Plant Virus Plus Immune Cell-Activating Antibody Clear Colon Cancer in Mice, Prevent Recurrence

A new combination therapy to fight cancer could one day consist of a plant virus and an antibody that activates the immune system’s “natural killer” cells, according to a study by researchers at the University of California San Diego.

In mouse models of colon cancer, the combination therapy eliminated all tumors and prevented their recurrence, which in turn resulted in 100% survival. The therapy also increased survival in mouse models of melanoma.

The work is reported in a paper published June 17 in Nano letters

The proof-of-concept therapy enhances the activity of cancer-killing immune cells known as natural killer cells, which are naturally present in the body and in tumors. The job of natural killer cells is to attack and destroy cancer cells, releasing molecules called antigens that the immune system can recognize and produce antibodies against.

The problem is that there aren’t enough natural killer cells in or near cancerous tumors to be effective. And those that are inside the tumors can’t do their job because cancer cells can secrete molecules that bind to and suppress natural killer cells.

The therapy solves these problems using two main ingredients: cowpea mosaic virus, a plant virus that infects legumes but is harmless to animals and humans, and an antibody called anti-4-1BB. Cowpea mosaic virus has a special ability to attract natural killer cells to the tumor microenvironment, while anti-4-1BB binds to receptors on these cells to take them out of their immunosuppressed state. By joining forces, the plant virus and antibody not only attract a large enough amount of natural killer cells to the tumors, but also fire them up for attack.

“With combination therapy, we are significantly improving cancer response,” said senior author Nicole Steinmetz, professor of nanoengineering and director of the Center for NanoImmunoEngineering at the UC San Diego Jacobs School of Engineering. “Cancers work by manipulating the body through multiple pathways. When we get to multiple avenues by combining different therapeutic agents (cowpea mosaic virus and anti-4-1BB), we get better results.”

“Today, cancer is not treated with just one drug — it requires a multi-pronged approach. Our work uses several strategies to activate the innate immune system and destroy tumors. This can then initiate an adaptive immune response to help prevent tumor recurrence. said first author Edward (Ted) Koellhoffer, a physician of radiology at UC San Diego Health, a clinician-scientist in Steinmetz’s lab.

The researchers first tested their combination therapy on mouse models of colon cancer. The treatment regimen consisted of one weekly injection of cowpea mosaic virus and two weekly injections of anti-4-1BB. The injections were administered into the abdominal cavities of the mice for three weeks. All mice receiving the combination therapy experienced complete tumor elimination and survived for at least 90 days. When these mice were later challenged again with colon cancer, all the new tumors were also eliminated, and the mice all survived. The researchers also tested cowpea mosaic virus as a solo therapy and while it showed potency, the combination therapy showed synergy and outperformed all controls.

“Remarkably, the treated mice acquire an immunological memory, meaning that their immune system remembers the tumor cells and can attack them on their own when the cancer returns,” says Koellhoffer.

The researchers tested the same treatment regimen on mouse models of melanoma. Again, the combination therapy reduced tumor growth and protected the surviving mice from disease recurrence when re-exposed to melanoma.

“While the combination therapy was most impressive in the colon cancer model, improvement was also seen in the melanoma model,” Steinmetz said. “Based on the data, more research is needed to understand whether this therapy is effective against a wide variety of cancers, or whether it has real potential for intraperitoneal disseminated disease.”

Steinmetz’s team plans to investigate that further. The researchers hope their combination therapy will lay the foundation for an in situ cancer vaccine.

Paper: “Cowpea Mosaic Virus and Natural Killer Cellagonism for In Situ Cancer Vaccination.”

This work was supported by the National Institutes of Health (R01 CA224605, R01 CA253615, U01 CA218292, and T32EB005970) and the Shaughnessy Family Fund for Nano-ImmunoEngineering at UC San Diego.

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