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, 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.
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.”