Research ArticleCancer

Repurposing rotavirus vaccines for intratumoral immunotherapy can overcome resistance to immune checkpoint blockade

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Science Translational Medicine  23 Oct 2019:
Vol. 11, Issue 515, eaat5025
DOI: 10.1126/scitranslmed.aat5025

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Repurposing a pediatric vaccine

Attenuated virus vaccines such as those used to protect against influenza or chickenpox have already passed manufacturing and regulatory hurdles. Given that many viruses have anticancer properties, Shekarian et al. reasoned that existing vaccines for infectious disease may be useful for treating cancer. They tested several vaccines in vitro and saw that rotavirus vaccines activated NF-κB in a human cell line and were protective against a tumor model resistant to immune checkpoint blockade. Further study of live or inactivated rotavirus strains in multiple tumor models showed RIG-I activation and durable immunity, especially when combined with other immunotherapies. These studies indicate that rotavirus vaccines already in production and circulation could be considered as anticancer agents.

Abstract

Although immune checkpoint–targeted therapies are currently revolutionizing cancer care, only a minority of patients develop durable objective responses to anti–PD-1, PD-L1, and CTLA-4 therapy. Therefore, new therapeutic interventions are needed to increase the immunogenicity of tumors and overcome the resistance to these immunotherapies. Oncolytic properties of common viruses can be exploited for the priming of antitumor immunity, and such oncolytic viruses are currently in active clinical development in combination with immune checkpoint–targeted therapies. However, the routine implementation of these therapies is limited by their manufacturing constraints, the risk of exposure of clinical staff, and the ongoing regulations on genetically modified organisms. We sought to determine whether anti-infectious disease vaccines could be used as a commercially available source of immunostimulatory agents for cancer immunotherapy. We found that rotavirus vaccines have both immunostimulatory and oncolytic properties. In vitro, they can directly kill cancer cells with features of immunogenic cell death. In vivo, intratumoral rotavirus therapy has antitumor effects that are dependent on the immune system. In several immunocompetent murine tumor models, intratumoral rotavirus overcomes resistance to and synergizes with immune checkpoint–targeted therapy. Heat- and UV-inactivated rotavirus lost their oncolytic activity but kept their synergy with immune checkpoint–targeted antibodies through the up-regulation of the double-stranded RNA receptor retinoic acid–induced gene 1 (RIG-I). Rotavirus vaccines are clinical-grade products used in pediatric and adult populations. Therefore, in situ immunization strategies with intratumoral-attenuated rotavirus could be implemented quickly in the clinic.

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