Mouse image courtesy of Stromnes et al./Cancer Cell 2015
A new study has found that a certain type of immunotherapy — even when used without chemotherapy or radiation — can boost survival from the nearly-always deadly pancreatic cancer by more than 75 percent in mice.
The study, which was led by Fred Hutchinson Cancer Research Center clinical researchers Drs. Sunil Hingorani, Phil Greenberg and Ingunn Stromnes, tested the immunotherapy on mice genetically engineered to grow pancreatic tumors very similar to those of human pancreatic cancer.
Pancreatic cancer is notoriously difficult to treat, said Hingorani, because it recruits patients’ bodies’ natural systems to construct both a tough physical barrier around tumors as well as an immune-cloaking device that keeps other, disease-fighting immune cells from recognizing the cancer.
Unlike any other cancer, pancreatic tumors are able to survive with a very limited blood supply — chemotherapy, administered via the bloodstream, has a difficult time getting inside. The tumors can also grow quite large before patients will ever notice something is wrong. And they are very prone to metastasize, or spread to other sites in the body.
Patients diagnosed with this cancer face very few treatment options. The median survival from time of diagnosis is six months. Only 7 percent of patients survive five years past their diagnosis, according to the National Cancer Institute.
“Pancreas cancers are probably the most lethal of all solid tumors,” Hingorani said. “This is the beast of all beasts.”
Hingorani, a pancreatic cancer specialist, teamed up with immunotherapy experts Greenberg and Stromnes on a new study to breach the cancer’s physical and immunological walls using immunotherapy, a type of treatment that harnesses or refines the body’s own immune system to recognize and destroy cancer cells. The team’s study was published Thursday in the journal Cancer Cell and was funded in part by the National Institutes of Health, the Giles W. and Elise G. Mead Foundation and Juno Therapeutics.
The researchers aim to launch an early-stage clinical trial testing the safety of this technology in humans with advanced pancreatic cancer within the next year. Because the researchers’ mouse model so closely matches the human cancer, they are hopeful that their preclinical results will translate to clinical benefit.
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The first iteration
The researchers devised a therapy using T cells, disease-fighting immune cells, that Stromnes engineered in the lab to recognize and attack pancreatic cancer.
T-cell therapy is showing promise as a treatment for several types of blood cancers, based on early results from Fred Hutch and other research centers, but aiming these cells at solid tumors like pancreatic cancer has historically proven more difficult, Hingorani said.
Part of the challenge comes from the access to tumor cells — or lack thereof. T-cell therapy is administered through the bloodstream, like chemo. It’s easy enough to see why solid tumors may present more of a challenge to treat with this kind of immunotherapy than blood cancers such as leukemia and lymphoma.
The researchers didn’t think the engineered T cells would stand a chance against pancreatic cancer on their own. But they needed somewhere to start, Greenberg said.
“What we thought was that this initial effort probably won’t work very well, if at all — at least the first iteration won’t work,” he said, but the team could then use the model that replicates the human disease to devise a strategy that would ultimately work for pancreatic cancer patients.
Hingorani and his colleagues have developed and tested other strategies against pancreatic cancers in their mouse model of the disease, including one that pulls back the tumor’s cloaking device, allowing the natural immune system to recognize and attack the cancer, and one currently undergoing testing in humans that deflates the cancer’s physical barrier, allowing chemotherapy access to the tumor. They assumed they’d have to ultimately combine the T-cell therapy with an approach like one of these to see any real effect against the cancer.
But to their surprise, the T cells — engineered to recognize and kill cells bearing a protein called mesothelin, which is overproduced by virtually all pancreatic tumors — homed to the mice’s tumors and started attacking them.
“Everything up until now indicated that T cells can’t get into these tumors,” said Stromnes, a research associate in Greenberg and Hingorani’s labs. But their study suggests that “all we may really need is the right kind of T cell to actually have a major impact,” she said.
Fred Hutch file
‘Not enough time in my lifetime’
The researchers first dosed the mice with Cytoxan, a drug that depletes some of the animals’ natural T cells (creating space for the engineered cells to grow in the marrow), and then delivered the engineered cells to them by intravenous infusion — no small feat in a mouse, Hingorani said. Eight days later, large numbers of the immune cells had trafficked to the tumor and were showing anti-cancer activity.
That was the first surprise. But somewhat less surprisingly, the T cells started to fizzle out by two to four weeks after infusion, not long enough to significantly counteract the cancer’s growth.
There are scientific solutions to that too-short burst of activity. The researchers are actively pursuing them, but they’ll take time to develop and test.
In the meantime, Stromnes had a simple idea: Give the mice more T cells. The team began giving the mice fresh batches of T cells every two weeks, and each new infusion of cells seemed to work as well as the first.
“So now we have a strategy. It’s not necessarily the most refined, but it’s workable,” Hingorani said. “And it’s also manageable in the clinic.”
In the mouse model of the disease — which is actually slightly more aggressive than the human version, Hingorani said — animals that received T cells engineered to recognize a non-cancerous protein survived on average 54 days after their cancer became detectable. Those that received the mesothelin-directed cells lived an average of 96 days, a 78 percent bump.
Although the researchers weren’t expecting to take this first version of the T-cell therapy to clinic, that’s now their plan.
Stromnes is continuing to work on refining the therapy in mice, but the team has already built the human version of the special T-cell protein that recognizes mesothelin. They’re planning to launch a phase 1 clinical trial to test the therapy’s safety in patients with advanced pancreatic cancer within the next year.
And they’re excited about its potential for these patients.
“As best we can tell, this would be a better therapy than anything that exists for pancreatic cancer right now,” Greenberg said. “It’s hard to be this optimistic without ever having treated a pancreatic cancer patient with this [therapy], but the biology of what we’re doing looks so good.”
Fred Hutch file
Hingorani said he and his team have developed other strategies they deemed too incremental to move to human trials.
“We’ve tested other approaches that might have translated to a 10 percent or 20 percent increase in survival, which is still significant in this disease. There have been lesser improvements that have been FDA-approved, but that’s not what drives us,” he said. “There isn’t enough time in my lifetime to keep doing 10 percent increments if we want to dramatically alter the prognosis for this disease.”
When the work is personal
For Hingorani and Greenberg, there’s a bittersweet side to their promising results — both the researchers’ fathers died of pancreatic cancer.
Hingorani was at the beginning of his oncology career when his father was diagnosed with pancreatic cancer in 1999, at the age of 64. He cared for his father while he was dying and that experience propelled him to dedicate his research life to the disease.
“Pancreas cancer for me is personal. It’s about settling a score,” the scientist said in a 2014 interview. “It’s truly a vendetta. … That doesn’t feel enlightening necessarily … but you know what, it’s incredibly motivating.”
Greenberg’s father was diagnosed with the cancer in July 2001 when he was 81. He died in September of that same year.
Greenberg spent much of his career focused on leukemia, but his family’s experience, too, shapes his view on the pancreatic cancer research. His father, a World War II veteran, had a very hard time when the doctors told him there was nothing to be done for his disease.
“He always had this idea that he could fight and overcome anything … that message was very difficult for him to accept, and yet it was the reality,” Greenberg said. There are now new chemotherapies that provide some benefit, he said, but their impact on survival is still minimal.
“This is a disease that desperately needs something new,” Greenberg said.
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Rachel Tompa is a staff writer at Fred Hutchinson Cancer Research Center. She joined Fred Hutch in 2009 as an editor working with infectious disease researchers and has since written about topics ranging from nanotechnology to global health. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Reach her at firstname.lastname@example.org.
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