Unlock the mystery of why a plant virus is so powerful in the fight against cancer, even metastatic cancer

Veronique Beiss, the first author of the study, is preparing a tray of plants to produce nanoparticles of the caupin mosaic virus. Credit: David Baillot / UC San Diego Jacobs School of Engineering

Cowpea mosaic virus, a plant virus that infects legumes, has a special power you may not know: when injected into a tumor, it activates the immune system to treat cancer — even metastatic cancer — and prevent it. come back.

Researchers at the University of California at San Diego and Dartmouth College have spent the past seven years studying and testing the caupine mosaic virus (in the form of nanoparticles) as cancer immunotherapy and have reported encouraging results in laboratory mice and patients with companion dogs. Its effectiveness has been unmatched by other cancer-fighting techniques examined by researchers. However, the precise reasons for its effectiveness remain a mystery.

In a recent study published in the journal Molecular Pharmaceuticalsresearchers are discovering details that explain why the caupin mosaic virus in particular is extraordinarily effective against cancer.

The beauty of this approach is that it not only takes care of that tumor, but also launches a systemic immune response against any metastatic and future tumors.

The work was led by Nicole Steinmetz, a professor of nanoengineering at the UC San Diego Jacobs School of Engineering, and Steven Fiering, a professor of microbiology and immunology at the Geisel School of Medicine in Dartmouth. Steinmetz and Fiering are co-founders of a biotechnology startup called Mosaic ImmunoEngineering Inc., which is licensed for cowpea mosaic virus nanotechnology and is working to translate it into the clinic as cancer immunotherapy.

“This study helps validate the nanoparticle of the caupin mosaic plant virus as the leading candidate for cancer immunotherapy,” said Steinmetz, who also serves as director of UC San Diego’s NanoImmunoEngineering Center. “We now have mechanical data to explain why he is the most powerful candidate, which further reduces his risk for clinical translation.”

Until now, Steinmetz, Fiering and their teams had a general idea of ​​how their main candidate worked. Kaupin mosaic virus nanoparticles, which are infectious in plants but not in mammals, are injected directly into a tumor to serve as bait for the immune system. The body’s immune cells recognize the nanoparticles of the virus as foreign agents and ignite to attack. When the immune cells see that the nanoparticles of the virus are inside a tumor, they go after the cancer cells.

The beauty of this approach, Steinmetz noted, is that it not only takes care of that tumor, but also launches a systemic immune response against any metastatic and future tumors. Researchers have seen it work in mouse models of melanoma, ovarian cancer, breast cancer, colon cancer and glioma. They have also been successful in using it to treat canine patients with melanoma, breast cancer and sarcoma.

What’s also interesting is that the kaupin mosaic virus has worked better to trigger an immune response to cancer compared to other plant viruses or virus-like particles that researchers have studied. “We’ve shown that it works, and now we have to show what makes it so special that it can induce this kind of response,” said lead author Veronique Beiss, a former postdoctoral researcher at Steinmetz’s lab. “This is the knowledge gap we seek to fill.”

To get answers, the researchers compared the caupi mosaic virus to two other plant viruses in the same family that have the same shape and size. A virus, the severe mosaic virus of the caupi, shares itself[{” attribute=””>RNA sequence and protein composition. The other, tobacco ring spot virus, is similar only in structure. “We thought these would be great comparisons to see if this potent anti-tumor efficacy runs in this particular family of plant viruses,” said Steinmetz. “And we can dig deeper by comparing to relatives with and without sequence homology.”

The researchers created plant virus-based nanoparticle immunotherapies and injected them into the melanoma tumors of mice. Each immunotherapy candidate was administered in three doses given 7 days apart. Mice given the cowpea mosaic virus nanoparticles had the highest survival rate and the smallest tumors, with tumor growth essentially stalling four days after the second dose.

The researchers then extracted immune cells from the spleen and lymph nodes from the treated mice and analyzed them. They found that the plant viruses all have a protein shell that activates receptors, called toll-like receptors, that are on the surface of immune cells. But what’s unique about cowpea mosaic virus is that it activates an additional toll-like receptor through its RNA. Activating this additional receptor triggers more types of pro-inflammatory proteins called cytokines, which help boost the immune system’s anti-cancer response. In other words, triggering a stronger inflammatory response makes the immune system work harder to look for and get rid of tumors, explained Beiss.

The team’s analysis also found another unique way that the cowpea mosaic virus boosts the immune response. Four days after the second dose, the researchers measured high levels of cytokines. And these levels stayed high over a long period of time. “We don’t see this with the other two plant viruses. The cytokine levels peak quickly, then go down and are gone,” said Beiss. “This prolonged immune response is another key difference that sets cowpea mosaic virus apart.”

While this sheds light on cowpea mosaic virus’s superior potency and efficacy, Steinmetz acknowledges that there is more work to do. “The answers we’ve discovered here have opened up more questions,” she said. “How does this virus nanoparticle get processed in the cell? What happens to its RNA and proteins? Why is the RNA of cowpea mosaic virus recognized but not the RNA of other plant viruses? Understanding the detailed journey of this particle through the cell and how it compares to other particles will help us nail down what makes cowpea mosaic virus uniquely effective against cancer.”

Reference: “Cowpea Mosaic Virus Outperforms Other Members of the Secoviridae as In Situ Vaccine for Cancer Immunotherapy” by Veronique Beiss, Chenkai Mao, Steven N. Fiering and Nicole F. Steinmetz, 25 March 2022, Molecular Pharmaceutics.
DOI: 10.1021/acs.molpharmaceut.2c00058

This work was funded by the National Institutes of Health (grants U01-CA218292, R01-CA224605 and R01 CA253615) and the Department of Defense, Congressionally Directed Medical Research Program (W81XWH2010742).

Leave a Reply