Multifaceted Nano-DEV-IL for Sustained Release of IL-12 to Avert the Immunosuppressive Tumor Microenvironment and IL-12-Associated Toxicities

Interleukin-12 (IL-12) demonstrates potent anti-tumor activity by enhancing Th1/Th2 response, facilitating cytotoxic T-cell (CTL) recruitment into tumors, inhibiting tumor angiogenesis, and depleting immunosuppressive cells in the tumor microenvironment (TME). Despite having encouraging preclinical and some clinical results, further development of IL-12 is limited because dose-limiting toxicity is observed in early clinical trials with systemic administration of recombinant human IL-12. Hence, strategies aiming to lower the toxicity and to improve response rates are unmet needs. In this study, IL-12 was encapsulated in extracellular vesicles derived from mature dendritic cells (DEVs) activated with tumor antigens. IL-12-encapsulated DEVs (DEV-IL) delayed the growth of murine glioblastoma by facilitating the recruitment of CD8 T-cells, NK-cells, and DCs and effectively depleting immunosuppressive cells in the TME. DEV-IL shifted the Th1/Th2 ratio toward dominating Th1 cytokines which further led to the inhibition of angiogenesis. In addition, DEV-IL also modulated systemic immunity by enhancing CTL activity and the levels of proinflammatory cytokines in the spleen. Interestingly, DEV-IL did not impart hepatic and immunotoxicity which was observed with free IL-12 administration. Hence, our study established DEV-IL as a potent platform for the sustained delivery of cytokines and could be a promising immunotherapeutic strategy for the treatment of cancer.

Automated summary

In this study, Interleukin-12 (IL-12) was encapsulated in extracellular vesicles derived from activated dendritic cells (DEVs) with tumor antigens. The DEV-IL delayed the growth of murine glioblastoma by recruiting immune cells, depleting immunosuppressive cells, and inhibiting angiogenesis. It also enhanced systemic immunity by increasing CTL activity and proinflammatory cytokines levels in the spleen.