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January 18, 2018

The Challenge of Immunotherapy: Staying on Target

Immunotherapies Can Produce Side Effects That Mimic Autoimmune Diseases

The Challenge of Immunotherapy: Staying on Target

Vitiligo, a depigmentation disorder caused by an autoimmune attack on melanocytes, is often seen in patients with melanoma who are treated with immune checkpoint inhibitors. [Getty Images/Donald Iain Smith]

  • The immune system is a powerful weapon. With proper management, it fights off deadly invaders. And, for decades, the idea has tantalized researchers: can we wield an immune response against targets of our choosing, such as cancer? Because cancer arises from the body’s own cells, it typically evades immune detection. And while immune cells can be tipped off to take out tumors, they sometimes go after normal healthy cells in the process, causing inflammation and other side effects.

    A review article, published January 11, 2018 in New England Journal of Medicine, takes a look at immune-related adverse events resulting from immune checkpoint blockade. Michael Postow, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center and the paper’s first author, says the successful treatment of these side effects will depend on multidisciplinary collaboration. “We as oncologists treating our cancer patients need to learn from specialists that have taken care of patients with autoimmune disease,” Dr. Postow told GEN. Some of the side effects of immunotherapy resemble symptoms of autoimmune diseases; he added that experts treating Crohn’s disease might be able to help oncologists treat colitis in cancer patients, for instance.

    Immune checkpoint blockade works by loosening the reins on the immune system. Checkpoint proteins, such as CTLA4 and PD-1, restrain the destructive cellular machinery from attacking the body’s own tissues. By blocking them, researchers effectively release the brakes, setting T-cells loose to find and destroy cancer cells. Although cancer cells look very like the body’s native cells, they also contain lots of mutations. Some of these mutations produce neoantigens, which are proteins that can attract immune attention.

    Sometimes, though, the T cells go overboard and attack noncancerous cells, and that leads to side effects that mimic the symptoms of autoimmune diseases. These symptoms mostly affect the skin, the gut, the endocrine glands, and the liver, causing inflammation or other symptoms. Autoimmune-like reactions can afflict as many as 40% of patients receiving checkpoint inhibitors, with the most common being vitiligo, colitis, hepatitis, and skin rashes. Rarely, severe and possibly life-threatening conditions can arise, including inflammation of the lungs or heart. “It’s common to have something, but it’s not that common to have severe side effects,” says Postow.

    Deciding whether such side effects are worth the benefit of treatment can be tricky, depending on the disease, says David Fisher, M.D., Ph.D., director of the melanoma program at Massachusetts General Hospital Cancer Center. “If a patient has metastatic stage IV melanoma, there really is no therapy that has a significant track record at producing long-term stable remission—besides immune therapy,” Fisher says. “The patient’s going to want to try it.” In other circumstances, he says, immune therapy provides a “statistical cure,” preventing a possible relapse after tumors have been removed.

    It’s a conundrum: Some patients will certainly see their cancers return, and that relapse will be metastatic, life-threatening disease. Immune checkpoint blockade, it appears, may prevent about half of those relapses. But there’s no way to tell which patients will relapse. “It raises some interesting and important questions,” Dr. Fisher says. “Why subject them to the toxicity risk, if they might never have relapsed?”

    Milder side effects may even provide a benefit in the form of research insights, says Fisher. Vitiligo, for instance, occurs when the immune system destroys normal melanocytes, causing white patches on the skin. Similar white patches may occur in patients taking immune checkpoint inhibitors to treat melanoma. This suggests that the T cells aren’t just fired up in response to neoantigens on the melanoma cells—some are going after related antigens in normal tissue. Understanding why this happens, Dr. Fisher says, could help expand the usefulness of immune checkpoint blockade. At present, the therapy works best in patients whose tumors already show evidence of inflammation before treatment begins.

    Much remains unknown about the mechanisms behind immune-related adverse events. Some studies suggest that having side effects correlates with better antitumor action, Dr. Postow says, but others found that treatment outcomes were similar across patients with and without these types of side effects. Different patients, he says, just respond differently. “Immune therapy in many patients alters the body in fundamentally different ways,” Dr. Postow says. That’s going to affect how long the side effects last and how fast the tumor disappears.

    Up to a third of patients taking immune checkpoint inhibitors go on immunosuppressive medications to treat their side effects. Surprisingly, this doesn’t seem to interfere with the antitumor effects of the checkpoint inhibitors, and some studies even show that patients who have to take immunosuppressants in conjunction with checkpoint inhibitors have similar outcomes overall to those who don’t.

    Fortunately, although side effects can linger for a while after the treatment is stopped, Dr. Postow says, “it doesn’t create a new permanent, chronic autoimmune disease condition.” For most people, the adverse effects will resolve after a temporary inflammatory reaction. In some cases, however, patients may develop long-term endocrine conditions—particularly thyroid dysfunction. Although the conditions can be managed, and are not considered a reason to halt treatment with the checkpoint inhibitors, it’s important for oncologists to watch carefully for possible endocrine effects, as they significantly affect quality of life and tolerance to immunotherapy.

    Overall, immune checkpoint blockade has a better overall safety profile than chemotherapy, and as more patients start receiving treatment with them, oncologists working with the autoimmune research community will learn more about treating these symptoms. “These autoimmune diseases are definitely underserved many times,” Dr. Postow says. “[The fact that] the immune system [is] getting so much attention in cancer therapy these days could hopefully help patients with autoimmune diseases.”

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