Abstract 4934: Immunostimulatory and oncolytic properties of rotavirus can overcome resistance to immune checkpoint blockade therapy
Authors: Shekarian Tala , Depil Stéphane , Jallas Anne-Catherine , Bergeron Christophe , Caux Christophe , Marabelle Aurélien , Valsesia-Wittmann Sandrine 
Published: August 2018

Abstract
Immune checkpoint targeted therapies against PD-1, PD-L1 and CTLA-4 are currently revolutionizing cancer care. However, only a minority of patients generate objective tumor responses with these treatments. Therefore, new therapeutic interventions are needed to increase the immunogenicity of tumors in order to overcome the resistance to immune checkpoint blockade therapy. Pattern recognition receptors (PRR) such as toll-like receptor agonists have been shown to overcome resistance to immune checkpoint targeted therapy in pre-clinical models. Besides their intrinsic ability to stimulate PRR, the oncolytic properties of common viruses can be exploited also for the priming of anti-tumor immune responses. Several oncolytic viruses are currently in clinical development for cancer immunotherapy. However the routine implementation of these therapies is limited by the ongoing regulations on GMOs. With the aim to analyze if anti-infectious vaccines can be used as a source or PRR agonists and/or oncolytic viruses, we infected different tumors cell lines with commercially available anti-infectious vaccines. We first confirmed that commercially available vaccines do have PRR agonist properties. More interestingly, we discovered that rotavirus vaccines also have oncolytic properties. These attenuated viruses can directly kill cancer cells with features of immunogenic cell death such as upregulation of calreticulin on dying cancer cells but doesn't have cytotoxicity on healthy primary fibroblasts. Moreover, they have pro-inflammatory properties and can activate the NF-KB pathway in a toll-like receptor and IRF3 independent manner. These in vitro biological properties translate into in vivo anti-tumor activity. Intra-tumoral (IT) rotavirus therapy has anti-tumor effects which are mainly immune mediated as demonstrated by their weaken activity in NSG mice. Interestingly, in immunocompetent syngeneic murine tumor models of neuroblastoma and lymphoma, IT rotavirus therapy can overcome resistance to immune checkpoint targeted therapy and in particular synergies with anti-CTLA4. This therapeutic effect relied on specific modifications of tumor immune infiltrates and immune activation pathways. IT rotavirus vaccines was associated to an increase of myeloid infiltrating cells expressing up-regulated level of CD86 in the tumor microenvironment, and upregulation of activation markers such as OX40/CD137 on T cells. Rotavirus vaccines are clinical grade products, including for children. Therefore, in situ immunization strategies with IT attenuated rotavirus can be implemented quickly in the clinic including in pediatric cancers. IT priming of the anti-tumor immunity with oncolytic and immunostimulatory rotavirus vaccines could be a feasible strategy to overcome resistance to anti-PD-1/anti-CTLA-4 therapy in patients with cancer.* co-last authors.
Citation Format: Tala Shekarian, Stéphane Depil, Anne-Catherine Jallas, Christophe Bergeron, Christophe Caux, Aurélien Marabelle, Sandrine Valsesia-Wittmann. Immunostimulatory and oncolytic properties of rotavirus can overcome resistance to immune checkpoint blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4934.