Harnessing the immune response to oncolytic viruses for glioblastoma

People diagnosed with glioblastoma have an average survival of 8 months, making this one of the most aggressive types of cancer. Chemotherapy and radiation have a limited benefit, and surgery is often too risky due to the sensitivity of the brain.

Juan Fueyo, MD, and Candelaria Gomez-Manzano, MD, two researchers at The University of Texas MD Anderson Cancer Center, have dedicated their careers to finding new treatment options for this and other brain cancers, with a focus on using a type of cell and gene therapy called oncolytic viruses.

Now, they are using grant funding from Alliance for Cancer Gene Therapy (ACGT) to try and improve the effectiveness of an oncolytic virus that has already shown the ability to kill glioblastoma cells.

Explaining how oncolytic viruses work

Oncolytic viruses – also called virotherapy – are a novel cancer treatment that uses modified viruses to infect and destroy cancer cells. The viruses are engineered to target only cancer cells, which can leave healthy tissue unaffected.

Drs. Fueyo and Gomez-Manzano have long-believed in the potential of oncolytic viruses to treat cancer, particularly brain tumors. They began their careers as neurologists (brain cancer experts), completing clinical residencies in neurology at the Autonomous University of Barcelona in Spain. From 1994-1997, their focus shifted to the potential of oncolytic viruses, completing research fellowships in experimental neuro-oncology at MD Anderson. They’ve worked in the cancer center’s Department of Neuro-Oncology ever since.

One of the main reasons these two scientists have dedicated their careers to oncolytic viruses is this therapy’s unique ability to activate the immune system against cancer. Dr. Gomez-Manzano said using oncolytic viruses doesn’t “manipulate the immune system like immunotherapy does,” but simply adds a foreign agent to “awaken” the immune system. 

Once the virus infects the cancer cells, it multiplies and causes the cells to break apart and die. This leads to a response from the immune system, which is in charge of defending our body from viruses. 

“When you use an oncolytic virus to treat a cancer patient, the patient’s immune system is alerted to the presence of the virus,” Dr. Fueyo said. “The immune system usually eliminates the virus, but now immune system cells (T cells) are in the area of the cancer. The immune system then begins attacking the tumor.” 

Drs. Fueyo and Gomez-Manzano’s oncolytic virus

The two scientists have developed an oncolytic virus to treat patients with glioblastoma, and the new therapy has shown it is capable of destroying cancer cells. In a clinical trial, approximately 20% of patients receiving the oncolytic virus have survived for at least three years, which is much longer than the average survival associated with this brain tumor.

Unfortunately, the therapy was ineffective for the other 80%. Given that oncolytic viruses are still viruses, most patients’ immune systems will treat it as a threat to the patient’s body. Their immune systems kill the modified virus before it can infect and destroy enough cancer cells to control the brain tumor’s growth.

“Data from our clinical trial demonstrates that to improve the percentage of patients that respond to the therapy, we need to decrease the immune response against the virus, which in turn will increase the immune response against the tumor,” Dr. Fueyo said.

Changing how the immune system reacts to the oncolytic virus

Drs. Fueyo and Gomez-Manzano are using this knowledge of how the immune system responds to the virus to make the therapy more effective for glioblastoma patients. They’re specifically researching ways to control the immune system’s response to their oncolytic virus therapy – and make the immune system focus more on the tumor. 

This is a shift in their philosophy, as they’re now manipulating the immune system through immunotherapy. 

“We will change and evolve our methodology however we need in order to help patients with glioblastoma,” Dr. Gomez-Manzano said. “The oncolytic viruses have taught us that we need immunotherapy.”

They will use ACGT grant funding to test two different strategies: Edit the virus genetically to make it less-detectable by the immune system; and make the patients’ immune systems numb to the virus through overexposure.

“One approach is swapping one of the proteins in the virus with a protein that the immune system won’t respond to right away,” said Dr. Fueyo, who is the ACGT Research Fellow for this project, which is funded in part by Swim Across America. “The other approach is making the immune system get used to the presence of the virus, which allows it to focus on the tumor.

“We are constantly evolving, just like the tumor and the virus evolve.”