Lung cancer remains among the most difficult-to-treat
malignancies and is the leading cause of
cancer-related deaths worldwide. The introduction of targeted
therapies and checkpoint inhibitors has improved treatment outcomes; however, most patients with advanced-stage
non-small cell lung cancer (NSCLC) eventually fail these
therapies. Therefore, there is a major unmet clinical need for checkpoint refractory/resistant NSCLC. Here, we tested the combination of aPD-1 and adenovirus armed with TNFα and
IL-2 (Ad5-CMV-mTNFα/
mIL-2) in an immunocompetent murine NSCLC model. Moreover, although local delivery has been standard for virotherapy, treatment was administered intravenously to facilitate clinical translation and putative routine use. We showed that treatment of
tumor-bearing animals with aPD-1 in combination with intravenously injected armed adenovirus significantly decreased
cancer growth, even in the presence of
neutralizing antibodies. We observed an increased frequency of cytotoxic tumor-infiltrating lymphocytes, including
tumor-specific cells. Combination treatment led to a decreased percentage of immunosuppressive tumor-associated macrophages and an improvement in dendritic cell maturation. Moreover, we observed expansion of the
tumor-specific memory T cell compartment in secondary lymphoid organs in the group that received aPD-1 with the virus. However, although the non-replicative Ad5-CMV-mTNFα/
mIL-2 virus allows high transgene expression in the murine model, it does not fully reflect the clinical outcome in humans. Thus, we complemented our findings using NSCLC ex vivo models fully permissive for the TNFα and IL-2- armed oncolytic adenovirus TILT-123. Overall, our data demonstrate the ability of systemically administered adenovirus armed with TNFα and
IL-2 to potentiate the anti-
tumor efficacy of aPD-1 and warrant further investigation in clinical trials.