Preclinical evaluation of triple-mutated oncolytic herpes virus expressing fusion-type interleukin 12 for malignant...

G47Δ, a triple-mutated oncolytic herpes simplex virus type 1 (HSV-1) marketing-approved for malignant glioma, has demonstrated high efficacy including survival benefits via robust oncolytic activities with efficient antitumor immunity induction. G47Δ-based, oncolytic HSV-1 expressing fusion-type interleukin 12 (IL-12), murine (T-mfIL12) and human (T-hIL12), were preclinically evaluated for the treatment of malignant melanoma. In DBA/2 mice harboring syngeneic clone M-3 melanoma, intratumoral T-mfIL12 not only suppressed the tumor growth but also upregulated the immune mediator gene expressions in both the injected and non-injected remote tumors. The efficacy was further enhanced by combined treatment with systemic PD-1 blockade. For clinical translation, safety evaluations were conducted in HSV-1-sensitive A/J mice. The toxicity was primarily tested by injecting T-mfIL12 or T-hIL12 into the brain. Also, after administering the viruses intradermally at high doses, clinical signs, body weight, histopathology, cytokine responses, and viral biodistribution were examined. No significant adverse effects were observed, and viral DNA remained confined to the injection site. Intratumoral T-mfIL12 injection caused a transient increase in the serum IL-12 level, with limited effects on the systemic cytokine/chemokine profiles. Based on these data, an investigator-initiated phase 1/2 clinical trial of T-hIL12 in patients with advanced malignant melanoma is currently underway (jRCT2033190086).