Gene Discovery Could Lead to More-Personalized Treatment with Immunotherapy

By Julie Grisham,

Wednesday, September 28, 2016

Nadeem Riaz and Timothy Chan

A review of nearly 200 patients receiving the immunotherapy ipilimumab for the treatment of melanoma has found two gene mutations that are linked to exceptional response to the drug.

  • Exceptional responders experience long-term remission or even are cured by a particular treatment, while the majority of patients see little or no benefit from the same treatment.
  • The two genes that were found are similar to genes already linked to immune responses.
  • The findings may result in basket studies to evaluate ipilimumab for other cancers that carry these mutations.
  • They may also lead to new approaches in developing cancer vaccines.

Memorial Sloan Kettering researchers have identified two gene mutations that are associated with an exceptional response to the immunotherapy drug ipilimumab (Yervoy®). Their findings could enable doctors to predict which patients will benefit from treatment with the drug.

The discovery may also expand the use of ipilimumab beyond melanoma, the type of cancer for which it’s currently approved. The findings were published this week in Nature Genetics.

“In the past, our lab has come out with studies showing that the more mutations a cancer has, the more likely it is that it will respond to immunotherapy drugs called checkpoint inhibitors,” says physician-scientist Timothy Chan, the study’s senior author. Checkpoint inhibitors such as ipilimumab are drugs that loosen constraints on the immune system and enable it to recognize and attack cancer.

“But this is the first time anyone has found specific gene mutations linked to good immune response to therapy,” he adds. “Also, because these genes provide instructions for making proteins that are known to be similar to proteins that elicit immune responses, our findings may teach us more about how cancer immunotherapy works and lead to new treatment approaches.”

Finding Common Ground in Exceptional Responders

In the study, the researchers looked at 174 patients who were receiving ipilimumab treatment for melanoma in the United States and Germany. They identified those who responded well to the drug, including some whose tumor completely disappeared; the majority of the patients saw little or no benefit.

The team then used gene sequencing to identify which mutations the exceptional responders had in common. They found mutations in two similar, related genes, SERPINB3 and SERPINB4. These genes are known to be related to autoimmunity, the process by which the body mounts an immune response against its own tissues. Interestingly, the proteins are the human versions of OVA, an egg protein that can lead to allergic reactions that has been studied for decades by immunologists.

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A Long-Lasting Benefit

“In patients who had either of the mutations, the response rates to ipilimumab were 60 to 65%, and many of those patients had complete, long-lasting responses,” Dr. Chan says. When all melanoma patients were included, the response rate was only about 15%. “Our findings have implications for more personalized treatment with immunotherapy drugs.”

Our findings have implications for more-personalized treatment with immunotherapy drugs.
Timothy A. Chan
Timothy A. Chan physician-scientist

He says that based on the new findings, it may be possible to set up basket trials that expand the use of ipilimumab to other types of cancer. “In the past, other types of cancer have shown very low response rates to ipi, but this may be because they have lower rates of SERPINB mutations,” he says. “If we can identify which patients have these mutations, we may find that the drug is effective against subsets of other tumor types — such as prostate, kidney, and head and neck cancers — as well.”

Because the mutations are known to affect proteins that enable the immune system to function, Dr. Chan says this discovery also may aid in the development of new cancer vaccines: “There’s a lot of interest in developing cancer vaccines. These findings may open the door for the development of better ways to stimulate the immune system to identify cancer.

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This work was funded by a Pershing Square Sohn Cancer Research grant, the Frederick Adler Chair, Stand Up 2 Cancer, and the Starr Cancer Consortium.


This is a potentially great happening. Personalized treatment cold be a huge market.

If I was a non responder ( I did this 4 X ) to keytruda, does this mean I wouldn't respond to ipi?

Hi Jean, although Keytruda and ipilimumab are both immunotherapies, they do not work through the same mechanism, so the fact that you don't respond to one doesn't mean that you would not respond to the other. We recommend that you speak with your doctor more about this. If you'd like to arrange for a consultation at MSK, you can call 800-525-2225 or go to for more information on making an appointment. Thank you for your comment.

As a new patient with MSK, I am reading about all these advances in cancer research and treatments but am disappointed each time I hear from my doctors "not enough data, we don't know very much" after being diagnosed with endometrial cancer "clear cell". If it is not known where "clear cell" comes from how can we do anything but damage control each time it shows up. Fortunately, I have a head start since it was contained within the endometrial lining, and no nodes or distant sites, caveat is because it is "clear cell" I still have to go the route of "slash and burn" as an insurance policy, short term at best, with slim statistics assuring me of a recurrence.

Dear Diane, we are sorry to hear about your diagnosis and agree that much more work needs to be done to help people with this diagnosis. We are hopeful that ongoing research at MSK and elsewhere will yield more effective therapies and better information to help guide treatment recommendations. Thank you for sharing your thoughts and experience on our blog.

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