Oncolytic virotherapy is an evolving but, as yet, unrealized treatment option for cancer. This approach harnesses
the cancer-restricted replicative activity of engineered viruses to achieve tumor cell kill. Tumors that are resistant
to chemotherapy or radiotherapy can be susceptible to viral oncolysis because of distinct cell kill mechanisms. There is
now compelling evidence that collateral induction of anti-tumor immune responses contributes substantially to viral antitumor
activities. In addition to the expected anti-viral immune clearance, the "danger" signal created by virus-infected
cells can generate immune co-stimulation known to override immune suppression and reverse tolerance within the tumor
microenvironment. Our recent findings indicate that immune activation augments the clinical outcomes of oncolytic virotherapy.
Strikingly similar and robust clinical response rates (>25%) were observed among advanced cancer patients
following intratumoral treatments with adenoviral (AdΔ24) and herpes simplex (JS1/34.5-/47) constructs armed with an
integrated granulocyte-macrophage colony-stimulating factor (GMCSF) payload. Both agents produced regressions in injected
as well as distant, uninjected lesions, demonstrating systemic effectiveness. We discuss the innate and adaptive
immune activating events that may contribute to these clinical outcomes, and examine systemic delivery strategies to tilt
the immunological balance from viral clearance to tumor elimination.
Keywords: Oncolytic virus, AdΔ24, GMCSF, ONCOVEX, cationic liposome encapsulation, stealthed virus, Oncolytic virotherapy, cancer, chemotherapy or radiotherapy, cell kill mechanisms, reverse tolerance, granulocyte-macrophage colony-stimulating factor (GMCSF)
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