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There has long been interest in innovating an approach by which tumor cells can be selectively and specifically targeted and destroyed. The discovery of viruses that lyse tumor cells, termed oncolytic viruses (OVs), has led to a revolution in the treatment of cancer. The potential of OVs to improve the therapeutic ratio is derived from their ability to preferentially infect and replicate in cancer cells while avoiding destruction of normal cells surrounding the tumor. Two main mechanisms exist through which these viruses are reported to improve outcomes: direct lysis of tumor cells and indirect augmentation of host anti-tumor immunity. With these factors in mind, viruses are chosen or modified to selectively target tumor cells, decrease pathogenicity to normal cells, decrease the antiviral immune response (to prevent viral clearance), and increase the antitumor immune response. While only one OV has been approved for the treatment of cancer in the United States, and only two other OVs have been approved worldwide, a wide spectrum of OVs are in various stages of preclinical development and in clinical trials. These viruses are being studied as alternatives and adjuncts to more traditional cancer therapies including surgical resection, chemotherapy, radiation, hormonal therapies, targeted therapies, and other immunotherapies. Here, we review the natural characteristics and genetically engineered modifications that enhance the effectiveness of OVs for the treatment of cancer.

Purpose: Metastatic breast cancer patients continue to have poor outcomes on current treatments, and thus, novel therapies in combination with standard treatments are needed. Towards this we studied the pre-clinical effects of combining ONC201, a first-in-class imipridone (which works via activation of ER stress, upregulation of TRAIL, and activation of death receptor 5 [DR5]) with radiation therapy (RT). Since the DR5 pathway is also required for RT-induced apoptosis, we hypothesized that addition of ONC201 could increase the effectiveness of RT. Pertinent Experimental Procedures: Human and mouse breast cancer cell lines were used to study in vitro cancer cell death (by AlamarBlue and clonogenic assays). Patient-derived breast cancer tissue and mouse cell lines were used to study in vivo tumor growth kinetics. Cell lines and mice were administered radiation (0-8 Gy) delivered via a Gammacell 40 exactor. ONC201 was given at does 0-10 µM. Mechanisms of tumor cell death were elucidated using western blots of cleaved PARP (cPARP) and caspase 3 (cC3). Immune response mechanisms were elucidated using in vivo cell-specific depletion. Summary of Data: Multiple breast cancer lines (MB231, MB468, and 4T1) exhibited decreased cell viability after combination therapy compared to either single therapy. In particular, ON201 (1 µM) followed by RT (8 Gy) resulted in a decreased MB468 breast cancer cell viability compared to no treatment (36.9%, P Citation Format: Sachin R. Jhawar, Devora Schiff, Hao Wu, Aditya Thandoni, Suemair Hassan, Joshua Allen, Martin Stogniew, Rohinton Tarapore, Wolfgang Oster, Mark Stein, Ann W. Silk, Sharad Goyal, Bruce G. Haffty, Andrew Zloza. Combination ONC201 and radiation therapy in the treatment of breast cancer [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 2765.