Metastatic cancer, which is cancer that has spread to other organs, is responsible for up to 90 percent of global cancer mortality (1). Standard therapeutic approaches like chemotherapy, while often effective, inflict significant collateral damage on healthy tissues. So, researchers are keen to develop innovative treatment strategies with improved tolerability and efficacy.

Now, researchers from the University of California San Diego, led by biomedical engineer Nicole Steinmetz, engineered a new plant-based immunotherapy. They chose a plant virus — cowpea mosaic virus (CPMV) — to mount an immune response against metastatic cancer in mice (2). Their approach, published in Advanced Science, could offer a safer treatment than traditional chemotherapies. 

The human immune system is often ineffective against metastatic cancers. These malignant cells evade immune detection by downregulating their expression of major histocompatibility complex molecules, which immune cells use to recognize foreign antigens. Metastatic cancer cells also secrete immunosuppressive factors that dampen the overall immune response. Consequently, the immune system fails to identify and eliminate these rogue cancer cells, allowing them to establish new colonies throughout the body.

Standard treatments like chemotherapy target all rapidly-dividing cells. While this approach can effectively shrink tumors, it also significantly damages healthy tissues that proliferate, such as bone marrow and the gastrointestinal tract, and causes debilitating side effects. So, the researchers wanted a safer, alternative way to activate the patient’s immune system.

“The plant virus doesn't replicate,” Steinmetz said. “But the body still recognizes this as a virus. … And the immune system becomes very alert. It's this readiness to fight off any disease that just primes the patient.”

The researchers investigated how CPMV can increase survival in different types of metastatic cancer. They systemically injected mice with CPMV, and one week later, they delivered CT26 colon cancer cells to the animals. Mice that received CPMV had significantly increased survival rates compared to control untreated mice, which succumbed to the disease within 25 days. 

The CPMV-treated group also had lower average circumference and body weight than control mice, indicating decreased tumor proliferation. When re-challenged with colon cancer cells 40 days later, CPMV mice survived longer compared to the control saline-injected group.

[CPMV] just really mimics so well being a pathogen without being one that it gets the immune system really fired up without the side effects of an infection. 
- Nicole Steinmetz, University of California San Diego 

To further understand the anti-metastatic properties of CPMV, the researchers injected the mice with the virus, and then one week later, with melanoma cells. Three weeks later, the researchers examined the mice’s lungs for the growth of metastatic nodules. The CPMV group exhibited a four-fold decrease in tumor nodules compared to control mice. The researchers also compared CPMV head-to-head with two chemotherapy adjuvants: diamidobenzimidazole and imiquimod. Again, CPMV was superior in reducing the number of metastatic lung nodules compared to existing adjuvants. 

“[CPMV] just really mimics so well being a pathogen without being one that it gets the immune system really fired up without the side effects of an infection,” added Steinmetz.

To determine the mechanism of CPMV action, the researchers collected blood samples from mice one day and one week after CPMV injection. Using a mesoscale discovery assay that quantified levels of secreted proteins, the team demonstrated that cytokines and chemokines were upregulated with CPMV injections. Notably, levels of pro-inflammatory interferon-gamma and monocyte attractant protein-1 were significantly upregulated compared to controls. Flow cytometry analysis of these blood samples showed increased levels of neutrophils and monocytes/macrophages, indicating a pro-inflammatory immune response against the administered cancer cells. 

“Cancer doesn't usually kill people unless it spreads or metastasizes, so the fact that a plant virus is able to arm the immune system and prevent metastatic disease is pretty cool,” said John Lewis, an oncologist from the University of Alberta, who was not a part of the study.

Steinmetz and her team are currently investigating the precise mechanisms by which CPMV stimulates the immune system. By harnessing the body's natural defenses and leveraging CPMV's inherent safety profile, this plant-based approach could be used for metastatic cancers, offering a future with fewer debilitating side effects and improved patient outcomes.

“The immune system has evolved to eliminate disease, just sometimes it doesn't work. It needs a little help or a little kickstarting,” said Steinmetz. “That's the way I see this therapy working.”

References

1. Hudock, N.L. et al. Future trends in incidence and long-term survival of metastatic cancer in the United States. Commun Med  3, 1–7 (2023).
2. Chung, Y.H. et al. Systemic Administration of Cowpea Mosaic Virus Demonstrates Broad Protection Against Metastatic Cancers. Adv Sci  11, (2024).