One Patient’s Exceptional Response Leads to a Surprising Discovery about Immunotherapy

Source: Memorial Sloan Kettering - On Cancer
Date: 04/30/2019
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Findings from a single person with cancer can kick-start a major scientific breakthrough. When one person benefits from treatment in an uncommon way, doctors call it an exceptional response. In this era of personalized medicine, exceptional responses offer clues about how a drug or class of drugs works.

In a study published online on April 22 by Nature Medicine, a group of Memorial Sloan Kettering doctors and scientists describes one such exceptional response. The research suggests that in some cancers, genetic changes called gene fusions can occasionally send signals that the immune system can recognize. These signals can boost the effectiveness of immunotherapy drugs called checkpoint inhibitors. Checkpoint inhibitors take the brakes off the immune system and allow it to attack tumor cells.

“This is a great reminder that despite what we know about how immunotherapy and other cancer drugs work, we’re far from understanding all the rules,” says physician-scientist Timothy Chan, one of the paper’s two senior authors.

“What we’ve learned from this one patient has opened a new door,” adds surgeon-scientist Luc Morris, the paper’s other senior author. “Our findings suggest a new way that the immune system can recognize and attack certain types of tumors. But we’re really just at the beginning of knowing how to apply this discovery and target these alterations. We are working on the next steps in the laboratory.”

An Unexpected Outcome

The exceptional response described in the paper was in a teenage girl with a head and neck cancer that had spread to her lungs. She initially saw Dr. Morris, a head and neck cancer surgeon, who began tests to genetically profile the tumor, saving samples in the hopes of learning more about her cancer in the future. She was then treated by MSK pediatric oncologist Leonard Wexler with chemotherapy, which kept the disease stable. When the cancer started growing again, Dr. Wexler decided to try the immunotherapy drug pembrolizumab (Keytruda®).

“Further chemotherapy was unappealing because of the side effects and the limited chance that it would be effective,” Dr. Wexler says. “We also knew that the tumor had some unusual features for a head and neck cancer. We decided to think outside the box about how to treat the patient.”

Only about 12 to 15% of head and neck cancers respond to drugs like pembrolizumab. An initial analysis of this patient’s tumor suggested that she was not likely to be one of them.

There were two reasons for this belief. For one, her tumor had very few mutations. It’s known that the more mutations a tumor has, the more likely it is to respond to checkpoint inhibitors. That’s because having a lot of mutations means a tumor is more likely to produce proteins called neoantigens, which the immune system recognizes as foreign. This discovery was first reported in 2014 by Dr. Chan and his colleagues.

Additionally, her tumor was “cold,” meaning it had little immune activity around the tumor cells. By contrast, tumors described as “hot” — with many immune cells interspersed among the tumor cells — are more susceptible to checkpoint inhibitors. Immune cells can more easily find and attack a cancer when they’re already in the vicinity.

Despite these factors, the girl’s cancer had begun to shrink within five months. After three more months, it had completely disappeared. The MSK team decided to take a deeper dive, studying the tumor in greater detail to figure out why.

A Focus on Neoantigens

After sequencing the entire genome of the patient’s tumor, the MSK team discovered it had a kind of alteration called a gene fusion. Gene fusions occur when a gene from one chromosome breaks off during cell division and attaches to a gene on another chromosome. This new combined gene can make a protein that drives cancer growth.

“The fusion that this patient had was totally unheard of, something that has not been seen before,” Dr. Morris says. “But this gene fusion is probably what caused her cancer.”

The researchers discovered that the protein created by the gene was a neoantigen. “Neoantigens are seen as foreign by the immune system. They’re something that doesn’t belong in the body,” says Dr. Chan, who is Director of MSK’s Immunogenomics and Precision Oncology Platform. “In this case, the neoantigen resulting from the gene fusion made the patient’s cancer susceptible to immunotherapy.”

Looking for Potential Benefit in More Cancer Types

Although this patient’s particular gene fusion was rare, other fusions are more common in certain cancer types. The investigators analyzed tumors from other people treated at MSK for a type of head and neck cancer with common fusions. They found that immune cells in these people were able to recognize tumor cells with these gene fusions.

“One of the things that our team is doing now is systematically going through every single gene fusion across human cancers and predicting which ones may result in neoantigens that can be seen by the immune system,” Dr. Chan says. “We expect these findings are going to apply broadly to many different types of cancer.”

The original patient completed treatment with pembrolizumab and has remained free of cancer. It has been more than 30 months from when she started immunotherapy.

Genetic Variations Help Explain Why Immunotherapy Works Differently in Different People

Source: Memorial Sloan Kettering - On Cancer
Date: 11/07/2019
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Since 2011, the immunotherapy drugs called checkpoint inhibitors have become an increasingly important treatment for certain cancers. This is especially true for people with melanoma and lung cancer.

Early on, investigators observed that these drugs are extremely effective for some people, even eliminating their cancer entirely. Unfortunately, they don’t work at all for many others. Considerable research has tried to understand why this is the case and exactly how these drugs work.

Memorial Sloan Kettering physician-scientist Timothy Chan has focused on these efforts. He is one of the corresponding authors of a study published November 7, in Nature Medicine that reports a new way to determine who is most likely to benefit from immunotherapy. The findings may help explain why immunotherapy works differently in people around the world.

“Our results help solve part of the mystery of why there is such a large variation in the effectiveness of immune checkpoint drugs,” says Dr. Chan, who leads the Immunogenomics and Precision Oncology Platform at MSK. “It’s important that future clinical trials of immune checkpoint drugs take our discovery into account. This is especially important for international phase III trials.”

Looking to Evolution and Population Diversity for Answers

For decades, the human leukocyte antigen (HLA) genes have been known to govern how the immune system responds to foreign substances in the body. Over thousands of generations, as early humans migrated out of Africa and around the planet, they evolved variations in their HLA genes. These changes protected them from infectious organisms that were found in different parts of the world.

“The classic battle between pathogens and the human immune system plays out in the HLA genes,” Dr. Chan says. A 2017 study from Dr. Chan was the first to show that HLA genes are important for the body’s ability to see cancer after immunotherapy as well. That study reported that people who had a greater number of different copies, or alleles, in their HLA-1 genes responded better to immunotherapy compared with those whose HLA-1 genes had fewer alleles. The new study builds on this previous work.

To quantify how efficient the immune system is at detecting cancer, the researchers looked at the HLA genes from more than 1,500 people who had received immune checkpoint drugs as part of clinical trials at MSK and other hospitals. Most of those included in the study had melanoma or non-small cell lung cancer, but other kinds of cancer were also represented.

People inherit one copy of HLA-1 from each parent. For each person analyzed, the team found that the more molecularly diverse, or different from each other, the two copies of each of their HLA-1 genes were, the more likely someone was to respond to treatment and survive their cancer. The investigators developed a novel way to measure this difference, which they call HLA evolutionary diversity (HED).

Dr. Chan’s co-corresponding author on the Nature Medicine paper, Tobias Lenz of the Max Planck Institute for Evolutionary Biology in Germany, is an expert in the evolution of the human immune system and the HLA genes. Research fellow Diego Chowell and graduate student Chirag Krishna from Dr. Chan’s lab and graduate student Federica Pierini from Dr. Lenz’s lab were the co-first authors.

Recognizing Tumors as Foreign

Dr. Chan has also looked at other factors that make immune checkpoint drugs more effective. In 2014, he led the first studies finding that patients who responded to these drugs tended to have a large number of gene mutations in their tumors. This is known as having a high tumor mutational burden (TMB). When tumors have a greater number of mutations, it is more likely that they will produce proteins that the immune system hasn’t seen before.

“For checkpoint inhibitor drugs to be effective, the immune system needs to be able to recognize cancer cells as foreign,” Dr. Chan says. “High TMB and diverse HLA genes are two sides of the same coin. Both make it more likely that the immune system will see the cancer.”

The researchers note in their study that high TMB and high HED are independent of each other, but the combined outcome of the two led to benefits from immunotherapy drugs that were greater than either of these effects on their own. “These are the yin and yang of T cell–based immune checkpoint treatment,” Dr. Chan says. “High TMB is less useful if a person is unable to present the mutations to the immune system. Having a high HED allows that to happen.”

Finding New Ways to Measure Genetic Diversity

Recent immunotherapy clinical trials have begun to include TMB in their evaluation of how effective checkpoint inhibitors are, Dr. Chan notes. “But among different trials, there is great variation in the role that TMB plays. No one has been able to figure out what’s going on,” he says. “It turns out, we should also be looking at HLA diversity. This finding may account for the unexplained variation that’s seen in the role of TMB in immunotherapy trials.”

He adds that it may also account for the different response rates that have been observed in different parts of the world. HED can vary dramatically depending on where someone lives.

The investigators are now working to develop a standardized way to report HED, so that it can be incorporated into future clinical studies. Dr. Chan’s team is in the process of evaluating HED with industry partners using global phase III trial data. They hope that this measure can eventually become a regular part of cancer diagnosis and be used to match people with cancer with the most personalized treatments.

This research was funded by National Institutes of Health grants (R35 CA232097, RO1 CA205426, and P30 CA008748), the PaineWebber Chair in Cancer Genetics at MSK, and a German Research Foundation grant.

Dr. Chan has filed for a patent related to HED. Additionally, he is an inventor on a patent application filed by MSK relating to the use of TMB in cancer immunotherapy. MSK and the inventors may receive a share of revenue from license agreements relating to these patent applications. Dr. Chan is also a co-founder of Gritstone Oncology and holds equity. He acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai, and he has served as an adviser for Bristol-Myers Squibb, Illumina, Eisai, and An2H.