During breaks from his doctoral research in London, Richard Vile, Ph.D., would visit a pediatric brain tumor clinic next to his lab for inspiration. Seeing children suffer changed the course of his career, igniting his passion for finding cancer treatments that would be easier for people to tolerate.

"I became very, very motivated to try and apply the science I learned to make cancer treatments gentler," says Dr. Vile. "My goal was to deliver an option that would extend and improve quality of life."

Decades later, Dr. Vile is leading research into genetically engineered viruses aimed at unleashing a two-pronged attack on cancer. One part of this technology, known as an oncolytic virus, is designed to infect, break open and destroy cancer cells while sparing healthy tissue. Dr. Vile's preclinical studies have shown that oncolytic viruses replicated in cancer cells and cascaded to kill other diseased cells. That, in turn, triggered an immune response in which the patient’s own T cells, stimulated by the virus, recognized and targeted metastasized tumors for a second wave of cancer destruction.

"Oncolytic viruses are a way to alert the immune system and mobilize it to kill cells infected with cancer," says Dr. Vile. "There's the direct killing of cancer cells with the virus, and then there's the major effect of immune activation. The immune system is incredibly well evolved to recognize infection, clear infection and kill all the cells around it that could be harboring infection."

In groundbreaking research, Dr. Vile's team is combining oncolytic viruses with chimeric antigen receptor T-cell therapy (CAR-T cell therapy) to target solid tumors from liver cancer. This experimental approach of loading CAR-T cells with oncolytic virus is a new way to expand CAR-T cell therapy beyond treatment for blood cancers into treatment for solid tumors.

CAR-T cell therapy is a regenerative immunotherapy in which a patient's T-cells are genetically modified to recognize and stop cancer. It has shown great promise by putting some B-cell lymphomas and leukemias into remission. CAR-T cells are highly targeted to tumor cells, with the goal of having fewer side effects than cancer treatments that also kill nearby healthy tissue.

"Loading the oncolytic virus onto CAR-T cells may give us three levels of killing. First, the CAR-T cells target the tumor and kill some of the cells," says Dr. Vile. "Next, it delivers the oncolytic virus, which infects tumor cells, replicates and kills them. Third, that alerts the immune system of the patient to the fact that there's something majorly wrong. The immune system starts to see the cancer and starts to react against it and kill it."

Mayo Clinic's Center for Regenerative Biotherapeutics supports Dr. Vile's research as part of its objective of delivering new cell therapies to people with complex disorders such as cancer.

Addressing the challenges

Oncolytic viruses are advancing from the lab to first-in-human clinical trials. Dr. Vile is working with the Center for Regenerative Biotherapeutics to biomanufacture oncolytic viruses onsite in Mayo Clinic's Current Good Manufacturing Practices (CGMP) facilities. CGMP facilities are sterile rooms that help ensure that the therapy meets the identity, strength, quality and purity standards that the Food and Drug Administration (FDA) requires for testing new therapeutics.

On-site biomanufacturing could lower production costs, allow for more individualized treatment and deliver the treatment to patients sooner than might be possible with an outside manufacturer.

"We are completing our studies in the lab and are transitioning to safety studies in the patient," explained Dr. Vile. "At the same time, we will manufacture the virus at a level of cleanliness (sterility) to meet FDA standards."

Oncolytic virus therapy is evolving, with more research needed to validate its safety and effectiveness. Dr. Vile hopes to test oncolytic viruses with CAR-T cell therapy for liver cancer in a phase 1 clinical trial in the next year or two.

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Research by Dr. Vile:
Oncolytic virus–mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice

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