Development of adoptive T cell immunotherapies targeting peptide-MHC antigens for Ewing Sarcoma using non-viral delivery platforms

• Applicant: Dr. Maximilian Koch
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology ; Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 551714776

Cellular immunotherapies are a novel kind of treatment leveraging modified living immune cells instead of synthetic drugs and have delivered impressive outcomes so far. Their successful applications are continuously extended, improving the prognosis of many diseases. On the other side and despite of the intensive application of traditional treatments such as surgery, radiotherapy and chemotherapy, mortality rates for some cancer entities like the pediatric bone cancer Ewing sarcoma are relatively bad. Further, current manufacturing principles of cellular immunotherapies are expensive and suffer from basic conceptual weaknesses, increasing the difficulty for launching new clinical trials and achieving broad applications. In this working program, I seek to develop a non-viral cellular immunotherapy targeting an already identified peptide of the intracellular cancer-testis antigen lipase member I (LIPI), which is generally expressed by Ewing sarcoma. The eventual resulting product will have been tested in extensive in vitro and in vivo orthotopic NSG xenograft models and therefore will be ready for clinical trials. Since I will target an HLA restricted epitope, first a T cell receptor (TCR) isolated from the naïve repertoire of healthy individual that was identified by the hosting lab will be used as antigen receptor. I will develop a novel, clinic-ready non-viral introduction approach similar to orthotopic TCR replacement to express the LIPI-specific TCR using homology independent targeted integration with nanoplasmid DNA. The engineered T cell’s effector function will be compared to products of conventional lentiviral delivery, which’s random integration brings relevant disadvantages, as well as products of orthotopic TCR replacement, which lacks sufficient efficiency. Further, by using a single-chain variable fragment library, I will create TCR-mimicking chimeric antigen receptor (TCRm-CAR) T cells with potentially increased affinities to LIPI compared to TCRs from the naïve repertoire that underwent thymic negative selection against self-antigens. I am convinced that this work will advance the field of cellular therapies in general and specifically will provide new treatment possibilities for patients with recurrent and refractory Ewing Sarcoma.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Sabine Heitzeneder