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 But top oncology researchers are concerned about the two emerging
technologies, citing dangers seen repeatedly in clinical trials
including the potentially fatal buildup of toxic debris from killed
tumor cells and damage to healthy tissue. Such side effects could
block regulatory approval if they aren’t controlled, researchers and
drug company executives said in interviews with Reuters.
In some trials, the two new approaches, known as CAR T cells and
bispecific antibodies, have eliminated all traces of blood cancers
in 40 percent to 90 percent of patients who had no remaining
options. The drugs could reap annual sales in the tens of billions
of dollars for their manufacturers, especially if they can also
eliminate solid tumors in such terminally ill patients.
CAR T cells, or chimeric antigen receptor T cells, are T cells that
have been removed from the body and attached through genetic
engineering to an antibody fragment that recognizes a specific tumor
protein. T cells are an especially powerful disease-fighting kind of
white blood cell. The result is a drug with the killing power of a
greatly enhanced T cell, combined with the tumor-spotting ability of
an antibody.
Bispecific antibodies are a twist on conventional antibodies,
Y-shaped proteins whose two arms grasp for the same protein target
found on cancer cells.
With bispecifics, one arm of the antibody typically grasps a cancer
cell while the other arm takes hold of T cells, bringing the mortal
enemies into contact. The T cell punches holes into the adjacent
tumor cell and injects deadly enzymes. Conventional antibodies, by
contrast, don't directly recruit T cells.
"Unleashing the killing power of the T cell directly on the tumor
cells allows a large increase in potency of these antibodies," said
Dr. David Scheinberg, chairman of molecular pharmacology at Memorial
Sloan Kettering Cancer Center.
Investor excitement over these therapies have helped boost interest
from companies including Amgen Inc and Roche and have fueled a jump
in share prices of smaller firms such as Kite Pharma Inc, Juno
Therapeutics and Bluebird Bio.
"We take patients that have failed every treatment, every chemo
combination, that have just two to six months to live. You give them
a CAR, and within 3 to 4 weeks you can see massive tumors melting
away," said Arie Belldegrun, chief executive officer of Kite. The
company went public in June and announced a partnership with Amgen
earlier this month.
CAR T cells could cost $300,000 to $500,000 per patient, if
approved, making them among the world's most expensive drugs and
testing the ability of insurers to pay for them, said Les Funtleyder
of E Squared Asset Management. The hedge fund owns shares of Kite
Pharma. Bispecific antibodies could command prices of $200,000 or
higher, he said.
The potency of the experimental drugs comes with some dangerous
potential side effects. In the killing process, inflammatory
chemicals from the medicines and the tumor cells, called cytokines,
are released into the bloodstream and can cause fever, low blood
pressure and rapid heartbeat that can be life-threatening.
The drugs, because of their unique structure and how they work, make
it harder to predict whether they will go astray, said Dr. Bindu
George, team leader of the U.S. Food and Drug Administration's
Office of Cellular, Tissue and Gene Therapies, who called CAR T
drugs perhaps the most interesting new technology.
Most CAR T cells and bispecific antibodies in development identify
blood cancer cells by a specific protein, CD19, found on the
surfaces of lymphomas and leukemias. Because the same protein can
also be found on non-cancerous cells, the drugs can go off track and
attack healthy tissues.
"Our biggest concern would be an off-target toxicity that wasn't
expected and we didn't know the cause of it," George said. In that
case, "we might have to ask (the drugmaker) for additional
information, how the toxicity happened, what organ it was, and
literally go back to the drawing board."
TAMING A POWERFUL DRUG
Researchers have used anti-inflammation medications to tame some of
the adverse reactions, not always successfully. A study of CAR T
cell treatment sponsored by Juno for patients with aggressive
non-Hodgkin's lymphoma was briefly put on hold after two people
died.
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Unlike antibodies, which are excreted from the body within days or
weeks, engineered CAR T cells are expected to circulate for years or
even a lifetime in the bloodstream, potentially providing lasting
benefits, but also risks.
"You can start to reject normal tissues; it can kill organs or cause
autoimmune disease, and you don't want that," said Zelig Eshhar, a
professor emeritus of the Weizmann Institute in Israel who pioneered
the CAR approach.
To reduce that danger, researchers are attempting to build "suicide
switches" into CAR T cells to turn them off after they have wiped
out all signs of cancer.
At least 30 bispecific antibodies are believed to be in development,
including ones from Roche, Johnson & Johnson, AbbVie and Eli Lilly.
A growing number of drugmakers are also racing to develop the first
CAR T therapies, including Kite, Novartis, Juno, Cellectis and its
partner Pfizer Inc, and Bluebird, in partnership with Celgene Corp.
EXPENSIVE OPTION
The FDA in December approved the first bispecific, Amgen's $178,000
Blincyto for acute lymphoblastic leukemia (ALL) that did not respond
to previous treatment. The cancer, prevalent in children, is
diagnosed each year in an estimated 6,020 Americans, killing about a
fourth of them.
One third of patients in the Amgen study had no detectable cancer
for nearly seven months after receiving the drug through a
month-long infusion.
A main hope for Blincyto is that it will keep patients alive until
they can receive stem cell transplants, their best chance of a
possible cure.
CAR technology may also come to the rescue where few options remain.
"If doctors and specialists learn how to control this very powerful
gun, CAR T cells could save hundreds of thousands of people in the
United States," said Ori Hershkowitz, a Tel Aviv-based fund manager
with Sphera Funds, which owns shares of Kite and rival CARs
developer Novartis.
A Novartis trial showed 27 of 30 children and adults with ALL had no
signs of the disease after being treated with its CAR T drug. Some
78 percent of patients were still alive six months after treatment,
while some sustained remission for up to two years.
But everyone in the study developed cytokine release syndrome,
including a severe form of it in 27 percent of patients.
"It certainly needs to be watched and evaluated," said Usman Azam,
global head of cell therapies for Novartis. He still believes the
drug’s benefits provide "compelling hope that you can potentially
cure patients."
Roche's Genentech unit is conducting a mid-stage trial of a
bispecific antibody to treat head and neck cancer and colorectal
cancer. It is studying a dozen others in preclinical trials against
cancer, Alzheimer's disease and inflammatory diseases.
Paul Carter, a Genentech executive, was cautious about the
prospects.
"It's too early to say whether this will be a home run, although
there's optimism it will be at least a base hit that will help us
figure out how to go further."
(Reporting by Ransdell Pierson; Editing by Michele Gershberg and
John Pickering)
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