Translational nanomedicine potentiates immunotherapy in sarcoma by normalizing the microenvironment

• Published in: Journal of controlled release Vol. 353; pp. 956 - 964
• Main Authors: Mpekris, Fotios, Panagi, Myrofora, Michael, Christina, Voutouri, Chrysovalantis, Tsuchiya, Masami, Wagatsuma, Chihiro, Kinoh, Hiroaki, Osada, Atsushi, Akinaga, Shiro, Yoshida, Sei, Martin, John D., Stylianopoulos, Triantafyllos
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2023
• Subjects: Angiogenesis; Animals; Bone Neoplasms; Cell Line, Tumor; Immune Checkpoint Inhibitors - pharmacology; Immunotherapy; Mice; Nano-immuno-oncology; Nanomedicine; NC-6300; Osteosarcoma; Translational research; Tumor Microenvironment; Angiogenesis; Translational research; NC-6300; Nano-immuno-oncology; Nanomedicine; Immunotherapy
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2022.12.016

Nanocarrier-based chemo-immunotherapy has succeeded in clinical trials and understanding its effect on the tumor microenvironment could facilitate development of strategies to increase efficacy of these regimens further. NC-6300 (epirubicin micelle) demonstrates anti-tumor activity in sarcoma patients, but whether it is combinable with immune checkpoint inhibition is unclear. Here, we tested NC-6300 combined with anti-PD-L1 antibody in mouse models of osteosarcoma and fibrosarcoma. We found that sarcoma responds to NC-6300 in a dose-dependent manner, while anti-PD-L1 efficacy is potentiated even at a dose of NC-6300 less than 10% of the maximum tolerated dose. Furthermore, NC-6300 is more effective than the maximum tolerated dose of doxorubicin in increasing the tumor growth delay induced by anti-PD-L1 antibody. We investigated the mechanism of action of this combination. NC-6300 induces immunogenic cell death and its effect on the efficacy of anti-PD-L1 antibody is dependent on T cells. Also, NC-6300 normalized the tumor microenvironment (i.e., ameliorated pathophysiology towards normal phenotype) as evidenced through increased blood vessel maturity and reduced fibrosis. As a result, the combination with anti-PD-L1 antibody increased the intratumor density and proliferation of T cells. In conclusion, NC-6300 potentiates immune checkpoint inhibition in sarcoma, and normalization of the tumor microenvironment should be investigated when developing nanocarrier-based chemo-immunotherapy regimens. A polymeric micelle formulation of epirubicin potentiates immune checkpoint inhibition more effectively than doxorubicin by modulating the mechanical and immune microenvironment of sarcoma tumors. [Display omitted]