Abstract B13: Injection of the viroimmunotherapeutic oncolytic herpes virus rRp450 increases survival of orthotopic mouse models of Group 3 medulloblastoma and atypical teratoid/rhabdoid tumors
Authors: Studebaker Adam W. , Hutzen Brian J. , Haworth Kellie B. , Pierson Christopher R. , Cripe Timothy P. 
Published: May 2016

Abstract
Background: Both Group 3 medulloblastomas and atypical teratoid/ rhabdoid tumors (AT/RTs) are highly aggressive pediatric brain tumors which have a tendency to metastasize early and are known for their poor outcomes. Current standards of care using chemotherapy and irradiation are associated with significant morbidities, giving impetus for the development of new treatments. Oncolytic virotherapy, the utilization of live attenuated viruses to selectively infect and induce destruction of neoplastic cells, is actively being pursued in pre-clinical and early phase clinical trials. rRp450 was derived from the KOS strain and attenuated by an insertion mutation in the UL39 gene, encoding the large subunit of ribonucleotide reductase, and is in clinical trials (NCT01071941). The mechanism of action of this novel cancer therapy is multi-faceted, and involves direct lysis of infected malignant cells, disruption of the tumor blood supply, and stimulation of the immune system to more effectively mount an anti-tumor response. The safety and tolerability of these oncolytic viral agents has been demonstrated in numerous clinical trials. Which cancer targets will ultimately be responsive to these agents is unknown.
Methods: We assessed the permissivity and sensitivity of two Group 3 medulloblastoma and two AT/RT cell lines to the oncolytic herpes virus rRp450 in vitro. We implanted tumor cells into the brains of athymic nude mice and administered a single intratumoral dose of 1 million plaque-forming units of rRp450 using the same injection coordinates as tumor cell implantation. We monitored animals for survival and performed immunohistochemical staining against HSV-1 on post-mortem tumor specimens.
Results: All four pediatric brain tumor cell lines were permissive to virus replication and sensitive to in vitro killing by rRp450, albeit to different degrees. There was not a direct correlation between permissivity to virus replication and cell killing. A one-time dose of rRp450 injected into tumor-bearing animals resulted in a significant survival advantage in all four tumor models, including the least permissive model, suggesting antitumor factors in addition to direct cell lysis. Post-mortem tissue sections showed no tumor or virus present in long-term surviving animals, whereas animals that died during the study had persistent tumor and persistent virus.
Conclusions: These data suggest that the oncolytic herpes virus rRp450 may have therapeutic benefit against medulloblastoma and AT/RTs.
Citation Format: Adam W. Studebaker, Brian J. Hutzen, Kellie B. Haworth, Christopher R. Pierson, Timothy P. Cripe. Injection of the viroimmunotherapeutic oncolytic herpes virus rRp450 increases survival of orthotopic mouse models of Group 3 medulloblastoma and atypical teratoid/rhabdoid tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B13.