Treatment of Schwannomas with an Oncolytic Recombinant Herpes Simplex Virus in Murine Models of Neurofibromatosis Type 2

Abstract

Gene therapy for schwannomas was evaluated in two mouse models of neurofibromatosis type 2 (NF2): (1) a transgenic model in which mice express a dominant mutant form of merlin and spontaneously develop schwannomas, and (2) a xenograft model in which human schwannoma tissue is implanted subcutaneously into immune- compromised mice. In both models, schwannoma volumes were monitored by magnetic resonance imaging (MRI) and showed strong gadolinium enhancement typical of these tumors in humans. Both types of tumor were positive for the Schwann cell marker S100, and highly infectable with herpes simplex virus (HSV) vectors. Schwannomas were injected with an oncolytic HSV-1 recombinant virus vector, G47Delta, which has deletions in genes for ribonucleotide reductase (ICP6), gamma34.5, and ICP47. In the NF2 transgenic model, schwannomas were reduced by more than half their original size by 10 days after infection. In the case of subcutaneous schwannoma xenografts, reduction in size after infection occurred more slowly, with a mean reduction of onethird by 42 days after treatment. Schwannomas injected with control vehicles continued to grow slowly over time in both schwannoma models. These studies demonstrate the ability of an oncolytic recombinant HSV vector to reduce the volume of schwannoma tumors in NF2 tumor models in mice and extend the possible therapeutic applications of oncolytic vectors for benign tumors to reduce mass while minimizing nerve damage.

Consensus Recommendations to Accelerate Clinical Trials for Neurofibromatosis Type 2

“…Human schwannomas are challenging to grow in vitro , although Schwann cell tumor lines are now available (25). Cell line xenografts into mice allow drug testing on the engrafted tumors (26). …”

Prospects and progress of oncolytic viruses for treating peripheral nerve sheath tumors

“…G47Δ, a third generation oHSV (ICP6 - , γ34.5Δ, ICP47Δ), was examined in a number of human xenograft and mouse transgenic schwannoma models 49, 50 . In a NF2 transgenic model, spontaneous subcutaneous schwannomas were treated with a single intratumoral injection of G47Δ after MR imaging to identify the tumors 49 . This led to a decrease in tumor volume within 2 weeks in G47Δ-treated tumors, however, in some cases control-treated tumors also regressed.…”

“…In addition, it took about 18 months for the transgenic schwannomas to become apparent, making treatment studies difficult. To get around this problem, human schwannoma xenografts were generated by subcutaneous implantation of schwannoma tissue from patients with NF2 or schwannomatosis in immunocompromised mice 49 . These tumors were histologically schwannomas and susceptible to G47Δ infection and replication 49 .…”

“…To get around this problem, human schwannoma xenografts were generated by subcutaneous implantation of schwannoma tissue from patients with NF2 or schwannomatosis in immunocompromised mice 49 . These tumors were histologically schwannomas and susceptible to G47Δ infection and replication 49 . Treatment with two doses of G47Δ resulted in a reduction in tumor volume, while the vehicle-treated tumors continued to grow 49 .…”

CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies

“…Drawing on his experience in NF research he described how oncolytic viruses, which selectively replicate in cancer cells, are a novel therapeutic strategy for cancer. He showed the use of oncolytic herpes simplex virus (HSV) for the treatment of tumors arising in NF, demonstrating the efficacy of this strategy, a new orthotopic MPNST model generated by implanting human NF1 MPNST stem-like cells into the sciatic nerve of immune-deficient mice was described [Messerli et al, 2006]. Oncolytic HSV is also efficacious in NF2 meningiomas andschwannomas.“Arming”oncolyticHSVwiththerapeutictrans-genes, such as IL-12, can enhance anti-tumor immunity and inhibition of tumor growth.…”