Brain Cancer Patient’s Own Immune Cells May Suppress Viral Therapy

Clinical trials have demonstrated that these therapeutic viruses are safe but less effective than once thought.

A new study led by researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James; Columbus, USA) revealed that the reason for this is partly caused by the patient’s own immune system, which quickly works to eliminate the anticancer virus.

The findings, published November 25, 2012, in the journal Nature Medicine, demonstrate that the body responds to the anticancer virus the same as it does to an infection. Within hours, specialized immune cells called natural killer (NK) cells move in to eliminate the therapeutic virus in the brain.

The researchers discovered that the NK cells attack the viruses when they express specific molecules on their surface called NKp30 and NKp46. “These receptor molecules enable the NK cells to recognize and destroy the anticancer viruses before the viruses can destroy the tumor,” stated cosenior author Dr. Michael A. Caligiuri, director of Ohio State’s Comprehensive Cancer Center and CEO of the James Cancer Hospital and Solove Research Institute, and a senior author of the study. “When we blocked those receptors, the virus has more time to work, and mice with these brain tumors live longer. The next step is to block these molecules on NK cells in glioblastoma patients and see if we can improve their outcome,” said Dr. Caligiuri.

This study of cancer-cell-killing (oncolytic) viruses exemplifies the benefits of translational research, in which a problem observed during clinical trials is studied in the laboratory to devise a solution. “In this case, clinical trials of oncolytic viruses proved safe for use in the brain, but we noticed substantial numbers of immune cells in brain tumors after treatment,” remarked senior author and neurosurgeon Dr. E. Antonio Chiocca, who was professor and chair of neurological surgery while at Ohio State University. “To understand this process, we went back to the laboratory and showed that NK cells rapidly infiltrate tumors in mice that have been treated with the therapeutic virus. These NK cells also signal other inflammatory cells to come in and destroy the cancer-killing virus in the tumor.”

The study used an oncolytic herpes simplex virus, human glioblastoma tumor tissue and mouse models, one of which hosted both human glioblastoma cells and human NK cells. Key technical findings include: NK cells in tumors triggered other immune cells (i.e., microglia and macrophages) that have both antiviral and anticancer characteristics; replication of the therapeutic virus in tumor cells in an animal model quickly drew subsets of NK cells to the tumor site; depletion of NK cells improves the survival of tumor-bearing mice treated with the therapeutic virus; NK cells that kill virus-infected tumor cells express the NKp30 and NKp46 receptors molecules that recognize the virus.

“Once we identify the molecules on glioblastoma cells that these NK cell receptors bind with, we might be able to use them to identify patients who will be sensitive to this therapy,” Dr. Caligiuri concluded.

Related Links:
Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute