Optimizing Measles Virotherapy in the Treatment of Gliomas
Building on its previous work, the research team in the Mayo Clinic Brain Cancer SPORE hypothesizes that by increasing the efficiency and extent of tumor cell destruction and by introducing a therapeutic transgene, the anti-tumor activity of measles virotherapy in glioma can be augmented.
The Brain Cancer SPORE project team was the first to demonstrate that engineered measles virus (MV) strains have significant anti-tumor activity against gliomas.
The tumor specificity of engineered measles virus is due to abundant expression of the measles virus receptor CD46 in glioma cells. Upon entering the tumor cells, the virus causes membrane fusion with neighboring cells, syncytia formation and death.
In addition, the Brain Cancer SPORE team has translated this approach into the first human clinical trial of a measles virus derivative producing human carcinoembryonic antigen, MV-CEA (CEA added to facilitate viral monitoring) in patients with recurrent glioblastoma multiforme.
The team plans to accomplish this by testing the translational potential of three novel approaches:
- A different measles virus strain, MV-NIS, which encodes the sodium iodine symporter (NIS) gene, thus allowing imaging of viral distribution in vivo
- Enhancing MV-NIS oncolysis by exploiting NIS as a therapeutic transgene with application of the beta and gamma emitter 131I (radiovirotherapy)
- Combing measles virus derivatives with cyclophosphamide, an agent that has been shown to suppress antiviral innate and adaptive immunity and increase viral proliferation in tumors
This project in the Mayo Clinic Brain Cancer SPORE has four aims.
Aim 1: MV-NIS-based virotherapy and radiovirotherapy
This project aims to evaluate the therapeutic potential of MV-NIS-based virotherapy and radiovirotherapy against glioblastoma multiforme and compare its anti-tumor activity with MV-CEA.
MV-NIS is a more recently constructed MV-Edmonston derivative, with similar backbone to MV-CEA, encoding the sodium iodine symporter gene. MV-NIS allows use of radioactive iodine and technetium isotopes for imaging of viral replication, and iodine isotopes for treatment purposes.
The project team has already developed Food and Drug Administration-approved methodology for production of MV-NIS. The virus is easier to manufacture than is MV-CEA and grows to higher titers.
This aim will test the hypothesis that MV-NIS is equivalent or superior to MV-CEA and that its potency can be further enhanced by 131I mediated radiovirotherapy.
Aim 2: Combination strategies with cyclophosphamide
The Brain Cancer SPORE is testing combination strategies with cyclophosphamide, a suppressant of the innate immune response, to further increase the potency of measles virotherapy or radiovirotherapy.
In preliminary experiments, the project team demonstrated that administration of cyclophosphamide before measles virus administration resulted in significant potentiation of the oncolytic activity of measles virus in orthotopic glioma xenografts by increasing viral proliferation in glioma tumors.
This aim is optimizing the dose and schedule of cyclophosphamide in order to achieve optimal anti-tumor activity of measles-based virotherapy or radiovirotherapy against orthotopic glioblastoma xenografts.
Aim 3: Toxicology and biodistribution studies
The Brain Cancer SPORE is performing toxicology and biodistribution studies in MV-susceptible transgenic mice and rhesus macaques in order to determine the safety of the optimal translational strategy.
These project aims are testing different approaches to further augment the efficacy of measles virotherapy in the treatment of gliomas. The safety of the optimal efficacy enhancing approach will be carefully assessed in measles-susceptible animal models prior to clinical translation.
Aim 4: Phase I trial in patients with recurrent glioblastoma multiforme
Researchers are employing the approach with the optimal safety and efficacy profile in a subsequent phase I clinical trial in patients with recurrent glioblastoma multiforme.
Collectively, these studies are providing information that is guiding the selection of the most promising approach to test in a subsequent phase I trial in patients with recurrent glioblastoma multiforme.
In preclinical models, measles vaccine strains have potent anti-tumor activity against gliomas and demonstrate synergy with existing therapies. The Mayo Clinic Brain Cancer SPORE team is investigating strategies to optimize the use of measles vaccine strains as novel anti-tumor agents in the treatment of gliomas.
Co-leaders of this Brain Cancer SPORE project are:
Significant contributors are: