12:40pm Monday 18 December 2017

Simple Shell of Plant Virus Sparks Immune Response to Cancer

The shells of a common plant virus, inhaled into a lung tumor or injected into ovarian, colon or breast tumors, not only triggered the immune system in mice to wipe out the tumors, but provided systemic protection against metastases, report researchers from the Geisel School of Medicine at Dartmouth and Case Western Reserve University, and published in the journal Nature Nanotechnology.
Cowpea mosaic virus particles (in blue) and Nicotiana benthamiana (or tobacco) plants – the production machinery (plants) of the cowpea mosaic virus (blue). Image courtesy of Case Western Reserve.

Cowpea mosaic virus particles (in blue) and Nicotiana benthamiana (or tobacco) plants – the production machinery (plants) of the cowpea mosaic virus (blue). Image courtesy of Case Western Reserve.

The scientists tested a 100-year-old idea called in-situ vaccination. The idea is to put something inside a tumor and disrupt the environment that suppresses the immune system, thus allowing the natural defense system to attack the malignancy.

That something—the hard coating of cowpea mosaic virus—caused no detectible side effects, which are a common problem with traditional therapies and some immunotherapies.

“The particles are shockingly potent,” said Steven Fiering, PhD, professor of microbiology and immunology at Dartmouth’s Geisel School of Medicine and the Dartmouth-Hitchcock Norris Cotton Cancer Center. “They’re easy to make and don’t need to carry antigens, drugs or other immunostimulatory agents on their surface or inside.”

“The cowpea virus nanoparticles act like a switch that switches on the immune system to recognize the tumor and get an immune response,” said Nicole Steinmetz, PhD, an assistant professor of biomedical engineering at Case Western Reserve, appointed by the Case Western Reserve School of Medicine.

The professors studied the nanoparticles with Dartmouth researchers Patrick Lizotte, Mee Rie Sheen, Jennifer Fields, and Pakdee Rojanasopondist, and Amy Wen, a biomedical engineering student at Case Western Reserve.
Taking another shot

The immune system’s ability to detect and destroy abnormal cells is thought to prevent many cancers, according to the National Cancer Institute. But when tumors start to develop, they can shut down the system, allowing tumors to grow and spread.

To restart immune defenses, the scientists used the tumor itself as if it were the antigen in a vaccine—that is, the target for antibodies produced by the immune system.

The cowpea virus shell, with virus removed, acts as the adjuvant—a substance that triggers and may enhance or prolong antigen-specific immune responses.
The process and results

The researchers first switched on the immune system in mice to attack B16F10 lung melanoma, leaving the mice tumor-free. When the mice were later injected with B16F10 skin melanoma, a common metastatic form, four out of five mice were soon cancer free and one had a slow-growing tumor.

The nanoparticles proved effective against ovarian, breast and colon tumor models. Most of the tumors deteriorated from the center and collapsed. The systemic response prevented or attacked metastatic disease, which is the deadliest form of cancer.

“You get benefits against disease you don’t even know is there yet,” Dr. Fiering said.

“Because everything we do is local, the side effects are limited,” despite the strength and extent of the immune response, Dr. Fiering said. No toxicity was found.

Harsh side effects, such as fatigue, pain, flu-like symptoms and more are common with chemo and radiation therapies and with some immunostimulation drugs.

The researchers are now trying to understand how the virus shell stimulates the immune system.

“It’s not cytotoxic, there’s no RNA involved or lipopolysaccharides that may be used as adjuvants, and it’s not simply an irritant,” Dr. Steinmetz said. “We see a specific immune response.”

Unlike most other adjuvants, Dr. Fiering said, the virus shells stimulate neutrophils, a type of white blood cell. What role that plays is not yet known.

The researchers are seeking grants to study whether the shell’s physical traits or something virus-specific causes the immune response. They are also seeking grants to test the therapy in animal models that have immune systems closer to humans.

If the virus shell continues to prove effective, the researchers believe it could eventually be used in combination with other therapies tailored to individual patients.

Authors
Rosemary Keane
 
Rosemary Keane is the Director of Communications at the Dartmouth-Hitchcock Norris Cotton Cancer Center.


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