Adoptive cell therapies have provided significant clinical benefits to cancer patients. However, ex vivo cell therapies are costly and associated with long vein-to-vein times. To overcome these limitations, we deliver cancer-targeting chimeric antigen receptor (CAR) mRNA via lipid nanoparticles (LNPs) to reprogram immune cells directly in vivo. To avoid expression of the CAR in other than myeloid cells when adminsterd systemically, we created a new FcaR I (CD89) based CAR construct whose expression and function depends on the co-expression the FcR γ-chain, a signal adaptor protein that is primarily restricted to myeloid cells. Using the same design principle, we also generated CARs that are only operative in NK and T cells, respectively.
Upon uptake of TROP2 CAR mRNA/LNPs in vitro, TROP2 CARs primarily expressed on mouse and human myeloid cells triggered CAR-dependent cytokine release and tumor cell lysis. Systemic mRNA/LNP delivery of the CAR showed robust anti-tumor efficacy against multiple tumor antigens in xenograft mouse models of human breast cancer, hepatocyte carcinoma, and ovarian cancer. Furthermore, using gp75-targeted CD89-based CAR/LNPs in the B16/F10 immunocompetent melanoma mouse tumor model, we demonstrated robust anti-tumor immune responses and profound changes in the tumor microenvironment characterized by tumoral infiltration of activated CD8+ T cells, diminished tumor-associated Tregs, systemic enhancement of dendritic cell activation and anti-tumor IgG production.
Encouraged by our preclinical data, we advanced the TROP2-targeting CAR to a phase I clinical trial to assess the safety and efficacy in epithelial malignancies.