By Bill Berkrot
NEW YORK, Aug 7 (Reuters) - Some of the most heralded new
cancer drugs fight the disease by removing brakes on the immune
system. Now a few leading drugmakers are paying attention to a
second, opposing force: medicines that accelerate the immune
system's attack.
Pfizer Inc (NYSE:PFE) PFE.N , 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 BMY.N is hot on Pfizer's heels
with a handful of early-stage trials of its own 4-1BB antibody.
Others, including Johnson & Johnson (NYSE:JNJ) JNJ.N and AbbVie Inc (NYSE:ABBV)
ABBV.N 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 (NYSE:MRK) & Co MRK.N 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
ROG.VX 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 LLY.N
Erbitux in colon and head and neck cancers.
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 4151.T 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."