Ever since the first vaccines were created in the 1700s, doctors have been finding ways to force the body’s own immune system to fight disease. One of the more difficult targets for immunotherapy has been cancer, but recent advances in the field have turned immuno-oncology into one of the most promising frontiers in medicine.
At last these treatments have made their way out of labs and into the hands of doctors and are now saving the lives of cancer patients. Immuno-oncology is also big business for pharmaceutical makers in the Route 1 corridor. Companies like Bristol-Myers Squibb and Advaxis are at the forefront of the field that has become one of the hottest sectors in biotech in the past several years. And at the Rutgers Cancer Institute of New Jersey, researchers are field testing the new arsenal in the war against cancer.
Dr. Janice Mehnert is a medical oncologist in the melanoma and soft tissue oncology program and director of the Phase 1 investigation program at the Rutgers Cancer Institute of New Jersey. She has personally treated hundreds of patients using the latest immunotherapy drugs. In a recent trial she tested an antibody called Pembrolizumab, made by Merck and marketed as Keytruda, on a range of different types of cancer. She has seen results from the trials of Keytruda and other drugs that have made her use a word that is rarely, if ever, uttered by doctors who treat cancer.
“When you treat advanced cancer, the word ‘cure’ is not used,” she says. “You are not used to seeing responses that last.” Like most oncologists, Mehnert doesn’t usually use the term “cure” because standard treatments suppress cancer without killing it off completely. Most of the time, the word “remission” is used after a successful cycle of chemotherapy. The cancer may be dormant, but cancer survivors know that the disease might still be there, waiting to come back. With immuno-oncology, Mehnert is cautiously using the C-word. “While not all patients respond, if you are one of those patients that does respond, it could last for a very long time. We’re maybe even thinking it’s a cure.”
Keytruda has so far been approved by the FDA for certain kinds of melanoma, lung cancer, and head and neck cancer.
The immune system regularly detects and destroys cancer cells. But in the case of cancerous tumors, the cells are able to disguise themselves from white blood cells and avoid attack. “When a tumor develops in your body, generally it’s because your immune system is asleep at the wheel,” Mehnert explains. “Some insult happens, and your immune surveillance goes off and your tumor is allowed to develop. It’s called immune tolerance,” she says. “The immune system becomes tolerant of the invader for some reason, and when that happens, sometimes tumors get flooded with tumor-fighting lymphocytes that are kept quiet and inactive. Immune therapy sort of wakes those lymphocytes up.”
Immuno-oncology research has focused on determining exactly how the cancer cells make themselves invisible to lymphocytes and finding ways to defeat the chemical disguise.
Keytruda targets the interaction of two proteins, PD-1 (programmed cell death) and PD-L1. These two proteins are what scientists call an “immune checkpoint” that stops white blood cells from attacking healthy tissue. By blocking this interaction, the Pembrolizumab allows the patient’s own cells to wipe out the tumors. When it works, it’s so effective that Mehnert flirts with the term “cure.” Furthermore, it seems to work for many different kinds of cancer.
“It works with multiple different tumor types and multiple different diseases,” Mehnert says. “That’s one of the things that’s so exciting about the field. We’re seeing responses that are durable, without a tremendous amount of side effects, although there are side effects that are significant.”
But the downside is that it only works for about 11 to 30 percent of patients. Part of Mehnert’s research is figuring out in advance which patients will respond to the antibody, and which won’t. The studies suggest so far that people who have high levels of the PD-L1 protein will do best with the treatment. But it’s not easy to measure.
“That is a question that a lot of us are working on very diligently,” Mehnert says. “Some people think the mutations within a tumor may predict a patient’s response.” One hypothesis is that cancers that are the result of mutation, such as lung cancer caused by tobacco smoke and skin cancer caused by sun damage, are the most responsive to treatment. “But that’s not a perfect hypothesis yet,” Mehnert says. Another possibility is that patients with microsatellite instability are more prone to getting cancer, especially colorectal cancer, but that they might also respond better to immunotherapy.
A third possibility is that patients whose tumors are virally driven may be responsive to immunotherapy treatments. But none of that has been proven, and much work lies ahead for Mehnert and the other doctors conducting clinical trials all around the world. “It may be a combination of all three,” Mehnert says. “It’s a huge undertaking to study this.”
And that’s just Pembrolizumab. She is also running a trial of Talimogene, made by Amgen. Talimogene is actually a custom-made virus that is directly injected into tumors. Rutgers is studying the effects of this treatment combined with immunotherapy, and Mehnert says they are getting “interesting results” from the combination.
They are also testing Pemrolizumab in combination with various other treatments including chemotherapy and other novel agents. Yet another drug targets IL-10, an anti-inflammatory receptor. “We have a spectacular menu to work with,” Mehnert says. “We’d love to get the word out about what we’re doing here.”
The arsenal of immuno-oncology is growing rapidly, and several Route 1 companies are at the forefront. Bristol-Myers Squibb has led the field with Opdivo, which has been shown in clinical trials to extend the lives of patients with certain cancers including malignant melanoma. In November Opdivo was approved for the most common type of head and neck cancer. An earlier trial of Opdivo as a first line of defense against lung cancer proved no better than standard treatment, however. (Currently the drug is a second-line treatment, to be used after conventional therapy has failed.) In that trial the drug was tested on patients with relatively low levels of PD-1, the protein that is thought to be a key for the drug’s effectiveness.
BMS is investing heavily in immuno-oncology for its future business. According to company reports, Immuno-oncology research makes up a large part of its $4 billion annual R&D budget. To follow up with Opdivo, the company has many anti-cancer products in the pipeline, each codenamed CheckMate.
“We have a comprehensive clinical portfolio of investigational and approved immuno-oncology agents, many of which were discovered and developed by our scientists,” the company said in a recent statement. “We pioneered the research leading to the first regulatory approval for the combination of two immuno-oncology agents and continue to study the role of combinations in cancer.”
Currently its three approved immunotherapy agents are Opdivo, Yerevoy, and Empliciti, delivered alone or in combination. BMS expects to have eight additional agents in clinical trials by the end of the year. The company says it is currently running 50 clinical trials for 20 tumor types.
The company appears to be in something of an immuno-oncology arms race with rival Merck, whose Keytruda is the main competitor to Opdivo at the moment. Other top pharmaceutical companies AstraZeneca, Pfizer, and Roche all have immune-oncology drugs in the pipeline as well.
Advaxis, based on College Road East, has three immuno-oncology agents under development. While the larger pharma companies are targeting the most common types of cancer, smaller companies like Advaxis are using their limited resources to pursue “orphan” markets where there is currently no effective treatment. Advaxis’ first agent is meant for late-stage recurrent cervical cancer caused by the HPV virus. It uses genetically modified bacteria that alert the immune system to the presence of a tumor, training it to develop anti-tumor antibodies in a process that is similar to what a vaccine does. (U.S. 1, September 11, 2013.)
Advaxis is a good illustration of the potential of immunotherapy within the wider biotech sector. In 2013, according to the trade magazine Stat News, the company was almost out of money and unable to make payroll for its six employees. But new CEO Daniel J. O’Connor was able to successfully turn the company around thanks to a successful clinical trial of its anti-cervical cancer treatment and a deal with Amgen that brought in $70 million in cash and stock. In short, a risky bet on immunotherapy for cancer paid off.
Looking at the picture worldwide, many companies are pouring billions into numerous new anti-cancer immunotherapies. Not all of them will work, and some will duplicate others’ efforts. But Mehnert and other scientists believe the end result could be a revolution in the way cancer is treated.
“Whenever there’s a hot drug out there, most companies try to develop something similar — the ‘me too’ phenomenon,” Mehnert says. “But competition is not a bad thing. It’s not bad to have smaller biotechs come along and concentrate on a space no one thinks about.”
It’s not just pharmaceutical companies making advancements, either. Long before anyone realized immunotherapy could be profitable, scientists in academic settings funded by public money were hard at work looking for ways to cure cancer. In fact, the history of immunotherapy goes back further than most people would think.
In 1796 Edward Jenner invented the world’s first vaccine when he administered the relatively benign cowpox disease to healthy people as a way of preventing deadly smallpox. Further research over the centuries led to more vaccines that wiped out smallpox entirely and effectively combated polio, whooping cough, measles, and other once-common scourges.
In the late 1980s Dr. Steven Rosenberg, working at the National Cancer Institute in Maryland, began using immune cells to treat patients who had melanoma. The techniques have become vastly more complex, but the basic idea is the same: activate the body’s natural defenses to destroy the invader.
For Mehnert testing new immuno-oncology therapies is more than just a scientific endeavor. As a New Jersey native, she believes she is helping her own community. Mehnert grew up in Bradley Beach and now lives in Holmdel. She studied biology and English as an undergraduate at Rutgers and the University of Sussex in Britain. She went to medical school at UMDNJ-Robert Wood Johnson, completing a year of lab research at the National Institutes of Health.
Growing up on the Jersey shore, where skin cancer from sun exposure was prevalent, had an effect on Mehnert’s career. Her mother was a teacher and her father worked for Federal Carbide. “I was incredibly close to my grandmother, who was ill a lot while I was a teenager,” Mehnert says. “I never understood anything that was going on, and that was a powerful motivating factor for when I went into medicine. I liked science; it was something I was good at and interested in. My uncle actually developed lung cancer when I was in medical school, and that was the key point where I knew I was going to go into oncology. He didn’t get into clinical trials.”
Mehnert says many patients don’t have the information they need about clinical trials, which in some cases could be life saving.
“It’s so important for patients to demand information about clinical trials. There are patients whose lives were saved for no other reason than they got into an immunotherapy study.”
Mehnert says ideally, doctors would inform patients about clinical trials that they might be eligible for. Currently, however, it is up to patients to seek out clinical trials if conventional therapy doesn’t work for them. “Patients need to be educated,” Mehnert says.
Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick 08903. 732-235-2465. www.cinj.org.
Advaxis Inc., 305 College Road East, Princeton 08540. 609-452-9813. Daniel J. O’Connor, CEO. www.advaxis.com.