Frederick National Laboratory teams help evaluate plant virus’ preclinical safety as cancer treatment

Researchers at the University of California San Diego, in collaboration with Frederick National Laboratory for Cancer Research (FNL), found that repeat injections with a plant virus may safely activate the immune system for cancer therapy.

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Cowpea mosaic virus (CPMV), which doesn’t infect humans or other mammals, was tested in a preclinical animal model to determine potential consequences of injecting the virus into cancer patients’ tumors.

The team, which included members of FNL’s Nanotechnology Characterization Laboratory and Molecular Histopathology Laboratory, published their findings in Toxicology Reports.

After receiving CPMV once weekly for three weeks, the animals displayed the expected immunostimulatory effects without major negative health effects. The administered dose was judged as at a high therapeutic dosage.  Given this, the lack of major observed toxicity provides evidence for the virus’ safety following administration.

The study adds to existing knowledge of CPMV’s treatment potential and moves the virus one step closer to human trials.

Side effects were small, with quick recovery

The team administered three doses of CPMV to two groups of animals. One group received the doses subcutaneously (injection under the skin), the other via intravenous infusion. Scientists tracked untreated animals for comparison. Since the study focused on potential toxicities from CPMV, not anticancer activity, none of the animals had tumors.

The subcutaneous group modeled how humans might respond when CPMV is injected into a tumor, the planned method for treating human subjects. The intravenous group modeled the potential scenario of CPMV circulating in a patient’s bloodstream.

Blood tests taken 24 hours after the third dose revealed these treated groups had elevated levels of white blood cells and immune system components, which aligned with previous evidence that CPMV can stimulate an immune reaction in mammals. Encouragingly, the subcutaneous group had the strongest reaction.

“That’s notable in that the subcutaneous route would be more relevant to the intratumoral route that would be used in the clinic and has been used in [past models],” said Stephan Stern, Ph.D., first author on the study and the co-director and head toxicologist at the Nanotechnology Characterization Laboratory.

Some blood marker levels in the treated groups were altered in comparison to untreated animals but within acceptable ranges, and those in the subcutaneous group returned to pre-treatment levels within 14 days of the third dose. (Some levels in the intravenous group didn’t recover over the 14-day recovery period but demonstrated a trend toward recovery.)

A study of all major organs revealed that both treated groups had enlarged spleens—a marker of immune system activation—and immune-related activity in several tissues. However, these returned to a normal range within 14 days of the third dose.

“The toxicology study in [the animals] demonstrates that there was no organ damage associated with the delivery of CPMV,” said Elijah Edmondson, D.V.M., Ph.D., staff pathologist at the Molecular Histopathology Laboratory, who studied the organs in the study.

During the 14-day period after the third dose, neither treated group developed severe or persistent side effects, like widespread inflammation, that cause concern with potential immunostimulatory therapies or nanomedicines. This indicated that the immune system is unlikely to mount a dangerous reaction to CPMV.

Study adds to historical data

The results build on over 10 years of CPMV research by Nicole Steinmetz, Ph.D., leader of the University of California San Diego team.

Steinmetz and colleagues’ previous trials in mouse models and in pet canine cancer patients showed that CPMV, when injected into a tumor, potently stimulates the immune system to attack cancer cells—including metastases elsewhere in the body.

Cancer often co-opts the body’s natural processes to evade the immune system and avoid destruction. Steinmetz’s team showed that CPMV doesn’t harm tumors but as a foreign invader, awakens the body’s defenses. As the immune system battles the CPMV in the tumor, it “discovers” the cancer cells and memorizes how to destroy them, too.

“In cancer therapy, that’s a very big thing,” said Marina Dobrovolskaia, Ph.D., co-author on the Toxicology Reports study and the co-director and head immunologist at the Nanotechnology Characterization Laboratory.

These latest safety findings warrant additional studies and clinical trials to determine whether CPMV is safe and effective in people, members of the team say. These trials will be needed, as animal models don’t perfectly reflect human biology.

“It’s encouraging and worthy of further investigation,” Stern said.