Melanoma-associated chondroitin sulfate proteoglycan (MCSP) as target antigen for specific immunotherapy; from the bench to the bed-side.

• Applicant: Professor Dr. Niels Schaft, Ph.D.
• Subject Area: Dermatology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 389786392

Targeting Melanoma-associated chondroitin sulfate proteoglycan (MCSP) for specific immunotherapy; from bench to bedside MCSP is a promising melanoma- and tumor-stroma-associated surface antigen. Within the previous funding period, we engaged in the induction of MCSP-specific T-cell responses, and established T cells specific for in silico-predicted HLA-A*02-restricted epitopes. These T cells failed to recognize endogenous MCSP and a peptide elution approach revealed that MCSP is apparently not processed and presented normally. Therefore we pursued the use of MCSP-specific Chimeric Antigen Receptors (CARs) to target this antigen, because they recognize MCSP in an HLA-independent fashion. In addition, MCSP was established as trogocytosis-acquired marker of tumor-specific T cells and the T-cell-stimulatory factor SLAMF6 was characterized. The Palestinian partner established the infrastructure required for cellular ex vivo and in vitro work. In the current application, we wish to take this approach to the clinic by performing a phase I clinical trial in which we intend to treat cutaneous melanoma and uveal melanoma patients with autologous T cells, which are electroporated with mRNA encoding an MCSP-specific CAR. Ten patients shall be included with the primary end-points safety and feasibility. Clinical efficacy will be addressed as secondary end-point. The Israeli partner will continue their investigation on SLAMF6 to determine whether it can be used to expand better T cells for adoptive transfer and will perform first in vivo experiments with these T cells, transfected with the MCSP-specific CAR in mice. The Palestinian group will examine the mutations and antigen-expression of non-cutaneous melanomas, which represent a large part of melanomas in the Palestinian population. With the help of a specialist for fluorescence microscopy from Erlangen, who will spend some time in Palestine, the Palestinian principal investigator, who is a cancer pathologist, will perform immunopathological investigations of tumor samples from Palestine, Israel, and Germany, including the trial patients, as well as from the CAR-treated mice of the Israeli group, to determine the inflammatory milieu, infiltration of T cells and other immune cells, and the MCSP-expression.

• DFG Programme: Research Grants
• International Connection: Israel
• Co-Investigators: Privatdozent Dr. Jan Dörrie; Galit Eisenberg, Ph.D.; Shoshana Frankenburg, Ph.D.; Professor Dr. Gerold Schuler; Privatdozentin Dr. Beatrice Schuler-Thurner
• International Co-Applicants: Professorin Dr. Areej Khatib; Dr. Michal Lotem