摘要
Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans.Here,we describe the application of virus-like vesicles(VLV)for delivery of three immunomodulators alone and in combination,as a promising approach for cancer immunotherapy.VLV vectors were designed to deliver single chain interleukin(IL)-12,shorthairpin RNA(shRNA)targeting programmed death ligand 1(PD-L1),and a dominant-negative form of IL-17 receptor A(dn-IL17RA)as a single payload or as a combination payload.Intralesional delivery of the VLV vector expressing IL-12 alone,as well as the trivalent vector(designated CARG-2020)eradicated large established tumors.However,only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice,indicating a benefit of the combined immunomodulation.The abscopal effects of CARG-2020 on the non-injected contralateral tumors,as well as protection from the tumor cell re-challenge,suggest immune-mediated mechanism of protection and establishment of immunological memory.Mechanistically,CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation.The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.
基金
This work was supported by an American Association of Immunologists Careers in Immunology Fellowship to Ju Chen,University of Connecticut Innovation Fund to Valerian Nakaar and Kepeng Wang
National Institute of Health/National Cancer Institute(NIH/NCI R01CA262430,USA)to Kepeng Wang
This research was also funded by NIDDK(Nos.R43DK113858 and R44DK113858,USA)
by NIAID(No.R43AI149798,USA)to Valerian Nakaar.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.The funders had no role in study design,data collection and interpretation,or the decision to submit the work for publication.
