Effective intravenous delivery of adenovirus armed with TNFα and IL-2 improves anti-PD-1 checkpoint blockade in non-small cell lung cancer

Oncoimmunology. 2023 Aug 2;12(1):2241710. doi: 10.1080/2162402X.2023.2241710. eCollection 2023.

Abstract

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.

Keywords: Immunotherapy; adenovirus; checkpoint inhibitors; intravenous administration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Humans
  • Immune Checkpoint Inhibitors
  • Interleukin-2* / genetics
  • Interleukin-2* / pharmacology
  • Lung Neoplasms* / drug therapy
  • Mice
  • Tumor Necrosis Factor-alpha* / genetics
  • Tumor Necrosis Factor-alpha* / therapeutic use

Substances

  • Interleukin-2
  • Tumor Necrosis Factor-alpha
  • Immune Checkpoint Inhibitors

Grants and funding

This study was supported by the Doctoral Program in Clinical Research (University of Helsinki), Jane and Aatos Erkko Foundation, Finnish Cultural Foundation, Ida Montinin Foundation, Orion Foundation, K. Albin Johansson Foundation, HUCH Research Funds (VTR), Finnish Cancer Organizations, Sigrid Juselius Foundation, Novo Nordisk Foundation, Päivikki and Sakari Sohlberg Foundation, Finnish Red Cross Blood Service, and TILT Biotherapeutics Ltd. This study received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Marie Skłodowska-Curie grant agreement No 813453. We thank Albert Ehrnrooth and Karl Fazer for their support. Part of this work was carried out with the support of the HiLIFE Laboratory Animal Center Core Facility, University of Helsinki.