Abstract LB027: In vivo delivery of novel CD89 fusion receptor to myeloid cells by mRNA activates anti-tumor immunity

Abstract Despite the revolution provided by immunotherapy, sustained clinical benefit has yet to be achieved for most of patients with advanced solid tumors. Myeloid cells readily accumulate in tumors, in some cases contributing up to 75% of the tumor mass. While supporting tumor growth and being associated with unfavorable prognosis, myeloid cells can mediate phagocytosis of cancer cells and cytotoxic tumor killing and promote adaptive immune responses through antigen presentation and co-stimulation, therefore representing promising targets in cancer therapy. The ability to engineer circulating and tumor associated myeloid cells to activate their ability to elicit anti-tumor adaptive immunity is an attractive approach to harness systemic anti-tumor immunity. However, it remains challenging to specifically target and activate myeloid cells in vivo. To overcome this hurdle, we have developed a novel in vivo myeloid cell engineering platform in which a chimeric antigen receptor (CAR) is generated by fusing a tumor recognition scFv with the alpha chain of human Fc receptors (CD89). The stable expression and function of these receptors requires the endogenously expressed common Fc receptor gamma chain (FcRγ), which expression is mostly restricted to myeloid cells. For in vivo engineering, the construct is encapsulated and delivered in lipid nanoparticles (LNP). Trophoblast cell surface antigen 2 (TROP2) is overexpressed in most human solid epithelial cancers, as compared to low expression in corresponding normal tissue. Increased TROP2 expression has been linked to increased tumor growth and has been implicated as a prognostic marker in these cancers, supporting the development of therapies targeting TROP2. Intravenous infusion of LNP encapsulating mRNA encoding the anti-TROP2-CD89 fusion protein results in the uptake of the LNPs and expression of the chimeric receptor fusion protein in myeloid cells. In immunodeficient xenograft models of hepatocellular carcinoma and triple negative breast cancer, delivery of LNP mRNA encoding GPC3-CD89 or TROP2-CD89 fusion proteins resulted in anti-tumor efficacy, confirming the ability of this approach to program myeloid cells. Repeat dosing studies showed significant anti-tumor efficacy following bi-weekly administration of TROP2-CD89. Furthermore, in the B16/10 syngeneic melanoma model, treatment with the melanoma antigen gp75-CD89 fusion protein was also associated with the initiation of broad systemic immune responses, characterized by tumor infiltration by activated CD8+ T cells, reduced tumor-associated Tregs and activation of antigen presenting cells in spleen. When infused in cynomolgus monkeys, TROP2-CD89 LNP led to cell surface expression of anti-TROP2 CAR in myeloid cells. Together these studies highlight the potential of in vivo delivery of CD89 fusion proteins to program myeloid cells to recognize and kill cancer. Citation Format: Thomas E. Prod'homme, Shannon Argueta, Hongyun Zhao, Michael Gorgievski, Neha Diwangi, Edward Cochran, Bruce McCreedy, Yuxiao Wang, Daniel Getts. In vivo delivery of novel CD89 fusion receptor to myeloid cells by mRNA activates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB027.