Peer Reviewed Cancer
Posted September 26, 2019
The Central Brain Tumor Registry of the United States (CBTRUS) estimates that approximately 4,300 children in the United States are diagnosed with brain tumors each year.1 The standard of care for pediatric brain tumors (PBT) involves surgical removal of the tumor followed by chemotherapy and/or radiotherapy. However, some PBT, like diffuse intrinsic pontine glioma (DIPG), infiltrate normal brain tissues, making surgical resection of the tumor impossible. Additionally, therapies administered to patients attack and kill not only tumor cells, but also the healthy, developing tissues of the pediatric brain. The toxicity of the therapies leaves survivors dealing with long-term neurological, endocrine, and neurosensory impairments.2, 3 For these reasons and because of tumor resistance to current standard of care therapy, novel therapeutic approaches with increased efficacy and decreased toxicity are greatly needed to treat PBT.
An exciting approach is the development of oncolytic viruses (OV) to treat PBT. OV are viruses that have been mutated to eliminate virulence (e.g., the Herpes Simplex Virus mutated so that it no longer causes herpes) and instead are engineered to infect tumor cells. Some of the advantages to using OV to treat solid tumors like PBT are that the OV selectively infect and replicate in tumor cells, not normal cells; they have the capacity to infect neighboring tumor cells; and the rupturing of tumor cells caused by the OV infection leads to a triggered immune response. Thus, treating tumors with OV provides a two-pronged method to eliminate the tumor by directly causing the rupture of tumor cells and indirectly activating the body’s immune system against the tumor. The Food and Drug Administration (FDA) approved the first OV for the treatment of melanoma in October 2015.4 This has eased the path forward toward developing additional OV, and several different types of virus are currently under development as therapeutics for treating different types of PBT.5, 6 The Peer Reviewed Cancer Research Program (PRCRP) has invested in several research projects seeking to capitalize on the characteristics of OV treatment for PBT. Table 1 summarizes some of the current and recently completed PRCRP OV projects.
Table 1: PRCRP Investment in OV Research for the Treatment of PBT (Fiscal Years 2014 - 2018)
|Investigator(s)||Institution(s)||Fiscal Year||Tumor Type||Virus||Current Investment|
|Gregory K. Friedman, M.D.||University of Alabama at Birmingham||2014||Medulloblastoma||Herpes Simplex Virus||$529,200|
Universidad de Navarra (Spain)
MD Anderson Cancer Center
MD Anderson Cancer Center
|2016||Diffuse Intrinsic Pontine Glioma||Adenovirus||$1,343,263|
|Eric M. Thompson, MD||Duke University||2017||Medulloblastoma||Poliovirus||$577,611|
||University of California, San Francisco||2018||Medulloblastoma||Measles Virus||$1,601,471|
Assessing the Safety and Efficacy of Herpes Simplex Virus to Treat Medulloblastoma
Gregory K. Friedman, M.D., University of Alabama at Birmingham, CA140089
The goal of Dr. Friedman’s recently completed Fiscal Year 2014 (FY14) Career Development Award was to investigate the safety and efficacy of delivering a version of Herpes Simplex Virus, called G207, directly to the cerebral-spinal fluid in a mouse model of group 3 medulloblastoma. This delivery method is called intraventricular (IVT) delivery and is able to bypass the complication of crossing the blood brain barrier while also reducing the risks associated with direct injection of the OV into the brain tumor. Dr. Friedman determined a delivery method that mitigated the toxicity associated with IVT delivery of G207 and found that G207 targeted both primary and metastatic group 3 medulloblastoma, which is a particularly devastating form of medulloblastoma with low survival rates. These findings were published in part in March 2019 in Cancer Gene Therapy.7
Adapting an OV Targeting Adult Glioma to Treat Pediatric Diffuse Intrinsic Pontine Glioma
Marta Alonso, Ph.D., Universidad de Navarra (Spain)
Candelaria Gomez-Manzano, M.D., MD Anderson Cancer Center
Juan Fueyo, M.D., MD Anderson Cancer Center
Prior to receiving this FY16 Translational Team Science Award from the PRCRP, Drs. Alonso, Gomez-Manzano, and Fueyo developed and tested in Phase I/II clinical trials the oncolytic adenovirus, Delta-24-RGD, in adult glioma patients. Among the exciting preliminary results of these trials was the observation that the treatment resulted in no significant side effects in patients and that administering the virus resulted in a complete response to therapy in some patients. However, because PBT like DIPG respond differently to therapy than adult tumors, Dr. Alonso and her colleagues are developing and testing new oncolytic adenoviruses specific for the treatment of DIPG.
The team is currently testing the DIPG-specific OV, Delta-24-ACT, in mouse models of DIPG. Preliminary studies show that, when administered directly to DIPG cells in mice brains, the virus is able to infect cells and replicate, which are important indicators that the virus would be effective in a human brain. Further studies evaluating the ability of Delta-24-ACT to selectively kill DIPG cells in mouse models of the disease are ongoing. These are important preclinical studies that are necessary to lay the foundation for future clinical trials in pediatric patients. Drs. Alonso, Fueyo, and Gomez-Manzano expect to have sufficient preclinical data at the completion of this project to initiate a radically innovative clinical trial for DIPG patients based on local delivery of an OV, a similar strategy to the one used in the adult glioma clinical trials, combined with an immune boosting strategy.
Investigating the Use of Oncolytic Poliovirus to Treat Medulloblastoma
Eric M. Thompson, M.D., Duke University, CA171067
As stated above, the fundamental weakness with the current standard of care for some PBTs, including medulloblastoma, is the modest efficacy of the treatments that come at the cost of profound toxicity. Dr. Thompson received an FY17 Career Development Award from the PRCRP to study an oncolytic poliovirus, PVSRIPO. During the first year of this award, he found abundant expression of the cell surface poliovirus receptor, CD155, in patient specimens and established mouse models of primary and metastatic models of medulloblastoma. Importantly, Dr. Thompson also discovered that a key mechanism by which PVSRIPO kills medulloblastoma is by inducing oxidative stress and generating reactive oxygen species. During the remainder of the award period, he will test the safety and efficacy of PVSRIPO to treat medulloblastoma in mouse models of the disease and explore the use of pro-oxidant and anti-oxidant agents in combination with PVSRIPO to improve its efficacy.
Using the Patient Immune System to Boost Efficacy of Medulloblastoma-Targeted Measles Virus
Aaron Diaz, Ph.D.
Noriyuki Kasahara, M.D./Ph.D.
Sabine Mueller, M.D./Ph.D.
University of California San Francisco
Drs. Diaz, Kasahara, and Mueller received this PRCRP FY18 Translational Team Science Award to perform a detailed analysis of pre- and post-treatment tumor specimens from patients with medulloblastoma, the most common malignant brain tumor in children. They aim to identify differences in immune system activation between patients who responded to an oncolytic measles virus, MV-NIS, or retrovirus, Toca 511, and those who did not. Dr. Diaz and his team will use this information to identify biomarkers that may predict patient response to OV in future clinical trials. Additionally, the team will conduct preclinical studies to evaluate the use of OV in combination with immune checkpoint inhibitors, which have shown considerable therapeutic benefit in many cancers but not in brain tumors thus far, to increase the efficacy of immunotherapy for medulloblastoma.
- Ostrom QT, Gittleman H, Farah P, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol 15(2):ii1-56.
- Tonning Olsson I, Perrin S, Lundgren J, et al. Long-term cognitive sequelae after pediatric brain tumor related to medical risk factors, age, and sex. Pediatr Neurol 51(4):515-5121. doi: 10.1016/j.pediatrneurol.2014.06.011.
- Krull KR, Hardy KK, Kahalley LS, et al. Neurocognitive outcomes and interventions in long-term survivors of childhood cancer. J Clin Oncol 36(21):2181-2189. doi: 10.1200/JCO.2017.76.4696.
- Varela-Guruceaga M, Tejada-Solis S, Garcia-Moure M, et al. Oncolytic viruses as therapeutic tools for pediatric brain tumors. Cancers. doi: 10.3390/cancers10070226.
- Totsch SK, Schlappi C, Kang KD, et al. Oncolytic herpes simplex virus immunotherapy for brain tumors: current pitfalls and emerging strategies to overcome therapeutic resistance. Oncogene 38(34):6159-6171. doi: 10.1038/s41388-019-0870-y.
- Bernstock JD, Vicario N, Li R, et al. Safety and efficacy of oncolytic HSV-1 G207 inoculated into the cerebellum of mice. Cancer Gene Ther. doi: 10.1038/s41417-019-0091-0. [Epub ahead of print].
Last updated Wednesday, September 25, 2019