Abstract 863: A novel SIRPA based FiCAR T cells therapy targeting TYRP1 to treat melanoma patients

Abstract Background: The first-generation immune checkpoint inhibitors anti-PD1/PDL1 and anti-CTLA-4 either alone or in combination have shown tremendous clinical success in BRAF wild type melanoma cancer patients. However, there is still a high unmet need as great proportion of melanoma patients relapsed after treatment with first generation immune checkpoint inhibitors and BRAF mutant patient relapsed after treatment BRAF inhibitors. Chimeric antigen receptor (CAR) expressing T cells have shown clinical success in hematological malignancies, recent studies have shown that CAR Ts cells were detected in circulation a decade after the first CD19 CART cell injection. Here, we generated a novel SIRPa based extracellular extension TYRP1 targeting CAR T cell, here onwards referred as TYRP1 FiCAR, that work independent of the tumor mutation burden and BRAF status. TYRP1 targeting FiCARs could be an alternative and attractive therapeutic strategy for treatment relapsed melanoma patients. Methods & Results: A well-known anti-TYRP1 binder flanvotumab’s scfv was inserted into FiCAR-structure containing CD28 and CD3zeta intra cellular signaling domain and those CAR T cells were studied for both in vitro and in vivo function. TYRP1 based FiCAR grew normally and good transduction rates with low vector copy numbers were achieved. In addition, upon co-culture of TYRP1 FiCAR T cells with tumor cells expressing TYRP1 a rapid and significant release of pro-inflammatory cytokines was detected. Moreover, killing of the target cells were observed by the TYRP1 FiCAR T cells. To study the in vivo functionality of the TYRP1 FiCAR-T cells, NSG mice were inoculated with melanoma cells subcutaneously. Three weeks after the inoculation mice were intravenously injected with a single dose of TYRP1 FiCAR T cells. Discussion: The data presented here shows a proof-of-concept study for the FiCAR structure to work against TYRP1 antigen. TYRP1 FiCAR T cells upon co-culture with TYRP1 expressing tumor elicited a significant increase in effector cytokines production and has not shown any signs of tonic signaling. Additionally, TYRP1 FiCAR T cells were able to kill tumor cells efficiently reaching 100% maximal killing. In vivo, TYRP1 FiCAR T cells significantly delayed tumor growth. However, full regression of the tumors was not achieved in vivo. Collectively, the in vitro and in vivo data support further optimization of TYRP1 FiCAR T cells to treat melanoma patients refractory to immunotherapy and BRAF inhibitors. Citation Format: Henrik Paavilainen, Sakari Pöysti, Veera Nikoskelainen, Marie Nyman, Anil K. Thotakura. A novel SIRPA based FiCAR T cells therapy targeting TYRP1 to treat melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 863.