Why Do Some People Beat the Odds against Pancreatic Cancer?

By Matthew Tontonoz,

Wednesday, November 8, 2017

An illustration of the human pancreas
Summary

Pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, is a notoriously lethal disease. Findings from a new study of rare long-term survivors may hold clues for designing better treatments.

Just 7% of people with pancreatic cancer survive more than five years. Less than 2% are alive after ten years.

Yet among these dismal statistics is a faint glimmer of hope. Some people with pancreatic cancer manage to beat the odds, surviving for many years after their initial diagnosis — maybe even long enough for doctors to use the word “cure.”

“Nobody knows why these patients live longer than other people with pancreatic cancer,” says Vinod Balachandran, a surgeon-scientist affiliated with the David M. Rubenstein Center for Pancreatic Cancer Research and a member of the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering who specializes in the disease. “But something is clearly setting them apart.”

In a new study, he and his colleagues set out to identify what that something is. Suspecting that the immune system might be involved, they looked at the number of immune cells present in a tumor and found the more immune cells, the longer the survival.

Nobody knows why these patients live longer than other people with pancreatic cancer, but something is clearly setting them apart.
Vinod P. Balachandran
Vinod P. Balachandran surgeon-scientist

What’s more, they were able to identify the particular components of the tumor that drew those immune cells in. The results, reported in the journal Nature, have implications for the design of more-effective immunotherapies for people with all types of cancer, including the deadly pancreatic cancer.

Uncloak and Dagger

Dr. Balachandran and his colleagues, including Jedd Wolchok, Timothy Chan, Steven Leach, and Taha Merghoub, looked at patients whose pancreatic tumors were surgically removed and who in some cases received subsequent chemotherapy. Compared with pancreatic tumors from people who had low survival rates, tumors from long-term survivors (average survival of six years) had nearly 12 times the number of immune cells called T cells inside them.

T cells are specialized at distinguishing foreign invaders, like infections and cancer, from normal body cells. They recognize bits of proteins on the cells’ surface called antigens, which serve as a kind of molecular fingerprint.

Dr. Balachandran and his team took a closer look at the antigens found in the tumors. They focused on a subset of these called neoantigens, which cancer cells accumulate as a result of mutations when they divide. The group discovered that tumors of long-term survivors contained particularly good neoantigens — ones that T cells could recognize as foreign. As Dr. Balachandran explains, these neoantigens may have, in effect, uncloaked the tumors to T cells, allowing T cells to attack and kill them.

Compared with pancreatic tumors from people who had low survival rates, tumors from long-term survivors had nearly 12 times the number of immune cells called T cells inside them.

Even more striking, T cells recognizing these neoantigens were present in the blood of long-term survivors up to 12 years after the tumors had been removed by surgery. This result suggests that the immune system in these people had generated long-lasting “memory” of the cancer and was keeping it in check. “We think that these long-term survivors highlight how neoantigens can be used in generating long-lasting immune responses against tumors,” Dr. Balachandran says.

An advantage of the study was its relatively large size. “Before our work, the largest study looking at long-term survivors of pancreatic cancer had only eight patients,” Dr. Balachandran says. “We had 82.”

To further define what makes a good neoantigen, the MSK team joined up with computational biologists Benjamin Greenbaum and Marta Luksza from the Icahn School of Medicine at Mount Sinai. They built an algorithm to predict the best neoantigens out of the many possible ones. These results were reported in a separate article, also published in Nature.

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Boosting Immune Responses

Knowing what the immune system is seeing in particular tumors opens the door to therapeutic approaches geared toward deliberately focusing on these targets. For example, doctors could make a therapeutic cancer vaccine composed of several distinctive neoantigens identified from a patient’s own tumor. A form of personalized immunotherapy, this type of vaccine would help boost the immune system against those targets that are most likely to generate an effective and lasting immune response. Recent reports have demonstrated the feasibility of this approach in people with other cancers.

“We think our findings are a step forward in being able to predict rationally which neoantigens will be the most effective at stimulating an immune response,” he says. “We envision using these new results to design more effective cancer vaccines to be used in combination with other immune therapies.”

The team is now engaging with the pharmaceutical companies Genentech and BioNTech to determine how to use these insights in clinical trials evaluating personalized neoantigen vaccines in a spectrum of cancers, including pancreatic cancer and melanoma. “We are determined to move this forward to clinical trials as quickly as possible,” Dr. Balachandran says.

Pancreatic Cancer Clinical Trials & Research
Through clinical trials, we’re studying new approaches to treating pancreatic cancer and coming closer to finding promising solutions.
Learn more
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This work received financial support from the National Institutes of Health, the Pancreatic Cancer Action Network-AACR Research Acceleration Network supported by Celgene, the Suzanne Cohn Simon Pancreatic Cancer Research Fund, the National Cancer Institute, the Damon Runyon Cancer Research Foundation, Stand Up To Cancer, the V Foundation for Cancer Research, the Lustgarten Foundation, the National Science Foundation, the Parker Institute for Cancer Immunotherapy, Dr. Robert and Mrs. Nancy Magoon, Cycle for Survival, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, the Ludwig Center for Cancer Immunotherapy, and Swim Across America.

 

Comments

I have been diagnosed with stage 4 pancreatic cancer that has metastasized to the liver. I was diagnosed August 15, 2017. Is there any hope for me?

Dear Federico, we're very sorry to hear about your diagnosis. If you would like to speak with someone at MSK about whether there may be a clinical trial that you could participate in, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.

Hi, my dad had been diagnosed with stage 4 pancreatic cancer in Malaysia earlier on this November 2017. The doctor in Malaysia advice not to have any surgery or chemotherapy but I feel there is hope after reading your website. Is there any hope for us to send him over to your hospital for treatment or your hospital actually have some working partner in Asia?

Dear Aerick, we're very sorry to hear about your dad's diagnosis. If he would like to come to MSK for treatment, or have his medical records reviewed, you can contact our International Center at international@mskcc.org or go to https://www.mskcc.org/experience/become-patient/international-patients for more information. Someone at the center may also be able to refer you to a hospital that is closer to you. Thank you for your comment, and best wishes to you and your family.

I will be a 5 year survivor in January! I had whipple January 22, 2013. I am cancer free at this time.

Thanks for sharing your great news, Jeri! We're glad to hear you're doing well. Best wishes to you.

My husband was diagnosed in May 2012 he passed on April 22 2013, when we met with surgeon he was not a candidate for the whipple I am assuming becuase of the stage I have blocked out many of my questions or meetings during that time. I am wondering if immunotherapy is helping new patients.

Dear Diana, we are very sorry for your loss. Best wishes to you.

My brother was diagnosed with stage IV PC, he is having issues with blood clots through out, also we can't seem to get him to eat or even drink. Is that normal? also seems to be over medicated.

Dear Judy, we're very sorry to hear your brother is going through this. We recommend that you discuss your concerns with his medical team. If he would like to come to MSK for a second opinion, he can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you and your family.

My wife is a 6-year survivor. She had the Whipple in 2012, but the cancer had spread to her lungs. She has numerous nodules which have been held in check by Abraxane and Gemcitobine, but she is worn out from 6 years of treatment. We have begun exploring options after two bouts with pancreatitis. Does Sloan Kettering have anything to offer in treatment options?

This is a super interesting article. I have a twist on it this Saturday morning. Could it be that the people who live longer than 5 years to 12 years really never had pancreatic cancer in the first place. Maybe they just had a tumor on their pancreas from another cancer and they were misdiagnosed!? Maybe they are being treated with the wrong chemotherapy in the first place and the wrong chemotherapy is actually decreasing their life span. Maybe people who are doing too well should be paid even more attention to to look at the reason why instead of just to continue to treat them incorrectly.

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