Frontline Cancer: DART takes aim at rare cancers
Feb. 27 is Rare Disease Day. The emphasis will be on research and the theme “Research brings hope.”
A “rare disease” in the United States is defined as a condition that affects fewer than 200,000 Americans at any given time. In a population exceeding 325 million people, that makes statistical sense — 200,000 is just 0.06 percent of the total populace — but it’s cold comfort if you’re among those uncommonly afflicted.
Because they are infrequently found and healthcare resources are indisputably finite, rare diseases do not attract much attention, comparatively speaking. True to its confounding nature, cancer is both an exception — and not.
There are literally scores of rare cancers that pass unnoticed or unknown until, of course, you or someone you know receives such a diagnosis. These cancers are not the subject of broad, deep, relentless study or the target of expensive, national, multi-institutional efforts to find new treatments or cures.
But rare tumors cumulatively comprise more than 20 percent of all cancers diagnosed worldwide. Seemingly diffuse, they represent a massive target worth addressing. A new clinical trial, called Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors or, more succinctly, DART, will take a shot.
DART is the brainchild of Razelle Kurzrock, M.D., senior deputy director of clinical science at Moores Cancer Center at UC San Diego Health, and colleagues at SWOG, an acronym for a worldwide network of researchers who design and conduct cancer clinical trials.
DART will leverage the emerging promise of immunotherapy (boosting the body’s immune system to fight malignancies) to test combination therapies using two leading-edge immunotherapy drugs — ipilimumab and nivolumab — on 80 rare cancer types, from acinar cell carcinoma to vulvar squamous cell carcinoma. Kurzrock is co-senior study chair with Francis J. Giles, M.D., of Northwestern University.
The senior principal investigator for DART is Sandip Patel, M.D., an assistant clinical professor and medical oncologist at Moores Cancer Center, who helped conceive the original idea. Donna Hansel, M.D., Ph.D., professor of pathology at UCSD School of Medicine, is also part of the DART team.
DART is the first federally funded immunotherapy trial devoted to studying the rare malignancies.
Charles D. Blanke, M.D., the chair of SWOG has described DART as three I’s: impact, immunotherapy and ingenuity. The impact is obvious: Thousands of Americans get a diagnosis of a rare cancer each year. Typically, they are under the age of 40. “DART could point to an effective treatment option for thousands of people,” wrote Blanke on his blog.
The trial is ingenious for a less obvious reason. Rare cancer trials are, well, rare because it’s invariably difficult to find enough suitable participants to conduct a dedicated, focused study. DART solves that problem by leveraging another ongoing clinical trial called NCI-MATCH (short for National Cancer Institute-Molecular Analysis for Therapy Choice), which looks at patients’ tumors for gene abnormalities for which a targeted drug already exists, something geneticists call an “actionable mutation.”
NCI-MATCH patients for whom there is no current treatment option or who have cancers that don’t respond to treatment on that trial may be eligible to enroll in DART.
“In a way, NCI-MATCH creates the haystack for DART while also identifying the needles in that haystack. It’s a way to speed treatments to a population in critical need,” said Blanke.
The two drugs being used in DART — ipilimumab and nivolumab — are notable, too. Both are monoclonal antibodies and both are checkpoint inhibitors. The former means they have an affinity for binding to a specific antigen or molecule on a cell. The latter means these antibodies target the CTLA-4 and PD-1 immune checkpoints — proteins that, in normal cells, are used to turn up or turn down signals to T cells so that they are not attacked by these immune system guardians. Many cancer cells protect themselves from the immune system by inhibiting the T cell signal. Monoclonal antibodies essentially strip this protection away from cancer cells, allowing T cells to zero in and attack.
Ipilimumab and nivolumab (marketed as Yervoy and Opdivo) are already approved for treating melanoma and, in combination, some cancers of the thorax, the main body cavity where the heart, lungs and other organs reside. There are high hopes that these drugs will prove effective against rare tumors as well.
— Scott M. Lippman, M.D., is director of UCSD Moores Cancer Center. His column on medical advances from the front lines of cancer research and care appears in La Jolla Light fourth Thursdays. Reach Dr. Lippman at email@example.com
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