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Published on: January 7, 2019
Targeting High-Risk Neuroblastoma Patient-Derived Xenografts with Oncolytic Virotherapy
Colin H Quinn1, Andee M Beierle2, Sara Claire Hutchins3
1Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35205, USA.
Abstract:
Cancer is the leading cause of death by disease in children, and over 15% of pediatric cancer-related mortalities are due to neuroblastoma. Current treatment options for neuroblastoma remain suboptimal as they often have significant toxicities, are associated with long-term side effects, and result in disease relapse in over half of children with high-risk disease. There is a dire need for new therapies, and oncolytic viruses may represent an effective solution. Oncolytic viruses attack tumor cells in two ways: direct infection of tumor cells leading to cytolysis, and production of a debris field that stimulates an anti-tumor immune response. Our group has previously shown that M002, an oncolytic herpes simplex virus (oHSV), genetically engineered to express murine interleukin-12 (mIL-12), was effective at targeting and killing long term passage tumor cell lines. In the current study, we investigated M002 in three neuroblastoma patient-derived xenografts (PDXs). PDXs better recapitulate the human condition, and these studies were designed to gather robust data for translation to a clinical trial. We found that all three PDXs expressed viral entry receptors, and that the virus actively replicated in the cells. M002 caused significant tumor cell death in 2D culture and 3D bioprinted tumor models. Finally, the PDXs displayed variable susceptibility to M002, with a more profound effect on high-risk neuroblastoma PDXs compared to low-risk PDX. These findings validate the importance of incorporating PDXs for preclinical testing of oncolytic viral therapeutics and showcase a novel technique, 3D bioprinting, to test therapies in PDXs. Collectively, our data indicate that oHSVs effectively target high-risk neuroblastoma, and support the advancement of this therapy to the clinical setting.
Insights
Oncolytic herpes simplex virus (oHSV) M002 effectively targets and kills high-risk neuroblastoma cells. This therapy shows promise for treating pediatric cancers, supporting advancement to clinical trials.
Area of Science:
- Oncology
- Virology
- Immunotherapy
Background:
- Neuroblastoma is a leading cause of pediatric cancer mortality, with current treatments often failing and causing significant side effects.
- Existing therapies for neuroblastoma have suboptimal outcomes, particularly for high-risk cases, necessitating novel therapeutic strategies.
- Oncolytic viruses offer a dual mechanism of action: direct tumor cell killing and stimulation of an anti-tumor immune response.
Purpose of the Study:
- To evaluate the efficacy of M002, an oncolytic herpes simplex virus (oHSV) engineered to express murine interleukin-12 (mIL-12), against neuroblastoma patient-derived xenografts (PDXs).
- To assess the potential of M002 as a therapeutic agent for neuroblastoma, focusing on its effectiveness in preclinical models that closely mimic human disease.
- To validate the use of PDXs and 3D bioprinting as methods for testing oncolytic viral therapies in neuroblastoma.
Main Methods:
- Genetically engineered oncolytic herpes simplex virus (oHSV) M002 expressing murine interleukin-12 (mIL-12).
- Testing M002 in three neuroblastoma patient-derived xenografts (PDXs) to assess viral entry receptor expression and replication.
- Evaluating M002's efficacy in 2D cell cultures and 3D bioprinted neuroblastoma models, including high-risk and low-risk PDXs.
Main Results:
- All tested neuroblastoma PDXs expressed necessary viral entry receptors, and M002 actively replicated within these cells.
- M002 demonstrated significant tumor cell death in both 2D cultures and 3D bioprinted models.
- A more pronounced anti-tumor effect was observed in high-risk neuroblastoma PDXs compared to low-risk PDXs, indicating differential susceptibility.
Conclusions:
- Oncolytic herpes simplex viruses (oHSVs) effectively target and induce cell death in high-risk neuroblastoma models.
- Patient-derived xenografts (PDXs) and 3D bioprinting are valuable tools for preclinical evaluation of oncolytic viral therapeutics.
- The findings support the advancement of oHSV M002 as a potential clinical therapy for neuroblastoma, particularly for high-risk disease.
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