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Multifaceted Nano-DEV-IL for Sustained Release of IL-12 to Avert the Immunosuppressive Tumor Microenvironment and
Anjali Barnwal1,2, Surajit Ganguly3, Jayanta Bhattacharyya1,2
1Centre for Biomedical Engineering, Indian Institute of Technology Delhi, Delhi 110016, India.
Interleukin-12 (IL-12) demonstrates potent antitumor 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.
Interleukin-12 (IL-12) demonstrates potent antitumor 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.
