Recruiting the Immune System to Fight Cancer. New Hope—and New Side Effects.

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Drs. Aarti Asnani - Beth Israel-New England Deaconess & David Borenstein MD discuss impact of new cancer immunotherapies

Promises and Cautions from Cancer Immunotherapy

by Heather Stringer

Recruiting the immune system to fight cancer brings new hope—and new side effects

Of all the advances in cancer treatment over the last few decades, perhaps none have generated more excitement than immunotherapy: treatments that harness the body’s own immune system to kill cancer cells.

In aggressive cancer types including melanoma, lymphoma, and lung cancer, reports have come in of immunotherapy shrinking or even eliminating tumors in some people who have exhausted other treatment options[i],[ii],[iii].

But no cancer treatment comes without side effects, and immunotherapy is not an exception to this rule. Doctors who are used to a fairly predictable set of side effects from chemotherapy drugs—such as nausea, hair loss, and infections—are suddenly seeing a wide range of unfamiliar symptoms that arise when the immune system is ramped up to fight cancer.

Turning the Immune System Loose against Cancer

The human immune system is incredibly complex, and can recognize a wide range of threats to the body, such as bacteria and viruses that cause illness. Importantly, it also normally identifies the cells of the body as “self,” and ignores them.

While cancer cells arise from the body’s normal cells, they have changed enough that the immune system should be able to recognize them as a threat and eliminate them. However, cancer cells can often trick the immune system into thinking that they’re still normal cells. Immunotherapy attempts to unmask these cancer cells and direct immune cells to attack them.

The most widely used type of immunotherapy today is a class of drugs called immune checkpoint inhibitors. Immune checkpoints are molecules produced by the body’s cells—and cancer cells—that serve as a stop sign for the immune system. Checkpoint inhibitors block this stop signal, freeing the immune system to attack. Examples of checkpoint inhibitors approved to treat a variety of cancer types include pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy).

In a newer type of personalized immunotherapy, called adoptive cell transfer, immune cells are first removed from a person’s bloodstream. Then, scientists engineer them in the laboratory to recognize a specific type of cancer. Finally, millions of these improved cells are infused back into the bloodstream to hunt down cancer cells. A type of adoptive cell transfer called CAR T-cell therapy has recently been approved for the treatment of some types of blood cancer, under the brand names Yescarta and Kymriah, but relatively few people have received this type of therapy to date.

No Emergency Brake for the Immune System

As doctors have been realizing, when the breaks are taken off the immune system by immunotherapy, they don’t have a way to make sure it only attacks cancer cells.

As might be expected, many of the side effects seen during immune checkpoint inhibitor treatment resemble those of common auto-immune diseases, as some of the body’s normal cells end up as collateral damage.

Auto-immune diseases occur when the immune system’s self-recognition system fails, and immune cells turn against normal healthy cells. For example, if the immune system mistakenly attacks the joints, rheumatoid arthritis results. If it goes after the lining of the nerve cells, a person can develop multiple sclerosis. Or if it confuses skin cells with a foreign invader, the result is psoriasis.

The parts of the body most commonly affected by immune checkpoint inhibitors are the skin, gut, endocrine glands (which produce the body’s hormones), liver, and lungs[iv]. But as more people take immunotherapy drugs, rarer toxicities are coming to light.

One of these emerging side effects that should be on people’s radar is inflammation of the heart, known as myocarditis, explains Aarti Asnani, MD, a heart specialist who works with cancer patients at Beth Israel Deaconess Medical Center in Boston.

The worry about myocarditis, she explains, is that while rare, “it can be life-threatening,” and often mimics other, less-serious side effects. For example, people with myocarditis may feel muscle pain in other parts of the body, sick to their stomach, or just very tired.

As more and more people take these drugs, “we tell our doctors that they should have a very low threshold to thinking that [a symptom] might be caused by injury to the heart,” she says. Such injury can be detected with a simple blood test, she continues, and earlier treatment reduces the risk of permanent heart damage or even death.

Broadly, side effects from immunotherapy are treated similarly regardless of where in the body they occur[v]. If the side effects are mild, a patient may be able to continue treatment while also taking a type of drug called a corticosteroid. Corticosteroids can calm the immune system and reduce inflammation.

If more serious side effects arise, immunotherapy may need to be stopped for a while. Sometimes, stronger drugs to calm the immune system may be used, such as those given to people who have received an organ transplant. With severe side effects, in cases where people’s lives are at risk, immunotherapy may need to be permanently discontinued.

CAR-T cell therapy works differently from immune checkpoint inhibition, and its major side effects also differ. The most common seen to date are a whole-body immune system over-reaction called cytokine release syndrome, and problems with the brain, including seizures and memory loss. But the supportive care is similar, using drugs that tamp down the immune system.

Dr. Asnani stresses that patients undergoing immunotherapy should not be afraid to report side effects for fear of being taken off an anti-cancer treatment that they hope will save their lives.

As doctors treating these side effects, “our job is to do everything we can to allow the oncologists to do what they need to do,” Dr. Asnani explains. “We don’t want to stand in the way of lifesaving cancer therapy. However, we want to make sure that we’re able to treat the toxicity” and keep patients safe, she says.

The decision about whether or not to restart immune checkpoint inhibition after experiencing a serious side effect will be an individual one for patients in consultation with their oncologists, and will take into account whether or not someone has any other cancer treatment options available to them, she adds.

Dr. Asnani also wouldn’t want someone to hesitate to try immunotherapy for their cancer because of concerns about side effects. “For many cancers, we know that immunotherapy can be very effective and prolong life, so I would never discourage a patient from pursing therapy because of the potential toxicities,” which can be addressed if they occur, she says.

Immunotherapy and Existing Auto-Immune Diseases: Safer than Expected

One question that arose early in the development of immunotherapy is whether it would be safe to stimulate the immune system in people who already have an auto-immune disease. Researchers largely assumed it would not be, and cancer patients with existing auto-immune diseases have been excluded from clinical trials of such treatments to date.

But as immune checkpoint inhibitors become more widely used in the community—and reflect a last-chance option for many cancer patients—more people with conditions like inflammatory bowel disease, rheumatoid arthritis, or multiple sclerosis are receiving the drugs. Such conditions are not uncommon. Somewhere between 3 and 8 percent of the U.S population is thought to have an auto-immune disease, and they are more common in women than men[vi].

So far, and contrary to what doctors expected, immune checkpoint inhibitors appear to be relatively safe for people with an auto-immune disease. Although the numbers treated so far are small, recent studies have found that most patients with existing auto-immune diseases did not experience a flare of that disease during immunotherapy. In addition, most patients who did experience a flare were able to continue treatment. Immune checkpoint inhibitors seem to be equally effective at fighting cancer whether or not a person has an existing auto-immune disease6.

Use of immunotherapy in people with auto-immune diseases will require close coordination between the patient, the oncologist treating the cancer, and the specialist overseeing treatment of the immune condition, says David Borenstein, M.D., an auto-immune disease specialist at the George Washington University Medical Center.

An oncologist may ask that a patient discontinue some types of drugs used to treat auto-immune conditions while taking immunotherapy, because these drugs suppress the immune system, he explains. In turn, a doctor keeping an eye on a patient’s auto-immune disease will want regular updates from the oncologist on how immunotherapy is affecting the body.

And if a person’s existing auto-immune disease does flare, the two doctors will need to work together—and with the patient—to figure out how best to keep them safe while hopefully continuing their anti-cancer therapy, he adds.

At least for now, he says, the potential benefit to someone with an auto-immune disease and cancer will most likely make immunotherapy worth a try. “When the rubber meets the road, if you had to choose whether you would give someone a checkpoint inhibitor if they had something like melanoma and an auto-immune disease, the general feeling would be that you would go ahead and use the checkpoint inhibitor and see what happens,” says Dr. Borenstein.

This risk-benefit equation may change if immunotherapy starts to be used in less-deadly cancers, but such applications remain a ways in the future.

So far, Dr. Borenstein has only had one patient of his, who has severe psoriasis, try immunotherapy. Although that patient did have to discontinue his anti-psoriasis drug before therapy, and experienced a flare in his skin during treatment, “when I talked to him today, he said his cancer is gone,” Dr. Borenstein says. “So at least for now, this was a good choice.”1.

  1. Robert C, Ribas A, Hamid O, et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Journal of Clinical Oncology. 2016:34(15 Suppl);9503-9503. DOI: 10.1200/JCO.2016.34.15_suppl.9503
  1. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncolcology. 2016 Sep;17(9):1283-94. doi: 10.1016/S1470-2045(16)30167-X
  1. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. New England Journal of Medicine. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694.
  1. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. European Journal of Cancer. 2016;54:139-148. doi: 10.1016/j.ejca.2015.11.016.
  1. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology. 2018 Feb 14:JCO2017776385. doi: 10.1200/JCO.2017.77.6385
  1. Donia M, Pedersen M, Svane IM. Cancer immunotherapy in patients with preexisting autoimmune disorders. Seminars in Immunopathology. 2017 Apr;39(3):333-337. doi: 10.1007/s00281-016-0595-8
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