Delivery of IL-12 by neoantigen-reactive T cells promotes antitumor immunity in murine osteosarcoma mode.

PURPOSE

Despite the proven clinical benefits of cytokine therapy in cancer treatment, systemic administration of cytokines such as IL-12 is constrained by dose-limiting toxicities and short half-lives. To address these challenges, we explored a localized cytokine delivery strategy using engineered neoantigen-reactive T (NRT) cells as carriers in a murine model of osteosarcoma.

MATERIALS AND METHODS

We used a neoantigen from K7M2 osteosarcoma cells to retrovirally transduce NRT cells to express an inducible form of IL-12. We evaluated the engineered NRT cells' antitumor activity and the production of IL-12 and IFN-γ upon in vitro co-culture with tumor cells. We systemically administered NRT-IL-12 cells in a mouse model of osteosarcoma to assess their impact on tumor growth and survival.

RESULTS

assays demonstrated that the engineered NRT cells exhibited enhanced antitumor activity and produced elevated levels of IL-12 and IFN-γ. In the mouse model of osteosarcoma, systemic administration of NRT-IL-12 cells resulted in a significant reduction in tumor growth and an increase in survival rates compared to the administration of control NRT cells. Further analysis revealed that NRT-IL-12 cells induced a profound increase in CD8+ T-cell infiltration and a decrease in Treg cells within the tumor microenvironment.

CONCLUSION

Our study presents a novel and efficacious strategy for osteosarcoma immunotherapy by harnessing NRT cells as targeted cytokine delivery vehicles.