Why Do Immune Checkpoint Inhibitors Work for Only Some People with Cancer?

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Physician­-scientist Luis Diaz focuses his research on applied cancer genetics — using information about the mutations in tumors to combat them.

Summary

MSK researchers are working to understand why one class of immunotherapy drugs 
is paying off — but only for some patients.

For people with advanced cancers, hope can be a valuable but rare commodity. In recent years, a new class of drugs called immune checkpoint inhibitors has shown remarkable promise, keeping tumors at bay and preventing them from growing, and allowing some people who receive the treatments to essentially be cured. But these groundbreaking therapies have a substantial challenge: They work for only a small number of people.

The drugs are a type of immunotherapy, a promising area of cancer treatment based on the idea that the immune system can be prompted to go after tumor cells in the same way that it goes after infectious microorganisms. The strategy has great potential to alter how cancers are treated — but it’s tricky. Because cancer forms from our own tissues, tumors often hide in plain sight from the immune cells, which are looking for foreign invaders.

Another reason that it’s hard to get the immune system to attack cancer is that the body has a built-­in safeguard that prevents it from going after its own cells. Immune checkpoint inhibitors were designed specifically to override that safety measure, temporarily empowering immune cells called T cells to seek out and destroy cancerous tumors.

By studying who responds to this type of therapy and who doesn’t, researchers at Memorial Sloan Kettering are uncovering what makes the treatments effective. Their goal is to determine who is most likely to be helped by these drugs — and to develop strategies that will bring the promise of a cure to more people.

Conspicuous Targets

MSK physician-­scientist Jedd Wolchok pioneered the clinical development of ipilimumab (Yervoy®), the first immune checkpoint inhibitor, which was approved by the US Food and Drug Administration in 2011. Since then, thousands of patients have been treated with this type of drug, with remarkable success. But many more have failed to respond, and researchers set out to discover why by looking for clues in those who did see results.

In a series of studies, researchers at MSK started to look at this in more detail. One of those, led by physician-scientist Timothy Chan and co-­authored by Dr. Wolchok, was published in Science in 2015. It reported that lung cancer patients who had smoked and whose tumors had many mutations were more likely to respond to checkpoint inhibitor drugs than those with fewer mutations. (Smoking-associated cancers have many mutations because the chemicals in cigarette smoke wreak havoc on the DNA.)

“From the early clinical trials for checkpoint inhibitors, it was clear that these drugs worked very well for certain cancers,” says Luis Diaz, who at the time was studying the drugs at Johns Hopkins University School of Medicine in Baltimore and observing the same phenomenon. Dr. Diaz recently joined MSK as Head of the Division of Solid Tumor Oncology in the Department of Medicine.

The more mutations you have, the more your chances increase [that immune checkpoint drugs will be effective].

Luis Alberto Diaz, Jr.
medical oncologist

“What became obvious was that the types of tumors that often responded well to these drugs, including melanoma and lung cancer, tend to have a lot of genetic mutations,” he adds. “So maybe those tumors were responding because of that.”

Over time, a theory began to emerge. Gene mutations can lead to the production of a foreign substance called a neoantigen. Neoantigens are an alien presence in the body that flag the tumor as something that doesn’t belong, thus eliciting an immune response. Could an abundance of mutations explain a tumor’s susceptibility to checkpoint inhibitors?

“If a tumor has only one mutation, there’s a small chance that the immune system could detect it. But the more mutations you have, the more your chances increase,” Dr. Diaz explains. “Ironically, you have more tickets in the lottery.” Having more tickets means there is a greatly increased chance that the tumor will manufacture a neoantigen that gets the immune system’s attention.

Understanding Why Worse
 Is Better


Researcher Tim Chan (right), with radiation oncologist Nadeem Riaz, leads the Immunogenomics and Precision Oncology Platform, which merges MSK’s expertise in immunology and genomics to drive innovation in immune­based therapies.

While at Johns Hopkins, Dr. Diaz noted that although immune checkpoint inhibitors worked well against certain cancers, against others, including colon cancer, the drugs were rarely effective. “Then one of my colleagues told me there was a single colon cancer patient taking nivolumab [Opdivo®] who had responded very well,” he says. “We decided to look more closely at that particular tumor, and sure enough, we found that it was characterized by a high number of mutations.”

The defect in the patient’s tumor, called DNA mismatch repair (MMR) deficiency, prevents cells from fixing mistakes that occur during DNA replication. As a result, MMR­-deficient cells can have hundreds or even thousands of mutations, compared with just a few dozen in a typical cancer cell.

Based on that discovery, Dr. Diaz began what would become a pivotal study, looking at whether the immune checkpoint inhibitor drug pembrolizumab (Keytruda®) would work in other patients whose tumors had MMR deficiencies. In 2015, he and his team reported that MMR­-deficient tumors were more likely to respond to pembrolizumab than those without the deficiency, regardless of where the tumor was located.

In May 2017, the FDA granted accelerated approval of pembrolizumab for any patient with an MMR deficiency, irrespective of where the tumor originated in the body. This authorization was remarkable because it was the first time a tissue-a­gnostic cancer drug — one that attacks tumors no matter where they develop — was approved. Up to this point, drugs were approved to treat cancers based on where they grew in the body.

“MMR mutations are relatively rare,” Dr. Diaz says, “but that small proportion translates to tens of thousands of people with cancer in the United States every year, and half a million worldwide. Our findings suggest that all cancer patients with late­-stage disease should have their tumors screened for MMR deficiencies.”

Developing Effective Combination Treatments


Dr. Diaz’s arrival at MSK in April brought the leading minds in immuno-­oncology under one roof — leading to new collaborations and more avenues for exploration. Together, these researchers are seeking to understand what it is about tumors with many mutations that appears to make them more recognizable to the immune system. Many clinical trials now under way at MSK are seeking to expand the benefits of checkpoint inhibitors to a greater number of patients.

One such trial, led by MSK gynecologic oncologist Roisin O’Cearbhaill, is looking at combining checkpoint inhibitor drugs with a cancer vaccine. The idea behind cancer vaccines is that they make it easier for the immune system to recognize the tumor by instructing it on what the antigen looks like. “It would be wonderful if we could teach the immune system to recognize and attack cancer cells,” Dr. O’Cearbhaill says. “But it’s not as simple as that. Cancer cells are continually changing, and they have a lot of tools enabling them to hide out in the body.”

The trick now is 
to figure out better ways to enhance the immune system's ability to see cancer.

Timothy A. Chan
physician-scientist

Combining checkpoint inhibitor drugs with cancer vaccines is just one of several tactics being studied. Other trials are looking at combining checkpoint inhibitor drugs with targeted therapies, chemotherapy, radiation therapy, and even other immunotherapies such as chimeric antigen receptor (CAR) T cell therapy, in which a patient’s T cells are engineered to recognize and attack cancer.

“The trick now is to figure out better ways to enhance the immune system’s ability to see cancer,” says Dr. Chan, who directs MSK’s new Immunogenomics and Precision Oncology Platform, which focuses on this type of research.

“Another big challenge is going to be to make sense of all these different trials,” he says. He adds it’s also important to refine the ability to predict who is not likely to benefit from this approach, so patients can avoid unnecessary treatment.

“Immunotherapy is still in the early stages, and a lot more research needs to be done,” Dr. Diaz concludes. “It’s important that we continue to evaluate all the hypotheses we have, and to determine which treatments are most likely to benefit patients. MSK is well­-poised to do this kind of research.”