In phase 1 study, researchers will use anti-p53 vaccine to boost immune response
DUARTE, Calif. - Immune cells have the potential to target and destroy tumors that contain cancer-causing proteins such as mutant p53, but a protein produced by tumor cells often blocks such immune responses. If this inhibition could be overcome, however, and if the immune system could be boosted, immune cells might have the ability to quickly clear cancers.
In a clinical trial to be launched at City of Hope in November, researchers Don J. Diamond, Ph.D., Vincent Chung, M.D., and their collaborators will combine two such approaches - an immune-boosting vaccine and a drug that blocks a tumor’s inhibitory signal - to more effectively activate a patient’s own immune system to fight his or her cancer.
The most frequent mutations across all cancers occur in a gene named p53, which makes cells produce a mutant form of the p53 protein. For the clinical trial, Diamond and his colleagues plan to use a vaccine manufactured at City of Hope that boosts the immune response to mutant p53. The researchers tested this vaccine, known as p53MVA, in a 2013 clinical trial and found it safe in patients with advanced, treatment-resistant gastrointestinal cancers.
However, patients whose T cells had pre-existing high levels of a protein named PD1 – a molecule that instructs immune cells to shut down – responded poorly to the anti-p53 vaccine. In a subsequent laboratory study, the City of Hope researchers showed that these patients’ immune cells could be reactivated by treatment with a PD1 inhibitor. In the new clinical trial, they’ll be testing the p53 vaccine with the PD1 inhibitor pembrolizumab against select malignancies.
If a patient’s body can develop a strong immune response against his or her cancer, and the immune cells are given a route to remain active, the cells have the potential to attack and eliminate tumors. The upcoming phase 1b clinical trial will attempt to produce this effect in patients with recurrent solid tumors such as nonsmall cell lung cancer, melanoma, triple-negative breast cancer, renal cell carcinoma and many other cancer types.
The PD1 inhibitor pembrolizumab is already approved for certain types of cancers, and the p53MVA vaccine recognizes only mutant tumor proteins. Nonetheless, the main focus of the upcoming trial is to evaluate the safety of combining the two treatments. “We have to ensure that combining the two does not create side effects that either agent alone doesn’t cause,” Diamond said.
Since p53 mutations are prevalent across myriad cancers, creating a robust immune response to mutant p53 could have far-reaching impact. “The great value of this vaccine is that p53 is a ubiquitous cancer antigen,” says Diamond. “This has the potential to be an off-the-shelf product, effective for a wide variety of patients.”
The clinical trial is registered as NCT02432963 at the clinicaltrials.gov website.
Tara-ImmunoOncology LLC has licensed the p53MVA vaccine and will be involved in future trials of the vaccine in combination with pembroluzimab or other agents.
About City of Hope
City of Hope is an independent research and treatment center for cancer, diabetes and other life-threatening diseases. Designated as a comprehensive cancer center, the highest recognition bestowed by the National Cancer Institute, City of Hope is also a founding member of the National Comprehensive Cancer Network, with research and treatment protocols that advance care throughout the nation. City of Hope’s main hospital is located in Duarte, California, just northeast of Los Angeles, with community clinics in southern California. It is ranked as one of "America's Best Hospitals" in cancer by U.S. News & World Report. Founded in 1913, City of Hope is a pioneer in the fields of bone marrow transplantation and genetics.