T cell-directed enzyme/prodrug therapy (TDEPT) combines tumor-targeted adoptive T cell therapy with tumor-specific chemotherapy for effective eradication of solid tumors

• Applicant: Dr. Johannes Kühle
• Subject Area: Hematology, Oncology
• Term: from 2015 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 283022602

The standard treatment of solid tumors like pancreatic cancer consists of chemotherapy in combination with radiation therapy. However, both therapies are limited by severe side effects due to destruction of healthy tissues. The development of specific targeted cancer therapies - like adoptive T cell therapy - is therefore of great importance. Adoptive T cell therapy involves the isolation, modification and ex vivo expansion of T cells that mediate targeted killing of tumor cells after infusion into the patient. During the process, specificity for tumor cells is generated by expression of a chimeric antigen receptor (CAR) which recognizes a tumor-associated antigen. In recent clinical trials, CAR T cell therapy has proven to be an exceptionally effective treatment option for refractory lymphoblastic leukemia. However, treatment of solid tumors by adoptive T cell therapy has been hindered by short-lived responses and relapses caused by antigen-negative tumor cell populations. The aim of our proposal is to reduce the frequency of antigen-negative tumor relapses by generation of bifunctional CAR T cells for adoptive transfer. Therefore, tumor-specific CAR T cells are modified with a CAR-inducable transgene cassette allowing secretion of the enzyme Cytosine Deaminase (bCD) which is capable of converting the non-toxic prodrug 5-Fluorocytosin (5-FC) into the potent cytostatic drug 5-Fluorouracil (5-FU). Such bifunctional T cells secrete bCD specifically after CAR-mediated activation and therefore lead to intra-tumoral accumulation of the enzyme in a tumor-antigen dependent manner during the primary cytotoxic attack of the tumor. In a second step, systemic application of 5-FC can then mediate a chemotherapeutic effect by tumor-specific localized generation of 5-FU, killing residual (antigen-negative or -positive) tumor cells meanwhile avoiding systemic side effects of 5-FU. Our concept of T cell-directed enzyme/prodrug therapy (TDEPT) thus maximizes the anti-tumor effect of adoptive immunotherapy by allowing primary antigen-specific cytotoxic activity and secondary antigen-independent chemotherapeutic activity through bifunctional T cells. We want to test the beneficial effect of our concept in the context of T cell therapy for pancreatic carcinoma using an available clinically relevant mouse model.

• DFG Programme: Research Grants