In the early stages of this clinical development, Medigene expects a production time of about six weeks from the beginning of an apheresis process until completion of the cell product.
For this “first-in-country” TCR-therapy trial in Germany, Medigene has trained and opened three study centers to conduct this personalized cell therapy so far. The university hospitals in Regensburg, Erlangen and Würzburg are actively screening to identify suitable patients and enroll them in the trial. Medigene is undertaking intensive preparations with a number of additional hospitals in order to increase the number of centers to allow for an accelerated patient recruitment.
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 TCR-Ts 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.