Oncolytic viruses as engineering platforms for combination immunotherapy.
Twumasi-Boateng Kwame,Pettigrew Jessica L,Kwok Y Y Eunice,Bell John C,Nelson Brad H
Nature reviews. Cancer
To effectively build on the recent successes of immune checkpoint blockade, adoptive T cell therapy and cancer vaccines, it is critical to rationally design combination strategies that will increase and extend efficacy to a larger proportion of patients. For example, the combination of anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitors essentially doubles the response rate in certain patients with metastatic melanoma. However, given the heterogeneity of cancer, it seems likely that even more complex combinations of immunomodulatory agents may be required to obtain consistent, durable therapeutic responses against a broad spectrum of cancers. This carries serious implications in terms of toxicities for patients, feasibility for care providers and costs for health-care systems. A compelling solution is offered by oncolytic viruses (OVs), which can be engineered to selectively replicate within and destroy tumour tissue while simultaneously augmenting antitumour immunity. In this Opinion article, we argue that the future of immunotherapy will include OVs that function as multiplexed immune-modulating platforms expressing factors such as immune checkpoint inhibitors, tumour antigens, cytokines and T cell engagers. We illustrate this concept by following the trials and tribulations of tumour-reactive T cells from their initial priming through to the execution of cytotoxic effector function in the tumour bed. We highlight the myriad opportunities for OVs to help overcome critical barriers in the T cell journey, leading to new synergistic mechanisms in the battle against cancer.
Oncolytic Viruses in Cancer Treatment: A Review.
Lawler Sean E,Speranza Maria-Carmela,Cho Choi-Fong,Chiocca E Antonio
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.
Integrating oncolytic viruses in combination cancer immunotherapy.
Bommareddy Praveen K,Shettigar Megha,Kaufman Howard L
Nature reviews. Immunology
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.