Adjuvant RNA vaccination augments CAR T cell activity against osteosarcoma
Mentor Name: Elias Sayour
Despite improved understanding surrounding the biology of osteosarcoma (OSA), there is still a dismal prognosis for this prevalent pediatric bone cancer. Chimeric antigen receptor (CAR) T cells have had success in hematological malignancies, but that success has not translated to solid tumors for various reasons, including the immunosuppressive tumor microenvironment (TME). Unleashing CAR T cell therapy against poorly immunogenic cancers (i.e., OSA) requires new technologies that activate the TME, while also inducing CAR T cell migration, proliferation, and persistence into the tumor to sustain tumor-specific immunity. In preliminary data, we show that intravenous administration of CD70-encoding RNA-NPs unlocks anti-tumor CD70-directed CAR T cell activity, improving the survival of mice in two aggressive lung metastatic tumor mouse models. Interestingly, the regression of CD70-expressing tumors correlated with CAR T cell mobilization from the peripheral blood into the TME and reticuloendothelial tissues. This mobilization is associated with the increase of vaccine-induced type I interferon and the activation of the immunoregulatory pathway, CCR2. We hypothesize that tumor trafficking and persistence of CD70 CAR T cells depend on a coordinated immunological response that can be ignited through intravenous RNA-NP vaccination. This project has two aims: 1) dissect mechanisms underpinning vaccine induced CD70 CAR T cell trafficking, and 2) determine CD70 CAR T cell phenotype necessary for persistence in the OSA TME.
