Study Uncovers Genetic Reasons Why Some People Respond to Immunotherapy Better than Others

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Model of a T cell receptor and an HLA-A white blood cell antigen bound to part of a virus

This molecular model shows a T cell receptor and an HLA-A white blood cell antigen bound to part of a virus. (Laguna Design / Science Source)

For some people with cancer, immunotherapy drugs called checkpoint inhibitors, which take the brakes off the immune system and allow it to attack cancer cells, have been a game changer. They can shrink even very advanced cancers to levels that can no longer be detected. But for most patients, these drugs have been disappointing. Researchers are trying to figure out why.

Now the largest-ever genetic analysis of people being treated with checkpoint inhibitors has found that certain genes people are born with (called germline genes) may play a critical role. We spoke to Memorial Sloan Kettering physician-scientist Timothy Chan, one of the study’s senior authors, about what his team found and what their findings may mean for people with cancer.

How is this study different from other studies looking at response to immunotherapy?

First, it was very large. We looked at more than 1,500 people who were treated with checkpoint inhibitors for a number of cancers. Our study included people across many different types of cancers. This leads us to believe that what we found applies very broadly, and not just to people with one type of cancer being treated with one particular drug.

Another difference is that we looked not only at genetic changes inside the tumor tissue, which many other studies have done, but also at certain genes that people are born with. Those genes make up people’s normal DNA. Specifically, we looked at human leukocyte antigen (HLA) genes. These genes are critical for regulating the immune system and dictating what it can detect and fight off.

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Importantly, the HLA system is used to match recipients and donors for stem cell and bone marrow transplants. HLA genes guide immune cells called T cells to recognize what is “self” and what is not. For transplants, we want the donor’s HLA system to be similar enough to the recipient’s that donated T cells will not attack the recipient’s tissues. In the case of cancer, we want to boost the T cells’ ability to destroy tumor cells, and HLA proteins determine what T cells can see. No previous study has closely examined the effects of HLA germline genes on immunotherapy response.

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What gave you the idea to look at these HLA genes and how they relate to immunotherapy response?

Researchers have known for a while that HLA genes play a role in how people respond to infections. Certain HLA profiles are associated with better outcomes in people with HIV, hepatitis B, and malaria. HLA genes are among the most diverse of all human genes. Our species has evolved such diversity to improve the ability of our immune system to overcome infections. For example, in Africa, where malaria is common, people have evolved HLA genes that help them recognize and fight off those particular infections. In other areas of the world, people may have evolved HLAs to fight off infections that are common there. The human body is constantly under assault from pathogens, and HLAs are how we recognize and eliminate them.

We wanted to see how HLA genes in patients affect their response to anticancer immunotherapy.

The human body is constantly under assault from pathogens, and HLAs are how we recognize and eliminate them.
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What was different in the HLA genes of people who responded to checkpoint inhibitors compared with those who didn’t?

We found in our study that people who had a greater diversity and more variation in their HLA genes responded much better to immunotherapy compared with those who had less diversity. Because no one had ever before looked at HLA genes in people undergoing immunotherapy, this was a new finding.

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Did this finding surprise you?

Not completely. Several years ago, our group at MSK and investigators elsewhere began looking at the effects of the tumor genome on immunotherapy response. We found that tumors with a greater number of mutations were more recognizable to the immune system.

Our latest findings represent the other side of the same coin: Just as tumors with a greater number of genetic changes are more recognizable to immune cells, having more-diverse HLA genes means that someone’s immune system has a greater ability to recognize what doesn’t belong inside the body. Both are important for maximizing the ability of the immune system to see and destroy cancer cells.

As more people around the world are being treated with checkpoint inhibitors, it was observed that different response rates occurred in different parts of the world. For example, studies conducted in northern Europe have shown that overall a lower percentage of people respond to some of these drugs. This makes sense in light of our new findings, because those populations are known to have less diversity in their HLA genes.

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Will this finding change how patients are treated?

I think it will have a strong effect very soon. There is a rush to develop genetic tests to measure how many mutations are present in tumors as a way to predict response to immunotherapy. We have shown that someone’s DNA — their HLA genes — is critical as well. We can combine information about HLA diversity with data on numbers of mutations to make much better prediction models for checkpoint inhibitor response.

For instance, in people who have a low diversity in their HLA genes as well as a low number of mutations in their tumors, we know they are much less likely to respond to checkpoint drugs, especially when those drugs are given alone. So we may want to treat them with a combination of different immunotherapy drugs instead of just one, or try targeted therapies or other treatments instead.

The MSK-IMPACTTM test, which recently received authorization from the US Food and Drug Administration, already analyzes the HLA genes in patients’ blood samples. So at MSK we can start using these new findings right away. Other tests that look at tumor genomes don’t include HLA analysis. This is one more component that illustrates the power of MSK-IMPACT and what makes it unique.

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What are the next steps for this research?

Our findings will need to be validated in prospective studies, but because we included such a large and diverse number of patients — more than a thousand — we think we’ve set the bar pretty high.

We can’t do anything about the HLA genes that people are born with. But we think that learning more about immune system recognition can help with the development of new cancer treatments, such as vaccines that could be used on their own or in combination with checkpoint inhibitors. The differences in how various HLA genes work to promote tumor rejection can help guide the choice of targets to use in new anticancer vaccines.

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This study was published in Science. It was funded by the National Institutes of Health and the National Cancer Institute (grants P30 CA008748, NIH K08 DE024774, and 1R01CA205426) the Damon Runyon Cancer Research Foundation, the Pershing Square Sohn Cancer Research Alliance, the STARR Cancer Consortium, and Stand Up 2 Cancer. The other senior author was Naiyer Rizvi of Columbia University Medical Center.

Comments

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I had stage 1b or 2a lobular bc estrogen posituve her neg prog neg, last year bmx and radiation. Should I consider getting an immunization to prevent it from coming back?
Also o am very anxious, from taking so and now tamoxifen. Any suggestions for a cure of that, I had 2nd opinion at msk a few weeks ago. What would the cost be for immunization, any bc survivors getting it thanks

Dear Kathy, we’re sorry to hear about your diagnosis. There are vaccines for breast cancer that are currently in clinical trials, but there is not a vaccine that is approved for general use at this time. If you are interested in participating in a research trial, we recommend that you discuss this with your care team. Thank you for your comment, and best wishes to you.

Looking for more aggressive approach to my husband’s small cell stage 4 lung cancer
Treatments, I feel we could of done more in a preventive way, take dna test to see how
To treat his cancer, being his mon died of the same cancer

Dear Dorothy, we’re sorry to hear about your mother-in-law’s death and your husband’s diagnosis. If your husband would like to come to MSK for a consultation, you can make an appointment online or call 800-525-2225. Thank you for your comment and best wishes to you and your family.

Hello,
I've been recently diagnosed with Stage 4 breast cancer (mets to bones and liver). Is there any way I can participate in a current immunotherapy study?
Sincerely,
Kelly

Dear Kelly, we’re very sorry to hear about your diagnosis. If you’re interested in learning about breast cancer trials at MSK, you can arrange a consultation by making an appointment online or calling 800-525-2225. Thank you for your comment and best wishes to you.