This project proposes to develop an oncolytic herpes simplex virus (oHSV) that expresses human tissue inhibitor of metalloproteinases 3 (TIMP3), for treatment of neuroblastoma cancer.
Neuroblastoma is the most common extra-cranial solid tumor of childhood, constituting 8-10% of all pediatric cancers. Neuroblastoma starts in immature nerve cells.
Advances in therapy have improved, but there has been little change in the prognosis, Relapse after therapy is common. Novel therapeutic options are needed for this tumor. We are exploring the potential of oHSV for the treatment of unresponsive or relapsed neuroblastoma.
Oncolytic virotherapy is emerging as a promising new therapeutics approach for human cancer treatment.
Attenuated oHSV mutants engineered with deletions of normally critical genetic functions that are dispensable in cancer cells are being actively pursued as novel therapeutic agents by many investigators and pharmaceutical companies. There are several recent, encouraging reports of early phase clinical trials exploring the safety of administering attenuated oHSV mutants to humans by intracranial (Markert et al. 2000; Rampling et al. 2000), intralesional (MacKie et al. 2001), and hepatic artery (Fong et al. 2009) routes. All of the studies have confirmed safety at the doses tested with no serious adverse events reported. Amgen reported initial results of the first phase III trial of an oncolytic virus, T-Vec (Sheridan et al. 2013). Patients with melanoma lesions of the skin were injected with either GM-CSF protein (control group) or an oHSV expressing GM-CSF (T-Vec). The relatively positive results, showing increased durable response rates in patients treated with virus (http://meetinglibrary.asco.org/content/117592-132), have been hailed at meetings as a landmark for the field.
Dr. Tim Cripe, our collaborator, has initiated the first trial of an oHSV in adolescents and young adults as the sponsor-investigator. The ViruBot was originally constructed (named as rQT3) and verified by restriction enzyme digestion and PCR in the laboratory of Dr. Timothy Cripe. The rQT3 exhibited enhanced anti-tumor efficacy against neuroblastoma and malignant peripheral nerve sheath tumor (Mahller et al. 2008). Working with Dr. Cripe, Microbial Robotics, the team will develop ViruBot for neuroblastoma, and other MMP-expressing cancers.
Potential Applications: Potential applications not yet defined for this project