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 The therapies could generate tens of billions of dollars in annual
sales for drugmakers including Kite Pharma and Juno Therapeutics
Inc, once they are approved.
The therapies involve using what are known as CAR T cells, which are
white blood cells taken from the body and genetically modified to
have the cancer-spotting traits of antibodies. These cells can
circulate inside a person for years, even a lifetime, relentlessly
seeking out cancerous growth.
But a third of the patients in some trials given CAR T cells have
developed life-threatening fevers and inflammation. Doctors say the
reason is that the modified T cells cause inflammation because they
kill so many cancer cells so quickly. Another concern is that when
the therapies are eventually targeted at solid tumors such as lung
or kidney cancer, they could also attack healthy cells containing
the same protein that's the target of the anti-cancer therapy.
As a result, some drugmakers are building in "switches" to suppress
CAR T cells if serious side effects emerge, or to make them
self-destruct if they attack healthy tissue, according to Reuters
interviews with company executives. The switches involve an
additional receptor on the CAR T cell that can be controlled by
giving the patient a second medication, such as the widely-used
cancer drug Rituxan.
The so-called suicide switches being developed for CAR T cells are a
refinement of the body's own natural process of apoptosis, by which
defective or unneeded cells are programmed to self-destruct.
Approval of the new therapies to combat blood cancers are not
expected for perhaps another three or four years, analysts said.
Approval for therapies to fight solid tumors will take years longer,
they said.
Intrexon Corp and Cellectis SA are among the leading switch makers
and could become acquisition targets or licensing partners for
drugmakers that need their technology, according to analysts.
Bellicum Pharmaceuticals Inc and Cellectis have their own pipeline
of switches and experimental CAR T cells. Intrexon has given
Ziopharm Oncology Inc exclusive oncology rights to its switches.
Juno has built safety switches into at least two therapies,
including JCAR014 for patients with advanced leukemias.
Kite has decided against using suicide switches until it better
understands how its CAR T cells work in patients. Other major
players, including Bluebird Bio and Swiss drugmaker Novartis AG,
have not disclosed their plans.
"If you can delete the engineered T cells at will, there will be a
lot more comfort" in using CAR T cells, said Dr. Laurie Glimcher, an
immunologist and dean of Weill Cornell Medical College in New York,
who is not involved in any of the studies. "If you have any evidence
they are hitting normal tissues, bang! You 'suicide' them out."
Having the switches would give researchers more courage to test T
cells against solid tumors, by far the biggest potential market for
cancer drugs. "The goal is to make them available and effective for
tumors for which we now have no good treatments, like pancreatic,
ovarian and head and neck cancer," Glimcher said.
Shares of most CAR T cell companies have risen sharply in the past
12 months, with Bluebird gaining 650 percent, Cellectis up 500
percent and Ziopharm gaining 200 percent.
Kite stock has more than doubled since it went public last June,
while Juno shares have risen 19 percent since its IPO in December.
Shares of Bellicum, which lags competitors in drug development, have
slipped 7 percent since its own Nasdaq debut in December. Intrexon,
led by billionaire biotech investor R.J. Kirk, has gained 160
percent in the past year.
FLIPPING THE SWITCH
Most CAR T cells target a protein, or antigen, called CD19 found on
the surface of B-cells, a type of white blood cell associated with
blood cancers.
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There have been at least six deaths and scores of severe
inflammatory reactions from the treatments in clinical trials that
landed patients in intensive care units. Although doctors have
stabilized most patients with steroids and anti-inflammatory drugs,
their safety is expected to face close scrutiny from regulators.
The effect of the self-destruct switches is also far from assured.
Only a few, including ones from Bellicum, Juno and Ziopharm, are
currently in clinical trials or expected to begin trials this year.
Dozens of others are on the drawing boards.
"Nobody knows how they will be applicable in the real world," said
Ran Nussbaum, co-founder of the Pontifax Group which holds more than
2 million Kite shares.
Greg Frost, health sector chief at Intrexon, believes switches will
become standard because of how long CAR T cells can circulate in the
body.
"About 70 million of the patient's T cells are removed, engineered,
and put back into the patient. Those cells will ramp up and multiply
in the body nearly 1,000 fold," Frost said. "That rush is very
powerful in controlling cancer, but they're off on their own."
The U.S. Food and Drug Administration declined to comment on whether
safety switches for CAR T cells would affect their approval, citing
their very early stage of development.
So far, CAR T cell trials mostly involve patients with advanced
blood cancers who had no other options, making the potential risks
acceptable.
That won't be the case when drugmakers test the therapies in less
ill patients or people with solid tumors. Antigen targets found on
solid tumors are far more likely to also reside in healthy tissue,
which the experimental drugs could strike.
That could put players without switches, like Kite, and possibly
Bluebird and Novartis, at a disadvantage, said Wedbush Securities
analyst David Nierengarten.
"When Kite pursues solid tumors, they will need to incorporate some
sort of switch to prevent serious adverse reactions," he said.
Kite plans at least four trials this year of CAR T cell therapies
for leukemias and lymphomas, none using switches. Chief Executive
Arie Belldegrun said the company is acting on the advice of its
partners at the National Cancer Institute.
Kite "decided not to complicate the products further by introducing
switches," Belldegrun said. The company might reconsider if side
effects become a bigger problem. But suicide switches could also
neutralize the beneficial anti-cancer effects of the CAR T cells,
putting terminal patients back at death's door, he said.
Christopher Clark, co-portfolio manager of RS Investments Growth
Funds, which holds major stakes in Kite, Juno and Bluebird, expects
safety switches will soon become fundamental technology.
"Every player in this space will eventually have them, because to
move from B cells (blood cancers) to solid tumors, it seems like
they are a must have," Clark said.
(Reporting by Ransdell Pierson; Editing by Michele Gershberg and
John Pickering)
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