Researchers at the University of Michigan have had initial success in mice using nanodiscs to deliver a customized therapeutic vaccine for the treatment of colon and melanoma cancer tumors.
“We are basically educating the immune system with these nanodiscs so that immune cells can attack cancer cells in a personalized manner,” said James Moon, the John Gideon Searle assistant professor of pharmaceutical sciences and biomedical engineering.
Personalized immunotherapy is a fast-growing field of research in the fight against cancer.
The therapeutic cancer vaccine employs nanodiscs loaded with tumor neoantigens, which are unique mutations found in tumor cells. By generating T-cells that recognize these specific neoantigens, the technology targets cancer mutations and fights to eliminate cancer cells and prevent tumor growth.
Unlike preventive vaccinations, therapeutic cancer vaccines of this type are meant to kill established cancer cells.
“The idea is that these vaccine nanodiscs will trigger the immune system to fight the existing cancer cells in a personalized manner,” Moon said.
The nanodisc technology was tested in mice with established melanoma and colon cancer tumors. After the vaccination, twenty-seven percent of T-cells in the blood of the mice in the study targeted the tumors.
When combined with immune checkpoint inhibitors, an existing technology that amplifies T-cell tumor-fighting responses, the nanodisc technology killed tumors within 10 days of treatment in the majority of the mice. After waiting 70 days, researchers then injected the same mice with the same tumor cells, and the tumors were rejected by the immune system and did not grow.
“This suggests the immune system ‘remembered’ the cancer cells for long-term immunity,” said Rui Kuai, U-M doctoral student in pharmaceutical sciences and lead author of the study.
“The holy grail in cancer immunotherapy is to eradicate tumors and prevent future recurrence without systemic toxicity, and our studies have produced very promising results in mice,” Moon said.
The technology is made of extremely small, synthetic high density lipoproteins measuring roughly 10 nanometers. By comparison, a human hair is 80,000 to 100,000 nanometers wide.
“It’s a powerful vaccine technology that efficiently delivers vaccine components to the right cells in the right tissues. Better delivery translates to better T-cell responses and better efficacy,” said study co-senior author Anna Schwendeman, U-M assistant professor of pharmacy.
The next step is to test the nanodisc technology in a larger group of larger animals, Moon said.
May even work on melanomas that have resisted treatment
An experimental cancer drug works differently than intended and shows significant promise for stopping melanoma and possibly other forms of cancer, research from the University of Virginia School of Medicine suggests. The findings also indicate the drug may be effective against melanomas that have resisted other forms of treatment.
The drug, pevonedistat, is already being tested in people. Scientists have been uncertain exactly how it kills cancer cells, as it shuts down many different cellular proteins – hundreds if not thousands. But the UVA researchers, led by Tarek Abbas, PhD, of the Department of Radiation Oncology and the UVA Cancer Center, have determined that the drug acts upon a particular protein that melanomas and other cancers rely on to replicate with great speed and deadly effect. By denying the cancers this essential ingredient, doctors may be able to stop melanomas and other forms of the disease.
“We think that this is what lets the cancer cells cope with the amount of replication they must undergo,” Abbas said. “They divide in uncontrolled fashion, and those cells that divide faster and more frequently are under tremendous replication stress, so these cancer cells needed to be able to develop a way to cope with that.”
The critical protein blocked by pevonedistat is produced by the gene CDT2, and it is vital for malignant cancer cells to survive. Without it, the cells stop replicating and begin to fall apart. “We have great understanding now for how the drug works,” Abbas said. “And we think the drug works not because of its intended target, but rather because it works on [the CDT2 protein] way downstream of that.”
Excessive amounts of the protein are produced in melanoma cells, and patients with high levels of it are less likely to survive. “These tumors, and not necessarily just melanoma, they are addicted to this gene,” Abbas said. “And that makes them very susceptible to the drug. In fact, we showed, that melanoma cells that have higher levels of expression of CDT2 are much more susceptible to the drug.”
High levels of the CDT2 protein are also found in many other tumors, he noted, including brain, breast and liver tumors. Doctors may one day use the level of the protein as a way to gauge disease prognosis.
‘We Have Great Hope’
The safety and effectiveness of pevonedistat in people is still being tested, and it is not yet available as a treatment. But Abbas, who has not been involved in the drug’s testing, is optimistic based on his findings. “We have great hope that this drug will have very significant impact on melanoma in general. … In fact, the drug is very effective on all melanomas, including those for which an effective therapeutic is lacking,” he said. “We actually show this drug can work on melanoma that resisted treatment, which is a major challenge in melanoma therapy. … If approved by the FDA and it moves forward, this drug could potentially be a good second-line therapy for those patients that fail initial treatment.”