Raphael Thys
Scientists have demonstrated that viral particles from a harmless plant virus can be used as an adjuvant therapy to prevent recurrence of disease and metastasis formation in several cancer models [1].
The challenge of keeping cancer at bay
Medicine’s progress in treating cancer has been patchy: impressive with some cancers, dead-slow with others. For instance, metastatic cancer remains a major problem, as a cancer’s metastasis dramatically lowers the survival rate. Up to 90% of all cancer-related deaths are attributed to metastases [2].
After a primary treatment, such as surgery, adjuvant therapies are given to lower the risk of the cancer coming back. These treatments can include chemotherapy, radiation therapy, and immunotherapy and aim to eliminate any remaining cancer cells and not let them engender metastases. However, even when successful, adjuvant therapies often cause powerful side effects that reduce life quality and are associated with shorter lifespans [3].
One promising novel approach to preventing metastases is oncolytic viruses, which attack cancer cells while supposedly sparing healthy cells [4]. They can cause lysis (cellular death) and/or recruit to the tumor the patient’s immune system, which recognizes the virus as a foreign pathogen. When immune cells arrive at the site, they also attack cancer cells.
Switching to “vegan” viruses
However, existing viral therapies are still not specific enough and can harm non-cancer cells. To overcome this problem, a team from the University of California in San Diego has been developing a treatment based on a plant virus. In their previous studies, the researchers showed that the cowpea mosaic virus that infects black-eyed peas can recruit the immune system when injected directly to the tumor microenvironment without actually infecting any cells, cancer or not [5]. Since the virus does not kill cells directly, precise local administration might not be needed, which was the hypothesis that the researchers tested this time.
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Not all plant viruses elicit immune responses in humans. In fact, the researchers tested several other viruses and found cowpea mosaic virus particles (CMVPs) to be exceptional in this regard. The team then tested CMVPs on a mouse model of colon cancer. Intraperitoneal cancers are among the deadliest and tend to metastasize quickly. Mice were injected with a dose of CMVPs and, one week later, challenged with an injection of colon cancer cells.
The treated mice demonstrated dramatically improved survival over untreated controls. 56% of the animals in the study group survived, while all mice in the control group succumbed to the disease within 25 days. On average, the treatment slowed tumor growth almost to a halt.
To see whether the treatment provided long-term protection, 40 days into the experiment, the surviving mice were re-challenged with a new dose of cancer cells. A subset of those mice was also injected with T cell-neutralizing antibodies to investigate the importance of T cells for any possible anti-tumor effect. The mice with their T cells intact showed robust survival, unlike those that had their T cells neutralized.
When another group of survivors were injected with cancer cells away from the original injection site, the protection remained robust, suggesting a systemic and tissue-agnostic nature. “Overall, the re-challenge experiments demonstrate that CPMV prophylaxis generates potent immune memory after initial challenge that is tumor-specific, but tissue-agnostic”, the paper says.
Effective in other cancers too
In cimilar experiments, the treatment proved effective against ovarian and breast cancer. The researchers also specifically analyzed lung metastases in a melanoma model, as lung metastases appear in many cancers, resulting in poor prognosis and low survival rates. The treatment effectively prevented melanoma cells from metastasizing into the lungs.
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All these experiments were designed to mimic an adjuvant treatment aimed at preventing the recurrence and metastasis of cancer. However, people with intraperitoneal cancer often already have metastases when they are first diagnosed. To address this situation, the researchers reversed the order of things, first challenging mice with a small dose of cancer cells and waiting a week to administer this treatment, which was found to still be effective. In another experiment, they let the cancer progress and then surgically removed the tumors before administering CMVP particles. The results were still impressive, with the number of long-term survivors increasing fourfold.
“Even if you perform surgery to remove the tumors, no surgery is perfect and there is outgrowth of metastasis if no additional treatment is provided,” said Nicole Steinmetz, a professor of nanoengineering at UCSD and the study’s leading author. “Here, we use our plant virus nanoparticles after surgery to boost the immune system to reject any residual disease and prevent circulating tumor cells from metastatic seeding. We found that it works really, really well!”
Literature
[1] Chung, Y. H., Zhao, Z., Jung, E., Omole, A. O., Wang, H., Sutorus, L., & Steinmetz, N. F. (2024). Systemic Administration of Cowpea Mosaic Virus Demonstrates Broad Protection Against Metastatic Cancers. Advanced Science, 2308237.
[2] Guan, X. (2015). Cancer metastases: challenges and opportunities. Acta pharmaceutica sinica B, 5(5), 402-418.
[3] Beisecker, A. E., Cook, M. R., Ashworth, J., Hayes, J., Brecheisen, M., Helmig, L., … & Selenke, D. (1997). Side effects of adjuvant chemotherapy: perceptions of node‐negative breast cancer patients. Psycho‐Oncology: Journal of the Psychological, Social and Behavioral Dimensions of Cancer, 6(2), 85-93.
[4] Shalhout, S. Z., Miller, D. M., Emerick, K. S., & Kaufman, H. L. (2023). Therapy with oncolytic viruses: progress and challenges. Nature Reviews Clinical Oncology, 20(3), 160-177.
[5] Wang, C., & Steinmetz, N. F. (2020). A combination of cowpea mosaic virus and immune checkpoint therapy synergistically improves therapeutic efficacy in three tumor models. Advanced functional materials, 30(27), 2002299.