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Addressing rare, toxic downside of immunotherapy

Two leading cancer organizations will collaborate on clinical guidelines for rare but life-threatening toxic effects caused by new cancer drugs widely viewed as transformative.

The American Society of Clinical Oncology and the National Comprehensive Cancer Network announced in mid-February their intent to issue day-to-day guidelines for physicians managing severe side effects from immune checkpoint inhibitors—a type of immunotherapy that works with a patient’s own immune system to attack cancer. They hope to release a document by the end of the year.

Although those highly tailored antibodies bring stunning successes in some patients, physicians say they also can overstimulate the immune system. When that happens, severe autoimmune reactions may occur not only in the intestines and lungs but also in the joints and muscles—and even the heart and brain. The body starts to attack itself, and patients may develop life-threatening inflammations around any of those organs, or experience hormonal imbalance in the thyroid, adrenal, or pituitary gland, requiring hormone replacement therapies. A rare type of diabetes also has been seen in a few patients, as have several deaths.

Checkpoint inhibitors act as “checks,” or brakes, on an immune system, which various cancers trick into using to their own advantage. Ordinarily, the immune system protects against an attack against “self”—a vital survival mechanism that cancers pervert.

“Most side effects will resolve [with immunosuppressive treatment] within two or three weeks, but if inflammation occurs in the brain, for example, it may not resolve,” said Steven Libutti, MD, director of the Rutgers Cancer Institute of New Jersey in New Brunswick and a surgical oncologist. “Still, we should stress there are potentially fatal side effects to standard chemotherapy, as well.”

The difference, Libutti and others said, lies in physicians’ familiarity with and ability to handle chemotherapy’s complications, such as raging infections and low blood counts. Checkpoint inhibitors, though increasingly viewed as the best hope for patients who’ve exhausted other options, are relative newcomers to the cancer field. So, many side effects arise unexpectedly or go unrecognized when patients show up in the emergency department or community physicians’ offices.

“We’re still learning about immunotherapies and the side effects of an overactive immune system,” said Clifford Hudis, MD, CEO of the Alexandria, VA–based American Society of Clinical Oncology and a consultant to Memorial Sloan Kettering Cancer Center in New York. “People have different kinds of organ dysfunction, but the unifying idea is these side effects are new.” Whether an immune reaction resembles a specific autoimmune disease, such as lupus or rheumatoid arthritis, he said, is not yet clear but may depend on the organs under attack and requires further study.

Over the past five years, the US Food and Drug Administration has approved four checkpoint inhibitors for 15 cancers. Bristol-Myers Squibb markets two of the drugs, ipilimumab (Yervoy), or “ipi,” which blocks the cytotoxic T-lymphocyte antigen; and nivolumab (Opdivo), which blocks the interaction between a protein known as programmed death 1 (PD-1) and a ligand, PD-L1, that binds to the protein when cancer cells are under attack.

“Checkpoint inhibitors, though increasingly viewed as the best hope for patients who’ve exhausted other options, are relative newcomers to the cancer field”

Merck’s drug, pembrolizumab (Keytruda), also blocks the PD-1 molecular pathway, winning FDA approval in late 2014, whereas Genentech’s recently approved atezolizumab (Tecentriq) works instead by targeting the PD-L1 ligand.

FDA gave all those drugs fast-track designations because of the survival benefits that some patients experienced early in clinical trial development. “Remarkably long survivals” were especially apparent in patients with melanoma and lung cancers, Hudis said, showing the transformative ability of these agents to “allow us to selectively target parts of the immune system.”

The serious side effects now emerging, he said, in no way diminish the importance of those drugs or the fact that researchers “are rightfully under meaningful pressure to make breakthroughs in treating terminal cancers.”

Checkpoint inhibitors offer far more benefits than harm, agreed John Timmerman, MD, an oncologist and immunotherapy researcher at the University of California, Los Angeles. But Timmerman, who lost one of his own patients to a fatal respiratory reaction, said that oncologists and patients need to be more aware and prepared for a possible downside if an autoimmune reaction sets in.

Investigators have reported that some of the more severe reactions happen when patients receive two checkpoint inhibitors together. The double dose strikes at the core of a fundamental difference between chemotherapy and immunotherapy, according to Timmerman and others.

Whereas chemotherapy drugs, once stopped, quickly leave the body, checkpoint inhibitors’ residual effects can last for months.

As researchers learn more about how to better harness the immune system, the hope is they can do so more selectively and more precisely.

Checkpoint inhibitors activate the immune system, but the response may not be specific to the tumor, acting against normal tissue as well, Libutti said, a similar problem seen in chemotherapy for years.

Although researchers have made some progress at the molecular level in determining which patients might do best on those drugs, he said, “right now, we don’t have enough information about how to give them or how to sequence them” to achieve the best results and avoid unwanted side effects.

But with active intervention, “if you catch them early, we can prevent damage.”

Libutti praised the guideline initiative, which will involve each organization’s appointing small expert panels to review all the existing data on immunotherapy’s side effects. That means looking at clinical trial results, FDA files, drug company files, and the “brains of the clinicians most highly involved with these therapies,” said Robert Carlson, MD, CEO of the National Comprehensive Cancer Network.

Each group is expected to issue its own review, based on the best evidence-based medicine, as early as this summer.

“We’ve had a lot of requests from physicians to come up with clinical guidelines,” Carlson said. “There’s a growing recognition among practicing doctors, the FDA, the research and scientific communities, and others that there needs to be a lot more education on this topic.”

“We’ll work with the panel to understand the limits of the guidelines,” Carlson said. “But they will be continually expanded” as more research in this rapidly evolving field becomes available.

A version of this article originally appeared in the Journal of the Nation Cancer Institute.

Featured image credit: Syringe by qimono. CC0 Public Domain via Pixabay.

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