Systems Biology Approaches for the Improvement of Oncolytic Virus-Based Immunotherapies

SIMPLE SUMMARY: This review provides a roadmap to develop safe and effective OV-based future therapeutics by using several novel synthetic and system biology strategies. Integration of system and synthetic biology can improve the genetic design of OVs backbone, maintaining enough virulence-associated genes. Furthermore, specific computation pipelines can refine target discovery in several types of cancer, identifying the MHC-I and II-restricted peptide repertoire recognized by T-cells and reinforcing anticancer immune responses. Using these versatile approaches could encourage the development of a next-generation of OVs-based therapies, overcoming current challenges such as on-target, off-tumor effects, and variable clinical responses. The efficacy and safety profile of the current OVs-based regimens could be further enhanced with additional long-lasting clinical effects. ABSTRACT: Oncolytic virus (OV)-based immunotherapy is mainly dependent on establishing an efficient cell-mediated antitumor immunity. OV-mediated antitumor immunity elicits a renewed antitumor reactivity, stimulating a T-cell response against tumor-associated antigens (TAAs) and recruiting natural killer cells within the tumor microenvironment (TME). Despite the fact that OVs are unspecific cancer vaccine platforms, to further enhance antitumor immunity, it is crucial to identify the potentially immunogenic T-cell restricted TAAs, the main key orchestrators in evoking a specific and durable cytotoxic T-cell response. Today, innovative approaches derived from systems biology are exploited to improve target discovery in several types of cancer and to identify the MHC-I and II restricted peptide repertoire recognized by T-cells. Using specific computation pipelines, it is possible to select the best tumor peptide candidates that can be efficiently vectorized and delivered by numerous OV-based platforms, in order to reinforce anticancer immune responses. Beyond the identification of TAAs, system biology can also support the engineering of OVs with improved oncotropism to reduce toxicity and maintain a sufficient portion of the wild-type virus virulence. Finally, these technologies can also pave the way towards a more rational design of armed OVs where a transgene of interest can be delivered to TME to develop an intratumoral gene therapy to enhance specific immune stimuli.