Improving CAR T cell therapy: Neutralisation of checkpoint ligands by recombinant co-receptors

A fundamental problem of CAR T cell-based immunotherapy is the local immunosuppression in nearly all tumor entities, which leads to the inactivation of effector cells. Despite promising successes in the field of hematological tumor diseases, only some patients can hope for permanent remission. It is already published that a large proportion of patients with DLBCL may relapse only a few months after CD19-specific CAR-T cell therapy. Another part of the patients reacts only partially or not at all to the CAR T cell therapy. The consistent neutralization of relevant immunosuppression mechanisms in tumor lesions is therefore crucial for sustained therapeutic success. This is particularly true for PD-1 and TIGIT mediated immunosuppression by tumor cells, which is very likely to contribute significantly to the formation of recurrences in haematological tumor diseases.

Current counter-regulatory strategies are based on the use of checkpoint inhibitors to counteract immunosuppression. However, the conceptual deficit lies in the lack of selectivity between tumor and healthy tissue. While a comprehensive blockade is desired in the tumor, a blockade in healthy tissue leads to severe autoaggression with life-threatening side effects due to auto-reactive T-cells.

The aim of my project is to additionally equip CAR T cells with chimeric checkpoint receptors (CCR) in order to prevent exhaustion of tumor-specific T cells by the defense mechanisms of recurrent tumor cells. This should lead to significant benefits in clinical practice by minimizing adverse events and increasing the efficiency of CAR-T cell therapy.