1338 Virus like vesicle based multivalent immunotherapy for solid tumors

<h3>Background</h3> 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. <h3>Methods</h3> VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin 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 the combination payload. This novel agent is designated as ‘CARG-2020’. We used mouse models of colorectal cancer (CRC) and liver cancer to test the efficacy and mechanism of action of the novel agent. <h3>Results</h3> 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 (figure 1). <h3>Conclusions</h3> 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. <h3>Ethics Approval</h3> All mice were kept at a specific-pathogen-free facility, and all mouse experiments were approved by the Institutional Animal Care and Use Committee at UConn Health.