Editors' ChoiceCancer

The “cancer flu shot”?

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Science Translational Medicine  15 Jan 2020:
Vol. 12, Issue 526, eaba2908
DOI: 10.1126/scitranslmed.aba2908

Abstract

Direct injection of an influenza vaccine into tumors in mice increases immune infiltration and prolongs survival.

Checkpoint inhibitors of the programmed death 1 (PD-1) axis are more efficacious in immune-infiltrated “hot” cancers than in immunologically bland “cold” ones. The development of methods to convert cancers from the cold to hot state is therefore an important topic of research in immuno-oncology. Antiviral responses offer a potential approach to “jumpstart” immune infiltration in tumors. Intratumoral injection of agonists of antiviral pattern recognition pathways promotes acute inflammation, and these are currently in clinical trials with mixed success. Newman et al. now report a study using direct intratumoral injection of an influenza vaccine to promote immune infiltration into cancer. They noted that lung cancer patients with influenza infections had lower cancer-specific mortality, and they hypothesized that exposure to the influenza virus may have increased immune infiltration in the patients’ tumors. In a mouse model of melanoma lung metastasis, they observed that intranasal administration of an active influenza virus resulted in decreased metastatic deposits in the lung. Intratumoral injection of the flu virus decreased the sizes of both injected and noninjected tumors and increased immune infiltration by dendritic cells (DCs) and T cells. These findings were replicated using a commercial inactivated flu vaccine, which synergized with PD-1 inhibition as well. Interestingly, depletion of immunosuppressive regulatory B cells within the tumors was critical for the anticancer effect in their mouse model. The ability to provide anti-influenza protection was also retained in these mice when the vaccine was injected intratumorally. Based on these findings, the authors proposed that intratumoral injection of clinically approved flu vaccines into accessible metastatic tumors would have a dual benefit of offering anti-influenza protection and anticancer immune infiltration.

This is a provocative thought, which could be easily translated into a clinical trial. However, the selection of an appropriate clinical setting to test intratumoral influenza injection requires that some key questions be answered first. Given that the immunologically “cold” state occurs due to multiple distinct immune suppressive pathways, will the “cancer flu shot” work only in those cold tumors where regulatory B cells play a dominant role? Are there genetic aberrations in cancers that promote or inhibit the response to influenza viral components, and, if so, can they be used as biomarkers of treatment sensitivity? Will the concomitant injection of viral components and a PD-1 inhibitor exacerbate immune toxicities? Further validation work in carefully selected immune-proficient cancer models will help answer these questions. Nonetheless, the established safety of influenza vaccines offers an attractive option for a simple “cold” to “hot” switch in cancer.

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