Good News: Gene therapy for sickle cell disease, and more

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Good News at Fred Hutch

Celebrating faculty and staff achievements

Feb. 2, 2017
Dr. Hans-Peter Kiem in his laboratory at Fred Hutch

“Approximately 300,000 children are born with sickle cell disease every year worldwide and there are about 100,000 affected patients in the United States ― a large patient population that could benefit from this treatment,” said Dr. Hans-Peter Kiem, who co-leads this gene-editing project.

Fred Hutch News Service file

Novel gene therapy for sickle cell disease and related disorders on the horizon

A multi-institutional research team in Seattle recently was awarded more than $3.7 million in federal grant funding to develop a novel gene therapy approach for dangerous genetic disorders that affect hemoglobin, the blood’s oxygen-carrying molecules.

The most well-known of these disorders is sickle cell disease, a major cause of death in young children in many African nations. There is no curative therapy for these disorders short of a tissue-type-matched bone marrow transplant, which carries its own serious risks and is out of reach for most.

This four-year grant from the National Heart, Lung, and Blood Institute is co-led by two experts in the emerging field of gene therapy: Dr. Hans-Peter Kiem of Fred Hutchinson Cancer Research Center and Dr. Andrew Scharenberg of Seattle Children’s Hospital.

One reason this project is exciting, Kiem said, is that it holds promise for huge numbers of people.

“Approximately 300,000 children are born with sickle cell disease every year worldwide and there are about 100,000 affected patients in the United States ― a large patient population that could benefit from this treatment,” said Kiem, the Fred Hutch Endowed Chair for Cell and Gene Therapy.

This project aims to use a type of gene editing called CRISPR to modify the DNA regulatory sequence that turns down the production of fetal hemoglobin, a variant of the oxygen-carrying molecule that is found at high levels in fetuses and newborns but at low levels in most adults. Research has shown that people with sickle cell disease who happen to have unusually elevated levels of fetal hemoglobin have much milder sickle cell symptoms than other people with the disease. This approach to boost the production of fetal hemoglobin, the researchers hope, will make up for the inborn problems in the adult form of hemoglobin.

“What we would like to do is take patients’ own bone marrow and modify it in a way that it would be therapeutic when we put it back into the patients,” said staff scientist Dr. Olivier Humbert, who is managing the project for the Kiem Lab.

A unique aspect of the project is this focus on the blood stem cells of the marrow, the researchers said.

“There is not much experience there [in the field] with CRISPR in hematopoietic stem cells, and we’re probably one of the first ones exploring this,” Kiem said. Making the genetic modification at the blood stem-cell level, rather than in mature cells, would ensure a continual supply of blood cells with amped-up abilities to produce fetal hemoglobin, as older blood cells die and new ones develop to replace them.

The trial also incorporates a strategy the Kiem Lab developed for boosting the numbers of cells that have a gene modification: A specially engineered genetic sequence to give the modified cells a selective advantage after transplantation. This can help the researchers make sure that there are enough of the modified cells producing high levels of fetal hemoglobin to ameliorate the symptoms of the underlying disease.

The CRISPR tools for making the gene modification are currently being created and tested. The first tests in preclinical models should begin in a few months, Humbert said. The team hopes to launch a clinical trial in humans in several years, he said.

— Susan Keown / Fred Hutch News Service

Dr. Paul Nghiem

Dr. Paul Nghiem speaks at an immunotherapy symposium at Fred Hutch last December.

Photo by Robert Hood / Fred Hutch News Service

Immunotherapy trial in rare skin cancer named one of 2016’s major advances in clinical cancer research and care

The American Society of Clinical Oncology has recognized an immunotherapy study led by scientists at Fred Hutch and the University of Washington as one of the top advances of 2016 in clinical cancer research and care.

The study, published last April, found that patients with the rare skin cancer Merkel cell carcinoma, or MCC, who received the immunotherapy drug pembrolizumab had much longer-lasting responses to therapy than what is typically seen with chemotherapy. The study is included in ASCO’s “Clinical Cancer Advances 2017: Annual Report on Progress Against Cancer,” an independent annual review of the biggest breakthroughs and latest trends in clinical research and care for cancer.

“It is very exciting for patients with Merkel cell carcinoma, that this rare, ‘orphan’ disease is getting attention at the national level and that new, promising therapies are increasingly available,” said study leader Dr. Paul Nghiem of UW, who is a Fred Hutch affiliate clinical researcher.

When the first results from the study were released, it became easier for patients to access the drug off-label, Nghiem said. It also generated increased interest from pharmaceutical companies in studying this type of drug in MCC, which is particularly important for a rare and aggressive cancer with no U.S. Food and Drug Administration-approved therapies.

The study was conducted at eight sites nationwide through the Fred Hutch-based Cancer Immunotherapy Trials Network, which is led by the Hutch’s Dr. Martin “Mac” Cheever.

The study enrolled 26 participants who had not yet received a systemic therapy, like chemotherapy, for their disease. Around half of the participants’ cancers responded to the pembrolizumab ― similar to the response rate for chemo in MCC. However, of the 14 patients in the trial who had confirmed responses to pembrolizumab, 12 still had tumor regressions between two to 10 months later, when the scientists analyzed their data for publication.

Dr. Paul Nghiem explains how his team uses immunotherapy to combat a rare, often misdiagnosed form of skin cancer. Nghiem is affiliate investigator in Fred Hutch’s Clinical Research Division and head of dermatology at the University of Washington.

The researchers calculated that more than two-thirds of patients on the trial would have no evidence of disease progression for at least six months after treatment. In contrast, previous research has shown that chemotherapy only keeps this cancer at bay for an average of three months; by 10 months after starting chemotherapy, more than 90 percent of patients will have had their disease return, typically more aggressive than before.

Furthermore, the therapy triggered anti-cancer immune responses in participants with two very different types of MCC — one type caused by the Merkel cell polyomavirus, the other caused by extensive DNA damage from ultraviolet light exposure.

Also notable was that most patients experienced only relatively minor side effects, another contrast to chemotherapy.

Several immunotherapy advances were recognized in the ASCO annual report, which named immunotherapy as its “advance of the year.”

— Susan Keown / Fred Hutch News Service

Dr. Cara McDermott

Dr. Cara McDermott

Photo by Robert Hood / Fred Hutch News Service

Dr. Cara McDermott receives AcademyHealth new investigator award

Dr. Cara McDermott, an affiliate researcher with the Hutchinson Institute for Cancer Outcomes Research, or HICOR, is among five U.S. researchers selected to be part of AcademyHealth’s 2017 New Investigator Small Grant Program.

She will use the funding to study care coordination and low-value care (care lacking sufficient evidence of benefit or not in line with patient goals) among patients with advanced cancer at the end of life.

McDermott, a senior fellow at the Cambia Palliative Care Center of Excellence at the University of Washington School of Medicine, said that cancer patients who are near death often receive low-value care. For example, hospitalization and emergency department visits for commonly occurring conditions among the dying — such as dehydration, pain management and constipation — are examples of potentially avoidable, low-value care that instead could be addressed in a home setting, thus avoiding hassle and expenses to patients and families during a difficult time.

In partnership with HICOR and local insurers, McDermott will study insurer-provided care coordination for enrollees in Washington state with advanced cancer and tease out patterns of health care use in the last month of life.

Findings from this study, McDermott said, will help determine how patients perceive and utilize care-coordination services in this setting and inform future interventions to improve care coordination and value-based care.

“We will learn how programs facilitating advanced care planning and care coordination impact how patients with life-limiting illnesses make choices about their health care,” she said. “In turn, an evaluation of such programs can help insurers determine if such programs are the most effective way to support their enrollees with serious illness.”

The AcademyHealth New Investigator program, which is designed to support the early careers of new health services researchers, is conducted in partnership with the Altarum Institute, the Association for Community Affiliated Plans and the March of Dimes.

— Kristen Woodward / Fred Hutch News Service

Dr. Stephen Schwartz

Dr. Stephen Schwartz

Photo by Bo Jungmayer / Fred Hutch News Service

Study documents sperm changes years after chemotherapy

Epigenetic changes in the sperm of males who undergo chemotherapy in their teens can influence how their genes are turned on and off, potentially affecting the health of tissues in subsequent generations. That’s according to a new study co-authored by Dr. Stephen Schwartz of the Fred Hutch Public Health Sciences Division and led by researchers at Washington State University and Seattle Children’s.

Published Wednesday in the online journal PLOS One, these findings suggest that male teens about to undergo chemotherapy may consider having some of their sperm preserved for when they would like to start a family, said senior author Dr. Michael Skinner, a professor in the WSU School of Biological Sciences and Center for Reproductive Biology.

The study examined sperm from 18 males who had undergone chemotherapy as adolescents and 18 untreated men whose sperm served as a comparison, or control. Skinner and colleagues at WSU collaborated with researchers at Seattle Children’s Research Institute and Schwartz of Fred Hutch, whose role was to recruit some of the control subjects, given his prior experience recruiting young men for studies involving biospecimens.

While the sample size was small, all of the sperm from the former chemotherapy patients had a similar pattern of molecular changes.

While direct exposure to chemotherapy could affect a lot of cells, those effects should have disappeared within months, as the testes take 75 days to make sperm, which remain in the body for 20 or 30 more days. So, for effects to be seen 10 years later, cells in the testes must be permanently altered, according to the researchers.

The researchers next plan to investigate what effects, if any, these changes are having on subsequent generations – both in chemotherapy patients and their offspring, as well as similar changes in rodents.

“This study represents the first observation in humans that an early life chemical exposure can permanently reprogram the spermatogenic stem cell epigenome,” the researchers wrote. “The germline (i.e. sperm) epimutations identified suggest chemotherapy has the potential to promote epigenetic inheritance to the next generation.”

The National Institutes of Health and Childrens Oncology Group funded the research.

— Adapted from a Washington State University news release


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