New Findings Clarify How Immunotherapy Works — and Why, In Some People, It Doesn’t

Pictured: Jedd Wolchok, Alexandra Snyder Charen and Timothy Chan

Jedd Wolchok, Alexandra Snyder Charen and Timothy Chan

The field of immunotherapy, centered on the idea that a person’s own immune system can be used to fight cancer, is rife with potential breakthroughs. One such example is ipilimumab (YervoyTM), which in clinical trials has produced practice-changing results for people with melanoma. The drug works by boosting the body’s natural immune defense against tumors. For some patients, it shrinks tumors and significantly prolongs lives.

But immunotherapy doesn’t help everyone. In fact, about 80 percent of people with melanoma get little or no benefit from ipilimumab. And thus far, doctors have had no way of predicting which patients are more likely to respond to the drug.

Now Memorial Sloan Kettering scientists have gained new knowledge about how ipilimumab works and why it controls melanoma in only some people. In a report published today in the New England Journal of Medicine, the researchers show that in patients who respond to the drug, their cancer cells carry a high number of gene mutations ­— and some of these mutations make tumors more conspicuous to the immune system.

“For the first time, it might be feasible to develop a reliable diagnostic test to help guide treatment decisions by predicting who will respond,” says physician-scientist Timothy Chan, who led the research. The findings could also inspire new research that potentially may lead to more-powerful immunotherapies for melanoma as well as for other cancers.

T Cell Emancipation

MSK physicians and scientists played a major role in the development of ipilimumab, which works by blocking a protein called CTLA-4. Normally, CTLA-4 keeps the tumor-fighting activity of the immune system’s T cells in check. In the presence of the drug, T cells are unleashed and their inherent ability to recognize and destroy cancer cells is enhanced.

Recent studies have shown that about one in five patients with metastatic melanoma who are treated with the drug live for more than three years after starting treatment. Before the drug became available, the median life expectancy for the disease was seven to eight months.

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Mining Clinical Samples for Clues

In the study, the researchers collected tumor samples from 64 melanoma patients who had been treated with ipilimumab or tremelimumab, an experimental drug that works in a similar way. The tumors were analyzed by whole-exome sequencing, a method of deciphering DNA changes across all parts of the genome that code for protein. About half of the tumors analyzed came from patients for whom the treatment had been successful and the other half from people who derived little or no benefit from it.

“We found that tumors that had responded to the drug had a higher mutational burden,” or overall number of DNA changes, explains fellow Alexandra Snyder Charen, the study’s first author. “But the correlation isn’t perfect. Not all patients with a high mutational burden in their tumors responded to the drug.”

“This made us ask, ‘What is the immune system seeing?’” adds Jedd Wolchok, a melanoma expert and immunologist who played a major role in the development of ipilimumab and co-led the NEJM study with Dr. Chan. “What is it about the mutational landscape of a tumor that helps the immune system recognize and attack it?”

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Foreign-Looking Tumors

Using sophisticated computational tools, the researchers were able to explore their data through the lens of immunity science. They found that drug-responsive tumors share a certain type of mutation that makes cancer cells express new antigens — substances that T cells can detect and recognize as foreign to the body.

“We identified a specific subset of tumor antigens found only in patients who respond well to CTLA-4 blockade therapy,” says Dr. Chan. The researchers believe these mutations make tumors express the new antigens that the immune system then reacts to — and ipilimumab works by enhancing that reactivity.

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Making Immunotherapies More Personalized and Effective

In the future, these findings could translate into a diagnostic test to detect the mutations in melanoma patients’ tumors. Results from such testing could help doctors and patients make more-informed treatment choices, taking into account the potential benefit of ipilimumab as well as the risk of side effects — which may include potentially dangerous inflammation of the colon or other organs.

In addition, the MSK team plans to investigate whether specific tumor mutations influence the effectiveness of other immunotherapy drugs.

“By mapping the mutations that make different types of tumors sensitive to different drugs, we might ultimately be able to offer more patients successful immunotherapy,” Dr. Chan says. “If we know a patient won’t respond to ipilimumab, we may be able to identify other drugs that are more likely to be effective against this person’s tumor.”

“The case of ipilimumab is unique in that we’ve been using a drug that empirically was found to be quite effective, and yet we didn’t have a detailed understanding of how it was working in people,” adds Dr. Wolchok. “It’s quite possible that in the future, we might learn how to introduce new antigens in people’s cancer cells to make their tumors more vulnerable to immunotherapy.”

“These advances would not have been made without the generosity of patients who consented to having their tumor tissue collected and analyzed,” Dr. Snyder Charen concludes. “Jedd Wolchok and his lab members have spent many years banking samples, and it’s an invaluable resource for research.”

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This research was supported by Ludwig Cancer Research and grants from the Frederick Adler Fund, the National Institutes of Health, Swim Across America, the Ludwig Trust, Melanoma Research Alliance, Stand Up To Cancer-Cancer Research Institute Immunotherapy Dream Team, Hazen-Polsky Foundation, and the STARR Cancer Consortium. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.


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I appreciate this. Having a stage 4 Mel diag since 10/2014 and getting ready for 2nd Yervoy infusion (Dec 2) makes me wish there was a way to tell now which profile I have.
I have no cancer physically or symptomatically showing itself since the complete lung resection of a SPN 1.1cm (mets) beg of Oct 2014.

I am thankful to be getting the standard of care but a 20% chance of being a responder is tough odds to face.
Phoenix, AZ

How many ways can an older male contact C L L.....

Diagnosed 4/11 with melanoma, treated with Yervoy at UAB in 10/2011...tumors never spread and surgery in 1/2014 removed last cancer cell. Have not had one sick day in all of it

Let me add I was stage 4, and not braf/no mutation "type". Tumors in lungs were treated with radiation and they became scar tissue in 90 days after 6 treatments. The remaining one cell in neck was then surgically removed in Jan 2014. Pet scans in april and then august showed no evidence of disease. Go again Jan 2015 for new scans

Nice to here some positive outcomes! I was diagnosed in 2013 with Anal melanoma. Had an APR resection. had my first recurrence this month. (Lymph node). PET scan next week and hopefully that's the only place that it shows up, and can have it removed.

After round of YERVOY unsuccessful. Metastasize into L2 and six lesions in liver. Now on OPTIVO (had 5 radiation treatments on L2) why did Yervoy completely fail?

Dear Allen, without more information, it’s hard to say why Yervoy was not effective in your particular case. However, we are working hard to enhance our ability to help patients like you make more-informed treatment choices, taking into account the potential benefit of immune therapies like ipilimumab as well as the risk of side effects. We wish you well as you continue with treatment. Thank you for your comment.

Hi! I was diagnosed with metastatic melanoma ( vaginal) on october 2016. I undergone a lot of tests. I had my first immunotherapy (combination of ipilimumab and nivolumab) last January 4, 2017. I on my 9th day but i feel very weak and feel pain in the pelvic. Area and at the back near the anus. I also have discharge with odor.

Dear Ghing, we are sorry to hear about your diagnosis. Please follow up with your oncologist to discuss all of your symptoms so that he or she can make appropriate recommendations to address them. We wish you well as you continue with your treatment. Thank you for reaching out to us.

I'm experimenting combining Yervoy with partial radiation of the tumor so that the antigens are exposed. I think that burning a disk in the center of the tumor rather that nuking the whole tumor is important.

I was diagnosed with melanoma 2c and went to a nearby hospital to Sloan. After 4 ipi treatments a new tumor was found on my SBL scar. Sloan does not take my insurance so I can not see Dr Willchok :( .thw want to start me on Nivo now, waiting for scans.I am concerned that they never checked my braf ? Any suggestions for those of us that Yevoy is letting down ?

Dear Kerry, because every case is different, we unfortunately are not able to offer medical advice on our blog. Depending on your situation, you may qualify to come to MSK for treatment even without the right insurance. You can contact our Financial Assistance Program at 212-639-3810 or go to to learn more. Thank you for your comment, and best wishes to you.