Nav: Home

Flaws in a tumor's genetic mending kit drive treatment response to immunotherapy

June 09, 2017

In an expanded, three-year clinical trial of 86 patients with colorectal and 11 other kinds of cancer that have so-called 'mismatch repair' genetic defects, scientists at Johns Hopkins Medicine and its Bloomberg~Kimmel Institute for Cancer Immunotherapy have found that half of the patients respond to an immunotherapy drug called pembrolizumab (Keytruda). In a report on the findings, which led the U.S. Food and Drug Administration to approve expanded use of pembrolizumab for patients, the researchers also say they found evidence that the immune responses closely aligned with mutations found in their cancers. The report is published online in the June 8 issue of the journal Science.

"Our study results may lead to a new standard-of-care that includes mismatch repair deficiency testing to help identify a wider group of patients who have failed other therapies but may benefit from immunotherapy drugs." says Dung Le, M.D., oncologist at the Johns Hopkins Bloomberg~Kimmel Institute, who led the clinical trial.

Mismatch repair (MMR) defects are part of a system that helps cells recognize and correct mistakes during DNA replication. For more than two decades, defective MMR genes have been linked to inherited and non-inherited (or sporadic) forms of colon cancer and used as biomarkers for diagnostic screening and chemotherapy treatment planning.

For the current Johns Hopkins study, designed and led by Le and Luis Diaz, M.D., who recently moved to the Memorial Sloan Kettering Cancer Center from Johns Hopkins, 86 adult men and women with 12 cancer types were recruited to the clinical trial at six U.S. hospitals, including The Johns Hopkins Hospital. All tested positive for mismatch repair defects and had failed to respond to at least one prior therapy. They received pembrolizumab intravenously every two weeks for up to two years. Johns Hopkins biostatistician Hao Wang, Ph.D., used a so-called "basket design" for the clinical trial to enroll MMR-deficient patients with multiple types of cancer into a single trial.

After a median follow-up of 12.5 months, imaging scans showed that tumors shrunk by at least 30 percent in 46 of the 86 patients (53 percent). Tumors completely disappeared in 18 of the 46.

In all, 66 of 86 (77 percent) had at least some degree of disease control, including those who had partial responses, meaning their cancers shrunk by at least 30 percent in diameter, and complete responses, meaning no radiologic evidence of the tumor. This also included those whose tumors did not grow, but remained stable. At one year after the start of therapy, 65 of the 86 patients (76 percent) were alive, and 55 of the 86 (64 percent) were alive at two years.

Five of 20 patients (two with colon cancer, two with pancreatic cancer and one with small bowel cancer), who were listed as having progressive disease, initially responded to pembrolizumab, but their cancers often regrew in areas such as the brain or bone. Three were treated additionally with surgery or radiation and continued treatment with pembrolizumab. All five remained alive at the time of the data cutoff.

Twenty-one of 40 patients with colorectal cancer (52 percent) and 25 of 46 patients with cancers (54 percent) in other organs, such as pancreas, ampullary, cholangiocarcinoma, gastric, endometrial, neuroendocrine, prostate, small intestine and unknown primary responded to the drug.

The most common side effects of the immunotherapy included fatigue, skin inflammation, joint pain and thyroid dysfunction.

At the time of the data cutoff of this report, 18 patients were taken off therapy after two years of treatment. Eleven patients have been off of immunotherapy for a median of 8.3 months, and none have shown evidence of a cancer recurrence. The remaining patients had some residual disease, were taken off therapy at two years (some because of side effects) and after an average of 7.6 months, none of these patients has had evidence of disease progression.

The median point of survival without disease progression and overall survival has not yet been reached. However, the scientists estimate that disease-free survival at one and two years is 64 percent and 53 percent, respectively. Without immunotherapy, patients with advanced, treatment-refractory cancers can expect to live less than six months.

"We still do not understand why only half of the patients in the study responded and half did not," says Drew Pardoll, M.D., Ph.D., director of the Johns Hopkins Bloomberg~Kimmel Institute and a co-author of the report. "But in testing for MMR deficiency, we essentially married genetic biomarkers with an immunotherapy drug to find patients we thought would be more likely to respond to this increasingly-used drug, and we believe it's a terrific example of the future of precision immunotherapy."

He added, "the hope is that other immunotherapy drugs can be aligned with genetic factors to further increase success."

Pembrolizumab and other immunotherapy drugs can cost $100,000 or more per year, fueling the need to identify patients who are likely to respond to the drug. Tests for defects in mismatch repair range in cost $300 - $600.

The researchers also performed biopsies on residual tumors in 20 patients. In 12, they found no cancer cells, only inflamed cells, fibrotic tissue and mucus. These patients were more likely to survive longer without progression of their cancer (25.9 months) compared with the other eight who had residual cancer cells in their biopsies (2.9 months). However, there was no difference in overall survival between these two groups.

Using gene sequencing and methods to stimulate T-cells, immunologists, led by co-author Kellie Smith, Ph.D., of the Bloomberg~Kimmel Institute, tracked T-cells in the tumor and circulating blood that could recognize the biochemical signatures of mutations in their cancers. In three patients, they found these cells rapidly increased in the circulating blood after immunotherapy was administered, peaking at one to two months later, often prior to detecting tumor regression via CT scans.

These MMR defects were first identified in 1993 by Bert Vogelstein, M.D., and fellow scientists at Johns Hopkins and other institutions. The mutations disable cells' ability to repair errors in the DNA replication process, which triggers unchecked cellular growth, a hallmark of cancer.

Two decades later, an idea for the current clinical trial took root when Johns Hopkins experts discovered mismatch repair defects in a single patient with colon cancer who responded to immunotherapy while other patients with colon cancer did not.

"This was the eureka moment that led us to develop this clinical trial," says Vogelstein, who co-directs both the Ludwig Center at the Johns Hopkins Kimmel Cancer Center and the Genetics Program of the Bloomberg~Kimmel Institute.

To estimate how many patients with cancer may be candidates for pembrolizumab based on their mismatch repair defects, the scientists sequenced 592 genes in 12,019 patients with 32 different tumor types. They estimate that mismatch repair defects occur in nearly 5 percent of patients with 11 types of cancer, including the endometrium, stomach, small intestine, colon and rectum, cervix, prostate, bile duct, liver, neuroendocrine system, non-epithelial ovary and uterine sarcomas. This translates to approximately 40,000 (8 percent) stage I-III cancers and 20,000 (4 percent) of all stage IV cancers.
-end-
Other scientists who contributed to this research include Jennifer N. Durham, Bjarne R. Bartlett, Laveet K. Aulakh, Steve Lu, Holly Kemberling, Cara Wilt, Brandon S. Luber, Fay Wong, Nilofer S. Azad, Agnieszka A. Rucki, Dan Laheru, Ross Donehower, Atif Zaheer, Matthias Holdhoff, Christian Meyer, Shibin Zhou, Deborah Armstrong, Katherine M. Bever, Amanda N. Fader, Janis Taube, Franck Housseau, David Spetzler, Nickolas Papadopoulos, Kenneth W. Kinzler, James R. Eshleman and Robert A. Anders from Johns Hopkins; George A. Fisher of Stanford University; Todd S. Crocenzi of the Providence Cancer Center at Providence Health & Services, Portland, Oregon; James J. Lee of the University of Pittsburgh Cancer Institute; Tim F. Greten and Austin G. Duffy of the National Cancer Institute; Kristen K. Ciombor of the Ohio State University Comprehensive Cancer Center; Aleksandra D. Eyring, Bao H. Lam, Andrew Joe and S. Peter Kang of Merck; Richard M. Goldberg of the West Virginia University Cancer Institute; and Nianqing Xiao and David Spetzler of Caris Life Sciences.

Funding for this research was provided by the Swim Across America Laboratory at Johns Hopkins, the Ludwig Center for Cancer Genetics and Therapeutics, the Howard Hughes Medical Institutes, the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, the 2017 Stand Up To Cancer Colon Cancer Dream Team, the Commonwealth Fund, the Banyan Gate Foundation, the Lustgarten Foundation for Pancreatic Cancer Research, the Bloomberg Foundation, the Sol Goldman Pancreatic Cancer Research Center, Merck & Co. Inc., and the National Institutes of Health's National Cancer Institute (Gastrointestinal SPORE grant P50CA062924, P30CA006973, CA163672, CA43460, CA203891, CA67941, CA16058 and CA57345).

Diaz, Le, Vogelstein, Papadopoulos and Kinzler are inventors on patents filed related to this work and Diaz, Vogelstein, Papadopoulos and Kinzler are a founder of PapGene and Personal Genome Diagnostics (PGDx). Diaz is a consultant for Merck, Illumina, PGDx and Cell Design Labs. PGDx and PapGene, as well as other companies, have licensed technologies from Johns Hopkins University, on which Diaz, Vogelstein, Papadopoulos and Kinzler are inventors. Some of these licenses and relationships are associated with equity or royalty payments. The terms of these arrangements are being managed by Johns Hopkins in accordance with its conflict of interest policies.

Johns Hopkins Medicine

Related Cancer Articles:

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Climate Mindset
In the past few months, human beings have come together to fight a global threat. This hour, TED speakers explore how our response can be the catalyst to fight another global crisis: climate change. Guests include political strategist Tom Rivett-Carnac, diplomat Christiana Figueres, climate justice activist Xiye Bastida, and writer, illustrator, and artist Oliver Jeffers.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Speedy Beet
There are few musical moments more well-worn than the first four notes of Beethoven's Fifth Symphony. But in this short, we find out that Beethoven might have made a last-ditch effort to keep his music from ever feeling familiar, to keep pushing his listeners to a kind of psychological limit. Big thanks to our Brooklyn Philharmonic musicians: Deborah Buck and Suzy Perelman on violin, Arash Amini on cello, and Ah Ling Neu on viola. And check out The First Four Notes, Matthew Guerrieri's book on Beethoven's Fifth. Support Radiolab today at Radiolab.org/donate.