The Women’s Health Initiative, a nationwide, federally funded research program coordinated by Fred Hutchinson Cancer Research Center in Seattle, has received the 10th annual Team Science Award from the American Association for Cancer Research. Fred Hutch biostatisticians Drs. Ross Prentice and Garnet Anderson, leaders of the WHI Clinical Coordinating Center, were on hand to accept the award April 17 on behalf of the WHI program during the American Association for Cancer Research 2016 Annual Meeting in New Orleans.
Launched in 1992 with a $625 million contract from the National Institutes of Health, the WHI is one of the largest U.S. studies of its kind and the largest, most ethnically and geographically diverse study of older women. It initially consisted of three randomized clinical trials and an observational study that together involved more than 161,000 postmenopausal women at 40 U.S. research centers.
According to Anderson, principal investigator of the WHI Clinical Coordinating Center and director of the Fred Hutch Public Health Sciences Division in which it is based, “This award recognizes that the tremendous successes of the WHI program are due to the contributions of tens of thousands of WHI participants and to the tremendous efforts by hundreds of WHI investigators and staff over more than two decades to build, maintain and enhance this resource for the larger goal of improving women’s health. This was and is team science writ large.”
The clinical trials tested the effects of postmenopausal hormone therapy, dietary changes, and calcium and vitamin D supplements on heart disease, fractures, and breast and colorectal cancer. Those studies ended between 2002 and 2005. Since then, more than 115,000 WHI participants have continued providing health information that is being used to investigate a variety of key women’s health questions. More than 80,000 of these women, ages 67 to 101, remain in active follow-up nationwide. Many of these women are also participating in two new trials: one is testing whether cocoa extract and multivitamins can help reduce the risk of cardiovascular disease and cancer; the other is testing the effect of physical activity on heart disease prevention.
The WHI is best known for its 2002 findings that combination hormone therapy — at the time prescribed to 5.5 million postmenopausal women in the U.S. to alleviate symptoms of menopause and to prevent fractures and heart attacks — significantly increased the risk of heart disease, stroke and breast cancer.
Those research findings singularly changed the face of women's medicine around the world. Researchers estimate that because of the decrease in hormone therapy use following the WHI publication, there have been 15,000 to 20,000 fewer cases of breast cancer each year in the United States.
Since then, the use of hormone therapy has plunged in the U.S. and many other countries, and this has been followed by measurable decreases in breast cancer in several countries and, in the U.S., decreases in heart attack and stroke.
The economic return on investment from that WHI trial alone was substantial, according to Fred Hutch health economist Dr. Joshua Roth, who in 2014 published an analysis of the economic impact of the hormone therapy findings. “The original NIH trial cost was $260 million [in 2012 dollars] and the net economic return was $37.1 billion. That’s a return of approximately $140 on every dollar invested in the trial,” he said. “It really brings the point home when you crunch the numbers. You see that millions of U.S. women likely stopped or never used [combined hormone therapy] and that this change resulted in important reductions in disease incidence and associated medical spending.”
Fred Hutch President and Director Dr. Gary Gilliland nominated the interdisciplinary WHI team for its broad impact on public health, not only through its contributions to understanding the effects of hormone therapy and nutrition on cancer risk and prevention, but also its development of unique national resources that support cancer research, such as a massive database and a biospecimen repository that are available to all researchers.
“The WHI, as a national resource open to collaboration, has been and continues to be an engine for driving cancer research in population and translational science both here and throughout the country,” he said.
Upon accepting the honor, which comes with a $50,000 honorarium, Prentice, who served as principal investigator of the WHI Clinical Coordinating Center from 1992 to 2010 as well as director of the Public Health Sciences Division for 25 years, acknowledged the contributions of the volunteers at the heart of the study. “These women have given generously of their time to participate in a complex protocol, some for more than 20 years,” he said.
The Team Science Award, supported by a grant from Eli Lilly and Company, is given to affect change within the traditional cancer research culture by recognizing those individuals and institutions that value and foster interdisciplinary team science.
This is the second AACR Team Science Award for Fred Hutch; in 2011 a team of researchers led by Dr. Denise Galloway of the Hutch’s Human Biology Division received the honor for their research that was instrumental in the development of the vaccine for cervical cancer and other human papillomavirus-related malignancies.
Dr. Andrew Hsieh of the Human Biology Division on April 16 was awarded a three-year, $450,000 NextGen Grant for Transformative Cancer Research from the American Association for Cancer Research. He accepted the award at the AACR’s annual meeting in New Orleans.
Hsieh focuses his research on a key step in the process that cells use to turn genetic information into protein. Messenger RNA molecules carry information from genes to cells’ protein-producing machinery, which translate this information into proteins. Translation of mRNAs into proteins often goes awry in cancer — but it’s not yet clear how this process goes wrong.
“Without knowing how [this mistranslation happens], we don’t know how to effectively drug that,” he said.
His NextGen Grant will allow Hsieh and his team to study a question central to cancer biology: how, exactly, mistranslation occurs in cancer cells. The grant also gives him the opportunity to work with collaborators from other scientific disciplines, including computational biology and RNA biology, and draw on tissue repositories at Fred Hutch and UW.
“Our lab is not just interested in today’s questions,” he said. “We want to attack questions that will be important in the future.”
Hsieh is a rising leader in the burgeoning field of mRNA translation in cancer. He noted that the AACR’s NextGen Grants for Transformative Cancer Research are designed to help support exploratory, paradigm-shifting research that cannot be funded through existing channels.
“We’re trying to identify and understand how regulatory regions of mRNAs are altered in cancer, and how this regulates mRNA translation,” explained Hsieh, who postulates that if these regions are found to be critical to cancer-promoting mistranslation, they could represent potential therapeutic targets.
“It would be a whole new way to target cancers,” he said.
Sabrina Richards / Fred Hutch News Service
Dr. Matthias Stephan, a researcher in Fred Hutch’s Program in Immunology, has been awarded a four-year Research Scholars Grant from the American Cancer Society to develop gene-containing nanoparticles that reprogram T cells to kill cancers. The $720,000 award was announced mid-April.
“My dream is that we truly will have an off-the-shelf product that outcompetes chemotherapy as a front-line therapy,” said Stephan, who is an assistant member of the Clinical Research Division at the Hutch, with additional appointments in the University of Washington’s Division of Oncology and Department of Bioengineering.
The nanoparticles are made of nontoxic, biodegradable polymers and contain bits of DNA instructions for making a specialized anti-cancer receptor called a chimeric antigen receptor, or CAR. Ongoing clinical trials at Fred Hutch and other institutions are testing CAR T-cell therapies in advanced cancers. In these trials, T cells are extracted from a patient’s blood and then “reprogrammed” with CARs that allow these immune cells to recognize and kill cancer cells. The cells are multiplied many times over and then reinfused into the patient.
Unlike these therapies, however — in which the reprogramming and multiplying steps are done in specialized laboratories, patient by patient — Stephan envisions his nanoparticles being made in large batches in a biotech factory, kept in a clinic’s refrigerator and injected into any patient’s bloodstream as needed.
“I’m trying to really make CAR T-cell therapy the standard of care, also affordable and easy to apply,” he said. “Something that can be done in infusion centers where people get chemotherapy from nurses. These centers are all over the U.S.”
Once in the blood, some of Stephan’s nanoparticles would bind to T cells, which then would take in the DNA instructions. In a few of the T cells, the DNA delivered by the nanoparticle would be integrated into the genome, allowing the cells to begin recognizing nearby cancer cells and killing them. Once activated, these new CAR-T cells would multiply rapidly until the patient had an arsenal. After destroying the patient’s cancer, the cells would remain in the body, ready to fight recurrences.
“We’re creating a spark, reprogramming a couple of cells. And then they amplify inside of the patient,” he explained.
Stephan said that this award, as well as complementary support from the Leukemia & Lymphoma Society, will enable him to lay the groundwork that he hopes will help launch this therapy into the clinic.
“We hope that with this grant we can show this is feasible and establish it as an off-the-shelf reagent that can easily treat large patient populations because you don’t have to customize it,” he said.
In Stephan’s initial tests in preclinical models, his team is studying how the reprogrammed T cells behave and is optimizing nanoparticle dosing. He also aims to study the effects of infusing of a mix of nanoparticles with CARs targeting different tumor markers. Finally, he plans to study nanoparticles containing not only CAR instructions but also a genome-editing agent for inactivating one of the signals that could reduce the reprogrammed T-cells’ activity.
Susan Keown / Fred Hutch News Service
The world’s attention, once riveted on the 2014-2015 Ebola outbreak in Guinea, Liberia and Sierra Leone, has turned to the Zika virus now sweeping the Americas. But public health experts know that Ebola will be back, which is why work on a preventive vaccine has not let up.
Early results from a clinical trial led by researchers at Oxford University in England and including Fred Hutch’s Vaccine and Infectious Disease Division, or VIDD, found not just powerful but durable immune responses from an experimental vaccine developed by Johnson & Johnson, boosted by a second immunization from biotech company Bavarian Nordic A/S. The results of the Phase 1 study were published Tuesday in the Journal of the American Medical Association.
Long-lasting protection is especially important where the Ebola virus is concerned, both for front-line health care workers — the long-running outbreak has killed nearly 500 of the affected countries’ already-scarce health workers — and because the virus has been found to survive in bodily fluids and be transmissible through sexual and other contact months after the patient has recovered.
The two-step vaccine regimen detailed in the JAMA paper is both better tolerated — that is, it showed fewer adverse effects — and generates longer lasting immunity than another experimental Ebola vaccine that was tested and found to be safe and effective during the outbreak. Having fewer side effects is especially valuable in an area where vaccines and other Western interventions may be regarded with suspicion.
During a press call, the paper’s lead author, Dr. Matthew Snape of the Oxford Vaccine Group, praised the speed with which the study was done. It was initiated in October 2014, enrolled the first patient that December and was fully enrolled by early 2015. Eighty-seven healthy volunteers in Oxford were randomly assigned to receive the two vaccines or a placebo; the order and timing of the vaccines varied. Among the randomized participants, 100 percent generated Ebola-specific antibodies after receiving both vaccines and 79-100 percent showed T-cell responses — another of the immune system’s infection fighters — depending on the dosing interval. Responses persisted through the eight months that volunteers were followed.
Fred Hutch’s role in the trial was to generate data on the cellular response to the vaccines. The work was done in the laboratory of Dr. Julie McElrath, VIDD director, principal investigator and director of the Hutch-based HIV Vaccine Trials Network Laboratory Center. Besides McElrath, VIDD researchers Drs. Nicole Frahm, Stephen de Rosa and Kristen Cohen contributed to the paper.
“Essentially, what we’re trying to do is understand, when we give a vaccine to a person, whether that person actually responds to the vaccine,” said Frahm. “We take samples from people who got the vaccine and study them to see if they had a response. We have developed criteria on how we define that for our HIV-vaccine trials. We have to make sure that what we measure is actually relevant and due to the vaccination, and not just a random response to cells being taken out of the body.”
Reflecting the urgency at hand, the lab provided all of the data for the study within nine months of receiving the first samples — a speed made possible because of expertise developed during HIV research.
“I’m very proud that we are able to leverage the knowledge that we’ve learned from HIV to other infectious diseases because we can run the assays in a similar way,” Frahm said.
Although the assays can tell researchers that the vaccine elicited a powerful and durable immune response, only further testing in humans will tell researchers that it’s the right response to protect against Ebola. But further testing of the two-dose vaccine regimen in humans is hampered by the otherwise good news that the outbreak — and thus the likelihood of being exposed — have abated. The two pharmaceutical companies have produced more than 2 million doses in preparation for testing in a future outbreak.
“Hopefully, we will never need it, but if it is a problem, we’ll be ready to step in,” said Dr. Paul Stoffels, Johnson & Johnson’s chief scientific officer, at the press briefing.
The West African outbreak, the largest in history, sickened more than 28,000 people and killed more than 11,000, according to the World Health Organization.
A report released March 31 by the Wellcome Trust and others expressed fear that progress might falter as memories of the West Africa outbreak begin to fade and public attention shifts to Zika and other new health emergencies.
— Mary Engel / Fred Hutch News Service