Clinical efficacy of immune checkpoint blockade is often enhanced by their co-administration with immunogenic chemotherapy. Here a novel chemo-immunotherapy combination is reported that successfully overcomes the immunosuppressive tumor microenvironment to elicit an effective anti-tumor immune response. The CD47-SIRPα innate immune checkpoint was blocked by surface engineering human ferritin with a SIRPα variant, and this FHSIRPα efficiently inhibited the “don’t-eat-me” signal of cancer cells, thereby enhancing cancer cell phagocytosis in a colon carcinoma (CT26) model in immunocompetent mice. Doxorubicin prodrug, EMC-DEVD-S-DOX, that binds to circulating albumin following intravenous administration showed enhanced half-life, and the active drug was released via caspase-3 at tumor site following radiation treatment. Radiation-induced apoptosis of cancer cells resulted in release of active drug doxorubicin and upregulation of CD47 on cancer cell surface, sensitizing cancer cells to FHSIRPα treatment. The induction of immunogenic cell death (ICD) by the prodrug was confirmed in vitro by upregulation of calreticulin, translocation of HMGB1 and increased release of chaperone proteins in CT26.CL25 mouse colon cancer cells by flow cytometric analysis and confocal microscopy. The ICD effect of the prodrug correlated well in vivo and increased phagocytosis of tumor cells by antigen-presenting cells (APCs) in immunocompetent mice as analyzed by flow cytometry of tumor tissue and draining lymph nodes. Tumor infiltrates analyzed by flow cytometry also showed enrichment of APCs; and T cell-mediated elimination of immunogenic tumors was confirmed by the tumor-specific activation of T cells ex vivo as detected by secretion of IFNγ. Whereas FHSIRPα monotherapy showed modest tumor growth inhibition, combination with a doxorubicin prodrug resulted in effective inhibition of tumor growth by 95.2% (p<0.001) compared to the control group, in an established tumor model. The combination therapy resulted in tumor free mice (57% complete response), also in an established tumor model, compared to none in monotherapy groups and controls.Taken together, we demonstrated that the synergistic anti-cancer effect and tumor targetability of the combination therapy FHSIRPα and EMC-DEVD-S-DOX successfully led to the linkage of innate to adaptive immunity to elicit a lasting anti-cancer immune response.
Citation Format: Na Kyeong Lee, Jeong Uk Choi, Jung Je Park, Ji-Hyun Seo, Mi Ra Kim, Hyo Won Chang, Sang Yoon Kim, In-San Kim, Youngro Byun. Nanocage therapeutics FHSIRPα mediating immune checkpoint blockade awakens immunity against cancer with an albumin-binding caspase-cleavable doxorubicin prodrug EMC-DEVD-S-DOX [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2251.