PD-1 IC Inhibition Synergistically Improves Influenza A Virus-Mediated Oncolysis of Metastatic Pulmonary Melanoma

Abstract

Recently, we showed that infection of primary lung tumorbearing mice with oncolytic influenza A viruses (IAVs) led to strong virus-induced tumor cell lysis but also to restoration of immune competence of innate immune cells. Murine B16-F10 melanoma cells are known for their high lung tropism and progressive growth. As these cells are also highly permissive for IAVs, we analyzed their oncolytic and immunomodulatory efficiency against pulmonary B16-F10 lung metastases in vivo. IAV infection abrogated the melanoma-mediated immune suppression in the lung and induced a more than 50% cancer cell lysis. The oncolytic effect reached maximal efficacy 3 days post-infection, but it was not sustained over time. In order to maintain the virus-induced anti-tumor effect, mice with melanoma-derived lung cancers were treated in addition to influenza virus infection with an immune checkpoint inhibitor against programmed death-1 receptor (PD-1). The combined IAV and immune checkpoint inhibition (ICI) therapy resulted in a sustained anti-tumor efficacy, keeping the lung melanoma mass at day 12 of IAV infection still reduced by 50% over the control mice. In conclusion, ICI treatment strongly enhanced the oncolytic effect of influenza virus infection, suggesting that combined treatment is a promising approach against metastatic pulmonary melanoma.

Influenza virus infection enhances tumour-specific CD8+ T-cell immunity, facilitating tumour control

“…The contribution of B-cells in our model remains to be further investigated. Although B16 melanoma cells seem to be per se permissive for IAV infection in vitro [ 25 , 26 ], IAV does not replicate in the tumour in our model. Therefore, the slowed tumour growth cannot be the result of direct tumour cell lysis by the virus, but is rather immune-mediated.…”

Current Status and Prospects of Clinical Treatment of Osteosarcoma

“…125 PD-L1 and PD-1 are immune checkpoint proteins involved in modulating the body's immune response. [126][127][128] Although checkpoint proteins have a role in preventing autoimmune disease, they can also suppress the immune system's ability to attack tumor cells. Research is deepening on the drug's use to inhibit the action of PD-1/PD-L1 and thereby increase the body's ability to fight tumor cells.…”

Perspectives for Combining Viral Oncolysis With Additional Immunotherapies for the Treatment of Melanoma

“…Several approaches using a variety of OVs and ICIs are in pre-clinical and clinical development. For example using a mouse model of metastatic pulmonary melanoma, it was demonstrated that virotherapy using influenza A viruses (IAVs) combined with ICI resulted in a sustained antitumor efficacy caused by the significant increase in the oncolytic effect ( Sitnik et al, 2020 ). In other lines of evidence, Vijayakumar et al, applied Newcastle disease virus (NDV) in combination with radiotherapy plus checkpoint inhibitors (PD1 or CTLA4 targeted mAbs) induces an abscopal effect in immunocompetent B16-F10 murine melanoma model.…”