Hyper-Interferon Sensitive influenza induces adaptive immune responses and overcomes resistance to anti-PD-1 in murine non-small cell lung cancer

Despite recent advances in immunotherapy with immune checkpoint inhibitors, many patients with non–small cell lung cancer (NSCLC) fail to respond or develop resistance after an initial response. In situ vaccination (ISV) with engineered viruses has emerged as a promising antigen-agnostic strategy that can both condition the tumor microenvironment and augment antitumor T-cell responses to overcome immune resistance. We engineered a live attenuated viral vaccine, hyper–IFN-sensitive (HIS) virus, by conducting a genome-wide functional screening and introducing eight IFN-sensitive mutations in the influenza genome to enhance host IFN response. Compared with wild-type influenza, HIS replication was attenuated in immunocompetent hosts, enhancing its potential as a safe option for cancer therapy. HIS ISV elicited robust yet transient type I IFN responses in murine NSCLCs, leading to an enrichment of polyfunctional effector Th1 CD4+ T cells and cytotoxic CD8+ T cells into the tumor. HIS ISV demonstrated enhanced antitumor efficacy compared with wild-type in multiple syngeneic murine models of NSCLC with distinct driver mutations and varying mutational burden. This efficacy was dependent on host type 1 IFN responses and T lymphocytes. HIS ISV overcame resistance to anti–PD-1 in LKB1-deficient murine NSCLC, resulting in improved overall survival and systemic tumor-specific immunity. These studies provide compelling evidence to support further clinical evaluation of HIS as an “off-the-shelf” ISV strategy for patients with NSCLC refractory to immune checkpoint inhibitors.