Engineered Oncolytic Vaccinia Virus Strategies for High-Grade Serous Carcinoma: Intraoperative Visualisation and Autoimmune Redirection

Background: High-grade serous carcinoma (HGSC) accounts for 70–80% of ovarian cancermortality, with five-year survival for advanced disease below 25%. Immune checkpointinhibitors have failed in this indication (objective response rates 10–15%), and no oncolyticvirus is approved for ovarian cancer. Two critical unmet needs persist: incomplete surgicalcytoreduction due to the inability to detect occult peritoneal disease invisible to standardwhite-light inspection, and the absence of effective immunotherapy. Methods: Two novel oncolytic virus therapeutic concepts were developed throughsystematic review of the published clinical and preclinical literature, consultation withpractising clinicians, and structured analytical interrogation using a multi-source triangulationmethodology designed to identify consensus findings and surface areas of genuine scientificuncertainty. All conclusions were verified against primary sources. Concept 1 (Intraoperative Visualisation): A replication-competent vaccinia virus armedwith near-infrared fluorescent protein (iRFP713) and melanogenic enzymes(tyrosinase/TYRP1) to make residual HGSC deposits visible during cytoreductive surgery.Unlike passively administered fluorescent dyes, the replicating virus self-amplifiesthroughout the peritoneal tumour burden, providing four independent detection channels(NIR fluorescence, naked-eye melanin pigmentation, MRI contrast, photoacoustic imaging)from a compact ~4.2 kb payload using only 21% of the viral insertion capacity. Concept 2 (Autoimmune Redirection): A replication-competent vaccinia virus expressingthyroid autoantigens (thyroperoxidase and thyroglobulin) with immunostimulatory copayloadsto redirect pre-existing Hashimoto’s thyroiditis autoimmunity against HGSC tumourcells in the up to 10% of HGSC patients with coexisting autoimmune thyroid disease. Results: Vaccinia virus was identified as the optimal platform based on unmatchedtransgene capacity (~25 kb), established HGSC clinical data (Olvi-Vec Phase II/III), validatedintraperitoneal delivery, and existing safety infrastructure. The immunologically cold HGSCmicroenvironment, typically a barrier to immunotherapy, was identified as strategicallyadvantageous for both concepts. A dual-territory development strategy is proposed: Concept1 via Western (FDA) pathway first; Concept 2 via China-first development to exploit higherHashimoto’s prevalence in East Asian populations, with both territories pursued in parallel. Conclusions: Both concepts integrate proven, published technologies into novelcombinatorial architectures addressing distinct unmet needs in HGSC. Concept 1 offers alower-risk pathway to improving surgical outcomes; Concept 2 offers potentially curativeimmunotherapy for a defined patient subset. Both are built on a shared vaccinia backbone,enabling a single manufacturing programme.