While it may not be a magic bullet, there’s still plenty of promise in activating
the body’s immune system against cancer.
Immunotherapy, just like it sounds, means using the body’s immune response to defeat a disease… like a measles shot! But when we read about immunotherapy in the grocery store checkout line or see an ad for an immunotherapy drug, the stories mostly concern a specific kind of immunotherapy — cancer immunotherapy, or using the immune system to fight cancer. This technique has been around for several years, and recently there have been impressive success stories. Immune checkpoint inhibitor drugs have been shown to cause some tumors to shrink, and in some cases, disappear altogether. How does immunotherapy work? How well does it work? Which cancers are susceptible? Buckle up, there’s a lot to learn.
Sometimes known as biologic therapy, immunotherapy has several avenues of approach. The American Cancer Society lists the most common models as follows:
• Vaccines prime the body to fight a cancer-causing virus by introducing a weakened or dead version of the virus to arouse an immune response. The vaccines act preventively to help the body kill the virus before it can cause cancer. Examples: HPV vaccine against cervical and related cancers.
• Immune checkpoint inhibitors. These drugs target checkpoint proteins – proteins that keep the immune system from attacking things it shouldn’t. (Some varieties target the proteins’ “opposite number” that they bind to on cancer or other target cells.) This binding action disrupts the connection that inhibits immune cells from attacking. Example: Keytruda for non-small cell lung cancer.
• Monoclonal antibodies. Not limited to cancer, these drugs attach to targeted cells, encouraging the body’s immune system to attack and destroy the target. Monoclonal antibodies may also be delivered in tandem with a chemotherapy drug. Example: Herceptin for HER2-positive breast cancer.
• General or non-specific immunotherapies. These drugs boost the immune system generally in the hopes of helping it fight cancer. Example: interleukin-2 for kidney cancer and metastatic melanoma.
Of these, the ones most commonly referred to as cancer immunotherapy are monoclonal antibodies and immune checkpoint inhibitors. Cancers treatable by immunotherapy so far include melanoma, lung cancer, head and neck cancers, breast cancer, kidney cancer, bladder cancer, Hodgkin lymphoma and gynecologic cancers, among others.
Michael J. Sundborg, MD, FACOG, is a gynecologic oncologist with FirstHealth Gynecologic Oncology and FirstHealth Cancer Center. He’s familiar with immunotherapy for many cancers that affect older patients.
“At FirstHealth, we participate in clinical trials, everything from advanced robotic surgeries to genetic testing and interpretation,” he says. “FirstHealth is very supportive of us as we care for women with cancer.”
In his field, Dr. Sundborg has seen exciting advances using immunotherapy. He refers to Avastin (bevacizumab), an anti-angiogenic medication used to prevent cancers from developing blood vessels to support them.
“Cancers travel from the site of origin, and they make their own blood vessels, their own life support systems,” he explains. “Anti-angiogenics target cancers and tell them to turn off [these systems]. One of the first targeted therapies with Avastin was using it to block those signals so the cancer starved. This was experimental ten years ago. Now, it’s in common use.”
Another promising line of research has been PARP inhibitors, Dr. Sundborg says. “That immunotherapy targets the DNA repair mechanism of the cancer cell,” he says. “[We’ve seen] an increase in length of survival in patients with recurrent cancers. The FDA just approved all three commercially available ones for ovarian cancer.”
This is particularly promising because ovarian cancer is often asymptomatic in the early stages and is frequently discovered late in the disease progression, when there is less hope for survival.
It’s important to note that these drugs don’t treat all forms of a cancer; they typically work best for cancers with a particular protein that renders them susceptible to immunotherapy intervention. For instance, only HER2-positive breast cancer is susceptible to monoclonal antibody Herceptin (trastuzumab), and only about 20 percent of breast cancers are HER2-positive. Therefore, only a fraction of breast cancer patients can benefit from this drug. Of that fraction, one large-scale, long-term study of 4,000 patients showed about 10 percent increase in 10-year survival in patients treated with chemotherapy plus Herceptin, as opposed to Herceptin alone (75.2 to 84 percent).
Help or Hype?
Drug ads on television promise miracle cures, especially when they portray people described as having late-stage cancer strolling, playing golf or tussling with grandchildren. Think about the “It’s TRU” Keytruda ads presently airing. In one ad, patient Donna was given just a few months to live after a diagnosis of late-stage non-small cell lung cancer that had metastasized to her brain. Her particular cancer was found to have high levels of PD-L1, a protein that binds to immune cells and keeps them from attacking the cancer, meaning it was a potential target for intervention with the immune checkpoint inhibitor drug. A trial of immune checkpoint inhibitor pembrolizumab (Keytruda) resulted in shrinking tumors and, as of the latest update on the drug maker’s website, Donna has been alive for two years, despite side effects such as disappearing thyroid function. Typically, five-year survival in patients with Donna’s diagnosis is less than 10 percent. More generally, patients with high PD-L1 non-small cell lung cancers treated with pembrolizumab have been found to live about twice as long (or 30 months, compared to 14 months) as patients treated with standard chemotherapy.
Is this a big-picture success or a “meh?” It depends on who you’re asking. A year is a lot of extra time for someone with a prognosis measured in months; it’s a small amount of time for someone who could easily have lived another 50 years had she not developed cancer. Clinical trials for all kinds of late-stage cancer treatments (not just immunotherapy) often present results in terms of weeks or months of cancer-free progression, or changes in overall survival measured in months.
On the other hand, some statisticians criticize the hype around
immunotherapy agents. Writing for medical journalism site Stat, hematologist/oncologists Nathan Gay and Vinay Prasad point out that only certain cancers present features amenable to many immunotherapy agents, so the improvements are measured as small changes in small populations. Restricting their argument to immune checkpoint inhibitor drugs, Gay and Prasad state that only about eight percent of people dying of cancer in the U.S. in a year have the potential to be saved by one of these drugs.
Still, with close to 600,000 cancer deaths in the U.S. each year, that’s a lot of people with the potential to be saved. Dr. Sundborg sees the general trend as positive, even for older patients.
“Clinical trials show even the elderly group, in their sixth decade and beyond, will do all right [with immunotherapy] if their health is good,” he says. “It’s an area [that’s] evolving right now, these therapies. I tell my patients, ‘You live in an exciting time. Patients ten years back asked to live ten years [when they were given a cancer diagnosis], but it was hard to do that with advanced cancer. Now we’ve crossed that frontier. Every day we’re learning new things. We are doing good research, and we are beginning to apply that in a regular clinical setting.”
Ask Your Doctor
Like other cancer-fighting modalities from surgery to radiation, immunotherapy has side effects of all kinds. Most common are flu-like symptoms, rashes, pain at the IV or injection site and intestinal problems. Since immunotherapy medications amplify immune reactions, patients may experience disorders such as inflammatory arthritis, inflammatory bowel disease and autoimmune thyroid failure. As with positive responses, there’s a wide range in type and intensity to negative effects to the drug — from mild reactions to extreme toxicity. Some clinical trials, such as one for an immunotherapy treatment for acute lymphoblastic leukemia, have been halted due to patient deaths.
But what will you or a loved one experience if you decide on immunotherapy? Will it be worth it?
“Cancer can affect people in their 50s, 60s, 70s, 80s and beyond,” Dr. Sundborg says. “Cancer is a reflection of the success of our longevity. Many generations ago, patients didn’t live past 50. [Longevity] is why we’re seeing all these different cancers now. So when we talk [about cancer treatments], it’s patients in that age range we’re discussing.”
Within that age range — people in middle life and older — Dr. Sundborg identifies two groups of patients. One group will do well with most cancer therapies.
“Patients who are between 50 and 70, fairly robust and in good health, tolerate treatments well, whether surgery, chemotherapy or immunotherapy,” he says. “Most clinical trials are performed using healthier patients.”
He notes that it’s important that clinical trials compare how patients within each group fare with the treatment.
“When it comes to age, we should look at patient overall health and functional status,” he says, explaining that this gives an indicator of how they’ll do on any therapy. “Most toxicities [associated with immunotherapy] are very similar to those of chemotherapy. They are exciting treatments, but with the same risk factors — they can make you anemic, affect your bone marrow and, ironically, impact your immune system. But most people do well on them if they start out in good health.”
Dr. Sundborg explains that physicians welcome patients to participate in clinical trials or avail themselves of a range of therapies, immunotherapy included. Many cancer centers, such as FirstHealth, offer clinical trial access. Age need not be a barrier to treatment.
“We want patients, no matter their age, to participate in clinical trials,” he says. “It’s like the PARP inhibitor trials — they tend to be tolerated well, regardless of age.”
By the same token, patients who are too frail to tolerate chemotherapy will likely not tolerate immunotherapy well, either. An unhealthy patient of 50 will do less well with treatments than a fit, active 90-year-old, in many cases. So, Dr. Sundborg says, immunotherapies are not to be thought of as a substitute for chemotherapy.
“They’re often the second- or third-line [treatment],” he says. “If you’re not well enough for conventional therapy, you will not be offered immunotherapy.”
But he’s quick to reassure: “In my experience, very few patients are too ill to receive therapy. Those patients, no matter what their age, who were diagnosed with very advanced malignancy [may not benefit from treatment]. But if a patient can walk into the office, then they are not too far gone to consider treatment.
“The general perception is that our immune system declines with age is simplistic. It does decline, but that doesn’t mean we can’t activate it against cancer. And as a side note, many immunotherapies are given in combination with chemotherapy, and people tolerate them well.”
Hope for the Future
The problem of cancer is a fascinating one. It’s not an alien invader to be killed off with an antibiotic; it’s intimately related to the sufferer. And therein lies both the difficulty and the promise of treatment.
“The problem with cancer is your cancer cells are you,” Dr. Sundborg says bluntly. “They have your identity — they’re not a germ or a virus. The cancer cells carry the identity of the host. The immune system doesn’t recognize them. You can activate the immune system, but you could cause damage [doing that], just as with chemo. We are now trying to activate the immune system just to activate against the cancer cell.
“The first immunotherapy, against melanoma, was a success story. Now there’s research into [therapies for] breast cancer and gynecologic cancer coming out of it. As our clinical trials mature, we are going to help patients more.”
Patients with cancer should ask for available clinical trials, he says.
“They’re ethically constructed,” he adds. “Ask whether your doctor participates in clinical trials, or whether there are any available for the treatment of your disease. We [offer] them at FirstHealth.”
He becomes more ardent as he speaks of the promise of expanding knowledge and better cancer treatments to come.
“Ten or 20 years ago we performed ovarian and uterine cancer research [separately],” he says. “Now we know these cancers that don’t seem related share common pathways at the molecular level — common ways how they interact with their environment. We can develop precision medicine, which immunotherapies are; we can develop precise targets. Now we have clinical trials of very different disease systems, but all using the same type of therapies, because [the diseases] have common molecular similarities. This is an exciting part of the 21st century.”
Questions? Find Dr. Sundborg at FirstHealth.org.