New angle on immunotherapy

Salk researchers get $2.5 million for pancreatic cancer trial involving vitamin D and Keytruda

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LA JOLLA, Calif.—Salk Institute professor and Howard Hughes Medical Institute investigator Dr. Ronald Evans has been awarded $2.5 million by Stand Up To Cancer (SU2C) as part of a multi-institution team to conduct clinical studies to open up a new avenue for immunotherapy in the treatment of pancreatic cancer. While the cancer normally excludes immune T cells, the Evans lab discovered that modified vitamin D reprograms the cancer environment in a way that may allow the Merck & Co. drug Keytruda to invade and destroy the tumor.
The award, spread out over three years, is part of SU2C Catalyst, which uses “funding and materials from the pharmaceutical, biotechnology, diagnostic and medical devices industries to accelerate research on cancer prevention, detection and treatment,” according to SU2C. This award is supported by the U.S.-based pharmaceutical company Merck (known as MSD outside the United States and Canada), which is providing funding and the immunotherapy drug Keytruda (pembrolizumab) for the clinical trial.
“The Evans lab’s discovery that vitamin D can make pancreatic tumors more susceptible to drug therapy suggested the added potential to also wake up the patient’s own immune system,” says Salk President Elizabeth Blackburn. “Combining vitamin D and immuno-oncology gives new hope to tens of thousands of pancreatic cancer patients whose treatment options have been devastatingly limited thus far. This could be a game changer.”
Pancreatic cancer is one of the deadliest types of cancers, both because it is often diagnosed late and because its unique tumor environment makes it impervious to both chemotherapy and immunotherapy, Salk points out. Pancreatic tumors co-opt the body’s natural wound-healing response, hiding behind a wall of immune cells and inflammatory molecules almost like an armor that drugs can’t penetrate. In the meantime, the tumor uses the nutrients that should be supporting the immune cells to nourish itself.
“We have to bring pancreatic cancer treatment into the modern age,” stressed Evans, who is the director of Salk’s Gene Expression Laboratory and holder of Salk’s March of Dimes Chair in Molecular and Developmental Biology. “This cancer is a particularly strong foe. It has resisted basically everything thrown at it. But we believe that it can be tamed, conquered and hopefully cured. This grant is a big step toward making that happen.”
As Salk notes, the “armor” surrounding and protecting pancreatic tumors is controlled by a molecular switch that the Evans lab showed can be controlled by a special synthetic form of vitamin D. When Evans and colleagues administered the drug to mice and a small number of humans, it “cooled down” the inflamed environment, allowing chemotherapy to be more effective.
“The Salk team will work with Translational Genomics Research Institute (TGen) in analyzing patient samples to figure out whether our theories about combining vitamin D and immunotherapy are correct or not—and we’ll know that pretty rapidly,” said Dr. Michael Downes, a Salk senior scientist and co-principal investigator of the new grant.
Heading the clinical group in Arizona is Dr. Daniel Von Hoff of TGen, who also is the chief scientific officer at HonorHealth, a primary clinical trial site. Salk will also work closely with Dr. Andrew Lowy and the clinical oncology group at the University of California, San Diego Cancer Center.
“We are extremely excited about this trial, because for the first time we’re able to get patients into remission—even stage IV patients—where we see the tumor shrink,” noted Von Hoff. “The high dose of this vitamin D derivative allows the body’s immune system to go from viewing the cancerous cells from something that is normal, to recognizing them for the invaders they are and hopefully attacking them as they would a common infection.”

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