Nerve-sparing therapy with oncolytic herpes virus for cancers with neural invasion

Purpose: The invasion of cancer cells along nerves is an ominous pathologic finding associated with poor outcomes for a variety of tumors, including pancreatic and head and neck carcinomas. Peripheral nerves may serve as a conduit for these cancers to track into the central nervous system. Cancer progression within nerves and surgical resection of infiltrated nerves result in a permanent loss of neural function, potentially causing cosmetic and functional morbidity. Herpes simplex viruses (HSV) have utility for gene transfer into nerves and as oncolytic agents, We studied the use of an attenuated HSV, NV1023, as treatment for cancers with neural invasion. Experimental Design and Results: NV1023 injection into the sciatic nerves of nude mice had no toxic effect on nerve function, whereas similar doses of wild-type HSV-1 (F' strain) caused complete nerve paralysis within 4 days and 100% mortality at day 6. NV1023 showed effective cytotoxicity in vitro on three neurotrophic human carcinoma cell lines, including pancreatic (MiaPaCa2), squamous cell (QLL2), and adenoid cystic (ACC3) carcinomas. A model of neural invasion was established by implanting human carcinoma cells in the sciatic nerves of nude mice. All control group mice developed left hind limb paralysis 5 to 7 weeks after tumor injection, whereas animals treated with NV1023 maintained intact nerve function and showed significant tumor regression (P < 0.0001). Conclusions: These results show that NV1023 oncolytic therapy may effectively treat cancers with neural invasion and preserve neural function. These findings hold significant clinical implications for patients with cancer neural invasion,