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 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.
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 is 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 did not 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 would 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.
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 will 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 were not expecting to take this
first version of the T-cell therapy to clinic, that is 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 are 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.”
“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.”
For Hingorani and Greenberg, there is 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.
This study is not
the only one focusing on the T cells immunotherapy investigation for pancreatic
cancer treatment. In this approach, T cells are removed from a patient,
genetically modified or treated with chemicals to enhance their activity, and
then re-introduced into the patient with the goal of improving the immune
system’s anti-cancer response. For example, Carl H. June, M.D., and Gregory L.
Beatty, M.D., Ph.D., are also actively exploring the potential of chimeric
antigen receptor (CAR) T cells modified to recognize mesothelin, which is
expressed in all pancreatic cancers but not in healthy pancreatic cells, to
treat patients in a phase I trial with pancreatic cancer.
Sources and
Additional Information:
