T cell receptor gene therapy of cancer

• Applicant: Professor Dr. Matthias Leisegang
• Subject Area: Immunology ; Cell Biology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409512914

Adoptive T cell transfer stands out among other therapies in being able to eradicate large and long-established human cancers even when they can no longer be cured surgically. Recent clinical experience supports the importance of mutation-specific T cells for cancer immunotherapy when inhibiting T cell checkpoints or when adoptive therapy using tumor-infiltrating lymphocytes was therapeutically effective. Unfortunately, the success of such immunotherapies has so far been restricted to relatively few cases. The efficacy might be limited because treatments often rely on stimulating tolerant T cells, which revert into an inactive state after transient activation. To circumvent this shortcoming, we propose that the transfer of genes encoding mutation-specific T cell receptors (TCRs) into fresh, unbiased T cells isolated from the patient`s peripheral blood could provide more effective T cells for adoptive therapy. Mutations are usually the cause of tumor development and mutant antigens are therefore found in every cancer, providing a constant source of T cell targets for therapeutic intervention - designated as TCR gene therapy. The long-term objective of this proposal is to identify the fundamental criteria and approaches to select mutation- specific TCRs that will be effective for clinical TCR gene therapy and thereby to overcome the current hit-or-miss approach. Aim 1 focuses on the definition of parameters that are impacted by TCR affinity and that determine the in vivo function of TCR-engineered T cells. Experiments in Aim 2 will determine whether patient-derived T cells can be used as reliable source for mutation-specific TCRs or whether mutation-specific TCRs must be isolated from antigen-free environments to achieve high therapeutic efficacy. All experiments in this application will focus on human TCRs and human tumor antigens with the ultimate goal to identify TCRs for clinical application.

• DFG Programme: Research Grants