Oncolytic viruses can be usefully integrated into tumour immunotherapies, as they target multiple steps within the cancer–immunity cycle. Oncolytic viruses directly lyse tumour cells, leading to the release of soluble antigens, danger signals and type I interferons, which drive antitumour immunity. In addition, some oncolytic viruses can be engineered to express therapeutic genes or can functionally alter tumour-associated endothelial cells, further enhancing T cell recruitment into immune-excluded or immune-deserted tumour microenvironments. Oncolytic viruses can also utilize established tumours as an in situ source of neoantigen vaccination through cross-presentation, resulting in regression of distant, uninfected tumours. These features make oncolytic viruses attractive agents for combination strategies to optimize cancer immunotherapy. Oncolytic viruses can target multiple steps in the cancer–immunity cycle and can be engineered to express therapeutic genes and, as a result, can be usefully integrated in combination tumour immunotherapies. Here, the authors discuss features of oncolytic viruses that make them appealing agents for combination approaches in cancer immunotherapy.

Integrating oncolytic viruses in combination cancer immunotherapy

Importance Oncolytic viruses (OVs) are emerging as important agents in cancer treatment. Oncolytic viruses offer the attractive therapeutic combination of tumor-specific cell lysis together with immune stimulation, therefore acting as potential in situ tumor vaccines. Moreover, OVs can be engineered for optimization of tumor selectivity and enhanced immune stimulation and can be readily combined with other agents. The effectiveness of OVs has been demonstrated in many preclinical studies and recently in humans, with US Food and Drug Administration approval of the oncolytic herpesvirus talimogene laherparepvec in advanced melanoma, a major breakthrough for the field. Thus, the OV approach to cancer therapy is becoming more interesting for scientists, clinicians, and the public. The main purpose of this review is to give a basic overview of OVs in clinical development and provide a description of the current status of clinical trials. Observations In 2016 approximately 40 clinical trials are recruiting patients, using a range of OVs in multiple cancer types. There are also many more trials in the planning stages. Therefore, we are now in the most active period of clinical OV studies in the history of the field. There are several OVs currently being tested with many additional engineered derivatives. In OV clinical trials, there are a number of specific areas that should be considered, including viral pharmacokinetics and pharmacodynamics, potential toxic effects, and monitoring of the patients’ immune status. Clinical development of OVs is increasingly focused on their immune stimulatory properties, which may work synergistically with immune checkpoint inhibitors and other strategies in the treatment of human cancer. Conclusions and Relevance Oncolytic viruses are an active area of clinical research. The ability of these agents to harness antitumor immunity appears to be key for their success. Combinatorial studies with immune checkpoint blockade have started and the results are awaited with great interest.

/pdf/oncolytic-viruses-in-cancer-treatment-a-review-4oufonhee1.pdf

Oncolytic Viruses in Cancer Treatment: A Review

Of all the gynecologic tumors, ovarian cancer (OC) is known to be the deadliest. Advanced-stages of OC are linked with high morbidity and low survival rates despite the immense amount of research in the field. Shortage of promising screening tools for early-stage detection is one of the major challenges linked with the poor survival rate for patients with OC. In OC, therapeutic management is used with multidisciplinary approaches that includes debulking surgery, chemotherapy, and (rarely) radiotherapy. Recently, there is an increasing interest in using immunomodulation for treating OC. Relapse rates are high in this malignancy and averages around every 2-years. Further treatments after the relapse are more intense, increasing the toxicity, resistance to chemotherapy drugs, and financial burden to patients with poor quality-of-life. A procedure that has been studied to help reduce the morbidity rate involves pre-sensitizing cancer cells with standard therapy in order to produce optimal results with minimum dosage. Utilizing such an approach, platinum-based agents are effective due to their increased response to platinum-based chemotherapy in relapsed cases. These chemo-drugs also help address the issue of drug resistance. After conducting an extensive search with available literature and the resources for clinical trials, information is precisely documented on current research, biomarkers, options for treatment and clinical trials. Several schemes for enhancing the therapeutic responses for OC are discussed systematically in this review with an attempt in summarizing the recent developments in this exciting field of translational/clinical research.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.2560

Ovarian cancer: Current status and strategies for improving therapeutic outcomes.

Oncolytic viruses are natural or genetically modified viral species that selectively infect and kill neoplastic cells. Such an innate or exogenously conferred specificity has generated considerable interest around the possibility to employ oncolytic viruses as highly targeted agents that would mediate cancer cell-autonomous anticancer effects. Accumulating evidence, however, suggests that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the cytopathic effect, but strongly relies on the induction of an endogenous immune response against transformed cells. In line with this notion, superior anticancer effects are being observed when oncolytic viruses are engineered to express (or co-administered with) immunostimulatory molecules. Although multiple studies have shown that oncolytic viruses are well tolerated by cancer patients, the full-blown therapeutic potential of oncolytic virotherapy, especially when implemented in the absence of immunostimulatory interventions, remains unclear. Here, we cover the latest advances in this active area of translational investigation, summarizing high-impact studies that have been published during the last 12 months and discussing clinical trials that have been initiated in the same period to assess the therapeutic potential of oncolytic virotherapy in oncological indications.

https://www.tandfonline.com/doi/pdf/10.4161/onci.28694

Trial watch: Oncolytic viruses for cancer therapy

Cancer vaccines and oncolytic immunotherapy are promising treatment strategies with potential to provide greater clinical benefit to patients with advanced-stage cancer. In particular, recombinant vaccinia viruses (VV) hold great promise as interventional agents. In this article, we first summarize the current understanding of virus biology and viral genes involved in host-virus interactions to further improve the utility of these agents in therapeutic applications. We then discuss recent findings from basic and clinical studies using VV as cancer vaccines and oncolytic immunotherapies. Despite encouraging results gleaned from translational studies in animal models, clinical trials implementing VV vectors alone as cancer vaccines have yielded largely disappointing results. However, the combination of VV vaccines with alternate forms of standard therapies has resulted in superior clinical efficacy. For instance, combination regimens using TG4010 (MVA-MUC1-IL2) with first-line chemotherapy in advanced-stage non-small cell lung cancer or combining PANVAC with docetaxel in the setting of metastatic breast cancer have clearly provided enhanced clinical benefits to patients. Another novel cancer vaccine approach is to stimulate anti-tumor immunity via STING activation in Batf3-dependent dendritic cells (DC) through the use of replication-attenuated VV vectors. Oncolytic VVs have now been engineered for improved safety and superior therapeutic efficacy by arming them with immune-stimulatory genes or pro-apoptotic molecules to facilitate tumor immunogenic cell death, leading to enhanced DC-mediated cross-priming of T cells recognizing tumor antigens, including neoantigens. Encouraging translational and early phase clinical results with Pexa-Vec have matured into an ongoing global phase III trial for patients with hepatocellular carcinoma. Combinatorial approaches, most notably those using immune checkpoint blockade, have produced exciting pre-clinical results and warrant the development of innovative clinical studies. Finally, we discuss major hurdles that remain in the field and offer some perspectives regarding the development of next generation VV vectors for use as cancer therapeutics.

https://jitc.bmj.com/content/jitc/7/1/6.full.pdf

Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection

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VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection