This story is part of the American Cancer Society’s Cutting-Edge Cancer Science series, which is exploring some of the most promising areas of cancer research in depth.
The cancer research world is dedicating increasing energy to a rapidly evolving type of treatment that has the potential to be more effective – and in some cases less toxic – than many of today’s existing options. Using the body’s own natural system for fighting disease, immunotherapy may also offer a lifeline for patients with certain types of cancer who have exhausted other treatment options. Researchers and drug companies are currently racing to create the best and most far-reaching cancer immunotherapy treatments.
THE BASICS: The human immune system is made up of cells that fight infection. When doing their job correctly, these white blood cells circulate in the body and spring into action to eliminate any foreign substance that does not belong, including bacteria and viruses. This is what happens when the immune system is working correctly.
When cancer develops, it seems that the immune system doesn’t work quite right. For some reason, the immune system doesn’t recognize the cancer cells as a threat – damaged, abnormal cells that do not belong – and destroy them. The cancer cells, scientists have discovered, are sometimes able to evade the immune system or to disrupt its function.
It is not that the immune system never tries to kill the cancer cells. It does make an attempt, says Padmanee Sharma, M.D., Ph.D., scientific director of the immunotherapy platform at the M.D. Anderson Cancer Center in Houston and a former American Cancer Society grantee. Sharma says that in mice, researchers can see that the immune system is able to get rid of cancer cells. “If we extrapolate to humans, we are probably all walking around with mutated cells and the immune system is getting rid of them – we just don’t know it is happening.”
For a variety of reasons, though, the immune system may eventually become less effective at fighting off the cancer cells. “It is really the accumulation of many mutations over time that causes cancer,” says Sharma. The immune system, she says, continues to kill off some cancer cells, but cancer cells evolve, get smarter, and learn to evade or suppress the immune system over time. “I say that the immune system caught what it could.”
The immune system eventually fails in eliminating the tumors or turns off its attack on the cancer cells, thinking it finished its job. “What we think now, is that with immunotherapy, we can reset the immune response and try to get things going again,” says Sharma.
Immunotherapies can work in several different ways:
- Immunotherapeutic vaccines trigger the body’s immune system to beef up its response to cancer cells when a person already has cancer. These vaccines are not meant to prevent disease, like the measles vaccine, but instead are being used to treat cancer. There is currently only one cancer treatment vaccine that has been approved by the Food and Drug Administration (FDA) – Sipuleucel-T (Provenge), which is used in advanced prostate cancer patients who are no longer benefiting from hormone therapy. Other cancer treatment vaccines for various types of cancer – from bladder to breast to lung – are in the works.
- What are known as checkpoint blockade drugs take the so-called “brakes” off the immune system, telling it to start attacking cancer, again. In many instances, tumors can put the “brakes” on an immune response, with certain molecules signaling to the immune system not to destroy a cancer cell. They are taking advantage of the mechanism the body uses to keep the immune system from going overboard and attacking normal cells. Currently, two such checkpoint molecules are the focus of most drug development in this area – these are called CTLA-4 and PD-1. Scientists are also finding additional checkpoint molecules – or brakes – which may lead to more ways to get the immune system to target cancer.
- Experimental adoptive cell transfer therapies involve removing immune cells from a patient’s body, reengineering them to learn to attack cancer, and then re-infusing them into the patient’s body. These treatments have to be personalized to each patient, making them resource-intensive and thus not as easily scalable as the checkpoint blockade drugs. There have been numerous examples of highly promising results with tumor specific, adoptive cellular immunotherapy in early clinical trials, but such treatments are not yet widely available.
Researchers are working on improving these immunotherapies, including combining them with one another and with other types of existing cancer treatments to make them as effective as possible.
As Sharma explains it, the immune system is like a car – with an ignition, gas, and brakes. Early experiments in immunotherapy, including her own work with cancer treatment vaccines, focused on stepping on the gas of the immune system. But then, researchers discovered that the immune system has brakes – and these brakes might need to be turned off.
“That was the paradigm shift in immunotherapy – for the first time someone suggested taking off the brakes to drive the anti-tumor response,” says Sharma. Now, she and others know that for the immune system to attack cancer, they need to make sure that not only are they turning it on and pressing the gas, but also that they have to take off the brakes.
WHY IT MATTERS: Leonard Lichtenfeld, M.D., deputy chief medical officer for the American Cancer Society, remembers attending a grim meeting about the lack of new treatments for melanoma just a couple years ago at the annual American Society of Clinical Oncology (ASCO) conference. “It was very disappointing,” says Lichtenfeld. “It turned out that just a couple of years later, though, we got some reports of very dramatic responses to the use of the drug ipilimumab in melanoma and from that point going forward the role of immunotherapy has increased dramatically as an effective cancer treatment.”
Stories like this one, about new immunotherapies offering renewed hope where not too long ago there was none, abound these days – and point to why cancer immunotherapies matter.
Immunotherapy is “providing options for people out of options,” says Catherine Diefenbach, M.D., an oncologist at the NYU Langone Medical Center. With the help of an American Cancer Society research grant, Diefenbach is studying a new immunotherapy treatment for patients with relapsed Hodgkin lymphoma.
“There are no really good options for these people now – most are cured upfront, but only about 50% of those who aren’t, can be salvaged with a stem cell transplant,” says Diefenbach. She is testing a combination of a drug currently used in isolation, Brentuximab vedotin, and the anti-CTLA-4 immunotherapy drug ipilimumab. “We want patients to have a long-term remission that they couldn’t get on Brentuximab alone.” “To date, chemotherapy for Hodgkin lymphoma has attacked the tumor cells, but no treatments have been aimed at turning the immune cells, which protect the tumor, against the tumor,” according to Diefenbach.
Diefenbach believes immunotherapies, like the one she is researching, will be “practice changing” in Hodgkin lymphoma. “These are very young patients – tend to be under age 35, so most deaths from Hodgkin lymphoma are in young patients … it is a tremendous loss of young lives.”
Sharma has the same types of hopes for the immunotherapy treatments she is testing – work previously supported in part by the American Cancer Society – in patients with advanced prostate cancer. Often, when patients reach this point, their cancer has failed to respond to radiation or surgery and they are given hormone therapy, which only works to slow prostate cancer’s progress. Hormone therapy also can have a lot of difficult side effects, such as reduced libido and impotence.
Sharma, in a clinical trial, treated metastatic prostate cancer patients with an anti-CTLA-4 drug. She and her team are still reviewing the data, but Sharma says “the study did look promising.”
“Some patients did have responses and didn’t need hormonal therapy for a long period of time,” says Sharma. The patients, she says, were grateful for that.
Examples like these appear in news stories fairly frequently these days. Recent reports include a New York Times story about an adoptive cell transfer therapy that achieved complete remission in a child approaching death from leukemia. And the Washington Post this year told the story of a checkpoint drug acting like “vanishing cream” to almost wipe out a man’s stage 4 melanoma. These reports highlight that the aura around immunotherapy is one of bright promise.
WHERE IT STANDS TODAY: Of course, much of this work in immunotherapy is early and experimental. This isn’t the first time that there has been great hope surrounding immunotherapy. “I always have to put a caution,” Lichtenfeld says.
“Back in early 1970s, immunotherapy was considered a breakthrough therapy that would harness the body’s own mechanisms to treat cancer and breakthroughs were on the very near horizon – and here we are 40 years later and there hasn’t really been a lot of progress on clinical translation.”
Progress in the past was slow and researchers didn’t have a lot of buy-in from the broader scientific community or pharmaceutical companies. But, since Bristol-Myers Squibb reported the first major trial results for an immunotherapy drug – ipilumumab – in 2010, the field has exploded.
Doctors and researchers are now making great strides at a more rapid pace – and they are hopeful. Years of research appear to be finally paying off.
“Now we are getting more excited because we are seeing real results and seeing ways immunotherapy can be used for cancer as a single or combined approach,” says Lichtenfeld. “Approaches researchers have been working on for decades are finally providing fruitful results that make it even more exciting for future applications.”
Importantly, pharmaceutical companies are getting on board and investing heavily in cancer immunotherapy treatments. “Major pharmaceutical companies are now making significant commitments to developing and testing immunotherapy drugs,” says Lichtenfeld. There are currently more than 900 cancer immunotherapy clinical trials listed on clinicaltrials.gov.
“Immunotherapy has now demonstrated its value in clinical trials in a way that impacts many patients, the range of diseases impacted appear to be expanded more than we would have predicted,” says Lichtenfeld.
WHAT’S NEXT: The pace of progress in cancer immunotherapy is faster than ever. Much of the highly active areas of research involve improving the existing experimental cancer immunotherapies – making them cheaper, faster, better – and easier to distribute widely, which will make them more appealing and profitable for drug companies.
This year’s ASCO meeting was again abuzz with news of successful trials of new immunotherapeutic treatments. From anti-PD1 drugs and combination treatments for advanced melanoma patients to an adoptive immunotherapy trial that showed strong results in cervical cancer patients – the message around immunotherapy was one of hope and progress.
But as Lichtenfeld noted, those in the field are aware of the challenges. Learning to manage the side effects of the new immunotherapy treatments is one such challenge, says Sharma.
“These agents drive up the immune response – they create a very strong immune response, so we are doing it to all the T-cells in the body, so that can create an inflammatory process.” This inflammation can happen anywhere in the body and cause issues such as loose stools or skin rash, but it doesn’t happen in everyone and it isn’t always severe. Sharma says, though, that these are “on-target side effects,” with the immune system reacting from “what we wanted it to do.” And, these side effects can be controlled. “We can use steroids to control these side effects and not get rid of [the good] anti-tumor effects we want.”
Dealing with these side effects is mostly a matter of education, according to Sharma. “We [doctors] are programed for how to handle chemo side effects and we need to educate doctors now about how to manage immunotherapy side effects – the community at large is not aware yet and they just need to be educated.”
Funding is another challenge. “Somehow NCI and NIH missed the issue,” says Sharma. “Immunotherapy is a big deal. It is saving lives and it is curing people – I like using the word cure, because I don’t get to use it often. NCI needs to start paying attention – these drugs are important.”
Lichentfeld agrees that better funding is needed to help get immunotherapy treatments into the mainstream, including support for both the basic research that makes these types of discoveries possible as well as “more engagement of the pharmaceutical companies and others in funding the translational research that brings these treatments from lab to bedside.”
Certain types of immunotherapy treatments are further along than others. There has been more growth in the realm of checkpoint blockade drugs as the technology for making and testing them is more widely available, says Lichtenfeld. Adoptive cell therapy, however, has a longer way to go. It is much more labor intensive and thus costs more and takes more time. This type of treatment “still remains very much a research approach,” says Lichtenfeld.
BOTTOM LINE: Cancer immunotherapy is at once old and new. While initial immunotherapy discoveries were made decades ago, viable treatments haven’t really become available until very recently. But, the rapid evolution of effective immunotherapy treatments has doctors and researchers eager to put them to use.
“We are still early on, it will take time, but it is certainly getting there – and it just has to get there otherwise we are doing our patients a disservice. It is a huge crime that there are patients with stage 4 melanoma who do not get anti-CTLA-4 drugs,” says Sharma.
Increasingly, immunotherapies appear to be taking on the role not of a single replacement for existing treatments, but instead of an additional option – and one that can in many cases be used in tandem with other therapies to get the best results for patients.
“I believe immunotherapy will be part of the treatment approach to cancer care – it is one more tool for our toolkit,” says Lichtenfeld. “Many times it has been results of small pieces over time coming together to make a difference now for cancer patients – and hopefully immunotherapy will give us a significant leap forward.”
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