UCSF Researchers Awarded Grant to Develop Immunotherapies for Pediatric Brain Tumors

UCSF researchers Aaron Diaz, PhD, Noriyuki Kasahara, MD, PhD, and Sabine Mueller, MD, PhD recently received a Translational Team Science Award from the U.S. Department of Defense (DoD) to support their immunotherapy research. 

This year, the DoD Peer Reviewed Cancer Research Program (PRCRP) was allocated $80 million to fund innovative, high-impact research on a variety of cancers, including pediatric brain tumors.

Combining Multiple Immunotherapy Strategies

Immunotherapy encompasses a variety of treatments, each employing different approaches to help a patient’s immune system target and attack tumor cells.  Together, researchers in the Diaz, Kasahara, and Mueller Labs are investigating the mechanisms underlying oncolytic virus therapy, to determine whether this strategy would be enhanced in combination with other immunotherapies for treating pediatric brain tumors. 

Oncolytic viruses refer to viruses, either naturally occurring or genetically engineered, that specifically infect and kill tumor cells without harming healthy cells. They are also considered a type of immunotherapy, since they trigger an immune response against the cancer. 

Oncolytic viruses infect cancer cells, and multiply within them until the cell bursts. In bursting, the tumor cell releases molecules called tumor antigens, which allows the immune system to recognize and target remaining tumor cells. 

However, local immune cells may also interfere with oncolytic virus therapy. The body’s immune system sometimes attacks the oncolytic virus, reducing its overall tumor-killing impact. Furthermore, some pediatric cancers including medulloblastoma are characterized by the presence of immune cells called myeloid-derived suppressive cells (MDSCs), which secrete factors that inhibit T-cells from attacking cancer cells. 

Even so, preliminary evidence from the Kasahara Lab suggests that oncolytic virus therapy accelerates T-cell killing by reducing MDSCs.¹ Therefore, there is critical need to understand how local immune cells interact with oncolytic viruses at the tumor microenvironment level, and – given the variability in tumor biology between different cancer types – a need to study effects on specific tumor types. 

The Diaz, Kasahara, and Mueller Labs will not only investigate interactions between oncolytic viruses and local immune cells, but also determine whether immune-checkpoint inhibitor drugs (another immunotherapy) can enhance the effects of oncolytic virus therapy in medulloblastoma. 

Specifically, they aim to identify combination strategies for MV-NIS and Toca 511, two oncolytic virus therapies with clinical trials underway at UCSF. Toca 511, an engineered retrovirus developed by Kasahara,² recently received a Breakthrough Therapy Designation from the FDA for recurrent high-grade glioma.  

“Understanding how these oncolytic viruses interact with the immune system is a critical step in advancing treatment for medulloblastoma, and improving the use of oncolytic virus therapy for other tumors in general,” says Diaz. 

References

1. Yagiz K, Rodriguez-Aguirre ME, Lopez Espinoza F, Montellano TT, Mendoza D, Mitchell LA, Ibanez CE, Kasahara N, Gruber HE, Jolly DJ, Robbins JM. (2017) A Retroviral Replicating Vector Encoding Cytosine Deaminase and 5-FC Induces Immune Memory in Metastatic Colorectal Cancer Models. Mol Ther Oncolytics 8:14-26.
2. Perez OD, Logg CR, Hiraoka K, Diago O, Burnett R, Inagaki A, Jolson D, Amundson K, Buckley T, Lohse D, Lin A, Burrascano C, Ibanez C, Kasahara N, Gruber HE, Jolly DJ. (2012) Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression. Mol Ther 20(9):1689-98.

This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs and the Defense Health Agency J9, Research and Development Directorate, through the Peer Reviewed Cancer Research Program under Award No. W81XWH1910348. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

In conducting research using animals, the investigator(s) adheres to the laws of the United States and regulations of the Department of Agriculture.

In the conduct of research utilizing recombinant DNA, the investigator adhered to NIH Guidelines for research involving recombinant DNA molecules.

In the conduct of research involving hazardous organisms or toxins, the investigator adhered to the CDC-NIH Guide for Biosafety in Microbiological and Biomedical Laboratories.