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 Pfizer Inc, which is lagging rivals in the lucrative field of cancer
immunotherapies, has been the first to report early data of an
"accelerator" treatment that targets a protein called 4-1BB. It has
at least five other Phase I studies underway or in planning stages
in solid tumor cancers and lymphomas, which are blood cancers.
Bristol-Myers Squibb Co is hot on Pfizer's heels with a handful of
early-stage trials of its own 4-1BB antibody. Others, including
Johnson & Johnson and AbbVie Inc are doing early testing of their
antibodies prior to starting human trials, company executives and
researchers told Reuters.
"What they have shown are some pretty phenomenal responses in
patients ... where you would not expect the drug to work very well"
because the patients had stopped responding to any available
treatments, said Dr. Holbrook Kohrt, a researcher from Stanford
University Cancer Institute, referring to results from a small trial
of Pfizer's treatment in patients whose lymphoma had progressed
after they received several other therapies.
4-1BB, also known as CD137, and its connection to the immune system
was identified more than 20 years ago by scientists at the
University of California San Diego. The approach was largely
abandoned in 2008 after early clinical trials of a Bristol therapy
showed dangerous signs of liver damage.
Scientists eventually realized that significantly lower doses of a
4-1BB antibody, given at the right time, could achieve the desired
anti-cancer effect without the toxicity.
They now believe immune system accelerator therapies could work for
many types of cancers, bolstering an arsenal of new medications that
are changing the field of oncology.
Bristol and Merck & Co have debuted potent drugs that work by
blocking a protein known as PD-1, which tumors use to evade
detection by the immune system. Doctors are seeing some patients
live for years with diseases like advanced melanoma, which had
nearly always meant death within months.
The expensive treatments are being tested in combination with many
other medicines to help them work for a wider group of patients, and
perhaps further improve the duration of responses. The immuno-oncology
market could reach $40 billion by 2025, according to Leerink
Partners.
TINY GAS PEDALS
When T-cells and "natural killer" cells in the body's immune system
identify cancer, the 4-1BB protein appears on their surfaces, which
researchers have likened to tiny gas pedals. They are using existing
cancer therapies, such as Roche's Rituxan, to help activate the
immune system, then add the new experimental treatment, which locks
onto the 4-1BB protein, stepping on the gas to intensify the cells’
attack.
In the study of Pfizer's antibody in 38 patients with advanced
lymphomas, nearly 40 percent of those with follicular lymphoma and a
third of those with mantle cell lymphoma saw a reduction in cancer
with no serious side effects.
One of Kohrt’s follicular lymphoma patients received two months of
the Pfizer treatment and has been cancer free for more than three
years. Her prior prognosis was about six months to a year to live.
John Lin, Pfizer's head of immunotherapy, said it began human trials
with a very small dose. "The safety profile looks to be excellent,"
he said. "That came as a surprise to some people in the field who
are familiar with 4-1BB, because in the past this target looked a
little bit dangerous."
The early success led Stanford researchers, including Kohrt, to test
other existing treatments with the new accelerator therapies from
Pfizer and Bristol. For example, they plan to test Pfizer's drug
with Roche's Herceptin in breast cancer, and Bristol's 4-1BB therapy
urelumab with Eli Lilly and Co's Erbitux in colon and head and neck
cancers.
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BRISTOL COMES BACK
Bristol's plans for urelumab also show how cancer experts are
overcoming their previous reluctance. The company halted human
testing of the therapy from 2008 to 2011 after seeing an unusually
high rate of severe and potentially fatal hepatitis in a melanoma
study.
Bristol is enrolling patients in five Phase I studies and planning a
sixth for urelumab against multiple myeloma, lymphomas and solid
tumor cancers in combination with other therapies, including its
PD-1 drug Opdivo.
Pfizer said it will test its 4-1BB drug in conjunction with an
immunotherapy from Japan's Kyowa Hakko Kirin and in combination with
Merck's PD-1 drug Keytruda, both in solid tumor cancers, with other
trials planned.
"This is an unbelievably competitive market. With 4-1BB they have an
interesting opportunity," Leerink Partners analyst Seamus Fernandez
said of Pfizer.
The pharma landscape is littered with drugs that looked promising
early only to fail when larger trials turned up safety problems or
disappointing efficacy, and that could happen with 4-1BB therapies.
But Phase I cancer trials have become better predictors of future
results, experts say, as researchers employ their growing
understanding of immunology and human genetics.
Health regulators have also accelerated their review of medicines
they deem to be important advances, particularly in cancer. In many
cases, they have allowed drugmakers to move from Phase I directly
into pivotal trials that can be used to seek approval, cutting years
off the development process.
Immunotherapy pioneer Dr. Lieping Chen, who did early work for
Bristol-Myers, in 2002 published the first paper showing a 4-1BB
antibody could stimulate a powerful anti-cancer attack.
"This is probably going to be the next big one," said Chen, who now
works at Yale Cancer Center. "4-1BB was always one of my favorites,"
Chen said, based on his observation of a 4-1BB antibody's ability to
shrink tumors in mice.
Chen was the first to identify PD-L1, a target related to PD-1 for
which Roche, AstraZeneca, Pfizer and others are developing
treatments. He said several companies looking to develop 4-1BB
antibodies, including Pfizer, have reached out to him in an advisory
capacity.
"Personally, I'm happy this field has finally come back," he said of
immuno-oncology. "Now it's almost overheated. Things are being
tested at amazing speed."
(Reporting by Bill Berkrot. Editing by Michele Gershberg and John
Pickering.)
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