ARMING STRATEGIES TO IMPROVE THE IMMUNOTHERAPEUTIC POTENTIAL OF ONCOLYTIC HERPESVIRUSES

Exploiting the capacity of oncolytic viruses (OVs) to selectively target and destroy tumor cells while triggering robust antitumor immune responses offers a highly promising avenue in cancer immunotherapy. Inside the wide viral repertoire for oncolytic virotherapy, Herpes simplex virus type 1 (HSV-1) stands out, due to its clinically demonstrated efficacy, safety and amenability to genetic modification. Finally, "immunolytic" capacity of HSV conferred by highly immunogenic cell death potential allows to elicit a potent antitumor immune response. Despite recent advancements, the full potential of oncolytic therapy remains hindered by key challenges, including viral attenuation and hostile tumor microenvironment. To overcome these issues, preclinical and clinical OVs have been further modified by "arming" strategies, where payloads can be encoded into viral genome to synergize with their oncolytic function. This approach allows the tumor-localized delivery of therapeutic immunological agents, maximizing immune reshape of the tumor microenvironment, minimizing systemic toxicity, ultimately raising therapeutic impact. Preclinical and clinical data indicate that each oncolytic viral platform has a unique signature, which we sought to leverage. In this work, I employed a multifaceted, data-driven approach across three distinct strategies to optimize payloads targeting the tumor microenvironment. The three different arming strategies rely on: i) the identification in purinergic pathway as a potent driver of immunosuppressive milieu in HER2+ tumors; ii) the characterization of oncolytic virus-mediated transcriptional perturbations as a readout to identify costimulatory molecules possessing the ability to boost antitumor immune responses; iii) exploiting the discovery of a tumor-intrinsic mechanisms of resistance to oncovirotherapy. These strategies demonstrate the power of data-driven, precision engineering in oncolytic virotherapy, addressing key immune evasion mechanisms and advancing the development of more potent immunotherapeutic approaches for cancer treatments.