Mielcarek study may change the practice of blood stem-cell transplantation

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Dr. Marco Mielcarek
Dr. Marco Mielcarek Photo by Robert Hood / Fred Hutch News Service

New study led by Dr. Marco Mielcarek may change the practice of blood stem-cell transplantation

New findings from a study led by Dr. Marco Mielcarek and colleagues in the Clinical Research Division at Fred Hutchinson Cancer Research Center offer new hope for reducing the risk of graft-vs.-host disease, or GVHD, in patients who receive transplants of matched related and unrelated donor blood stem cells for leukemia and other high-risk blood cancers.

GVHD occurs when newly transplanted donor cells attack the organs of the transplant recipient, regarding them as foreign. It affects up to 80 percent of patients who receive donor stem cell transplants. Symptoms, including skin rashes, nausea, diarrhea, weight loss and liver problems, among others, may develop within a few months after transplant (known as acute GVHD) or much later, and symptoms sometimes last up to a lifetime (known as chronic GVHD), which can significantly reduce quality of life.

The study found that treating patients with an immune-suppressing drug called cyclophosphamide three and four days after transplantation, followed by another immunosuppressive drug called cyclosporine on day five, reduced the relative risk of chronic GVHD by more than half: from the expected 35 percent to 16 percent.

The researchers also found that this post-transplant treatment reduced the risk of severe acute GVHD from the expected 10 to 15 percent to zero. 

The regimen used in the Hutch study had been adapted to blood stem cell transplantation from a regimen that had been introduced by researchers at Johns Hopkins University and had been shown to reduce chronic GVHD after bone marrow transplantation. The current study showed that the regimen was well-tolerated and the risk of death related to the procedure was relatively low. In addition, there was no indication that the immunosuppressive drugs compromised other important transplantation outcomes, such as the likelihood of blood cancer recurring after transplant and the risk of infection.

Published online ahead of print in the journal Blood, these findings “may change the practice of blood stem-cell transplantation,” said Mielcarek, medical director of the Adult Blood and Marrow Transplant Program at Fred Hutch’s treatment arm, Seattle Cancer Care Alliance.

The study, which was partially funded by the National Institutes of Health, involved 43 patients who received a type of transplant that used “mobilized” donor stem cells, which are harvested from blood instead of bone marrow. This kind of stem cell collection is popular among transplant physicians, Mielcarek said, since it is less invasive than bone marrow harvesting, which requires general anesthesia. A blood stem-cell harvest can be done in a few hours on an outpatient basis. In addition, compared to bone marrow grafts, blood stem cells lead to faster recovery of blood counts after transplant, which reduces the risks of infection and bleeding.

“Although the risk of chronic GVHD after marrow transplantation is significantly lower than that after blood stem cell transplantation, most institutions prefer to use mobilized blood cell grafts because the cells are easier to harvest and they engraft faster,” said Mielcarek, the paper’s lead author.

Mobilized blood stem cells are used in about 80 percent of transplants and about 35 percent of patients who receive this product develop chronic GVHD, Mielcarek said. “Our finding that post-transplant cyclophosphamide reduced the relative risk of chronic GVHD in this setting by at least 50 percent is therefore of great relevance for our transplant patients.

“If these findings are confirmed in future studies, mobilized blood cell transplantation may gain even greater acceptance and further replace marrow as a source of stem cells for most transplants,” he continued.

Co-authors on the paper were Fred Hutch clinical research nurse Terry Furlong and clinical researchers Drs. Paul O’Donnell, Barry Storer, Jeannine McCune, Rainer Storb, Paul Carpenter, Mary Flowers, Frederick Appelbaum and Paul Martin.

— By Kristen Woodward / Fred Hutch News Service

Drs. Marie Bleakley and Soheil Meshinchi
Drs. Marie Bleakley and Soheil Meshinchi Photos by Bo Jungmayer / Fred Hutch News Service

Drs. Marie Bleakley and Soheil Meshinchi receive $1M to design targeted immunotherapies for childhood leukemia

Today, Fred Hutch clinical researchers Drs. Soheil Meshinchi and Marie Bleakley were granted $1 million from Hyundai Hope on Wheels to develop new targeted immunotherapies to treat acute myeloid leukemia in children.

The researchers aim to identify leukemia-specific proteins and engineer T cells — disease-fighting cells of the immune system — with receptors that recognize these unique, tumor-specific protein markers. At the end of the four-year grant, they plan to launch a nationwide clinical trial in children with AML to test whether these engineered T cells can effectively destroy the patients’ cancer with minimal side effects.

“We aim to identify and target unique, leukemia-specific proteins, proteins that do not exist in nature. And by doing so, we’ll be able to target leukemic cells only and spare normal cells in order to minimize toxicity,” said Meshinchi, a member of Fred Hutch’s Clinical Research Division and a professor of pediatrics at the University of Washington.

Meshinchi co-leads the project with Bleakley, an assistant member of the Hutch’s Clinical Research Division and an assistant professor of pediatrics at UW.

“This is an exciting opportunity to leverage brand-new knowledge of the proteins that are unique to AML, employ high-throughput techniques to identify the rare T cells capable of recognizing fragments of these proteins and killing the leukemia, and use these discoveries to build novel therapies for patients who desperately need better treatment options,” Bleakley said.

This research builds on data recently generated by Meshinchi and nationwide collaborators in a five-year genomic sequencing project known as the TARGET AML Initiative. Funded by the National Cancer Institute, this project — the largest genetic sequencing undertaking ever in childhood AML — identified hundreds of tumor-specific variants in patients with this cancer.

This new project would not have been possible without the collaborative environment at Fred Hutch that made it possible to merge newly discovered genomic data with cutting-edge immunological engineering in the Bleakley Lab, Meshinchi said.

The research team will use the TARGET AML data to identify cancer-specific proteins and validate these proteins as immune-system targets. Led by Bleakley, the research team will engineer T-cell receptors that allow T cells to kill cancer cells bearing these markers. In the final stages of this project, the team expects to carry out preclinical tests of several T-cell receptors targeting the five most-promising leukemia markers, winnowed down from the more than 300 candidate markers they expect to validate in the first steps of the project.

In preparation for a future clinical trial of their T-cell therapy, the scientists have already initiated discussions with the Children’s Oncology Group, a nationwide cooperative group that conducts clinical trials of new cancer therapies for children. Dr. E. Anders Kolb, chair of the cooperative group’s myeloid disease committee and director of the Nemours Center for Cancer and Blood Disorders in Wilmington, Delaware, is a co-investigator on this project who will help to translate these laboratory findings into national clinical trials.

Hyundai Hope on Wheels is a nonprofit organization supported by Hyundai Motor America and U.S. Hyundai dealers that funds pediatric cancer research around the country. According to the organization’s website, it has funded more than $100 million in pediatric cancer research in the less than two decades since its inception. The nonprofit is a critical partner in advancing pediatric cancer research, Meshinchi said.

“The funding environment for research in pediatric cancer is extremely poor,” he said. “Hyundai Hope on Wheels and similar grants are critical in advancing pediatric cancer research.”

— By Susan Keown / Fred Hutch News Service

Dr. Sunil Hingorani
Dr. Sunil Hingorani Fred Hutch file

Pancreatic cancer treatment advancing in clinical trials

Results from an early-phase study in pancreatic cancer show that an enzyme called PEGPH20 is safe when used in combination with chemotherapy to attack tumors. The enzyme is designed to lower the extraordinarily high pressure within many pancreatic cancers, allowing chemotherapy to penetrate to attack tumor cells.

“We learned first that we could administer this drug safely with chemotherapy,” said Dr. Sunil Hingorani of Fred Hutch’s Clinical Research Division, the study’s principal investigator. The Phase 1 study results also suggest that PEGPH20 “is behaving in patients as predicted in mouse models and that the inability to get chemotherapy into the tumor may be a primary mechanism of disease resistance,” he said.

Randomized Phase 2 studies of the new combination treatment are nearing completion, and an international Phase 3 trial will begin within the next few months, Hingorani said. Although all of the study sites have not yet been finalized, the trial will be available at Seattle Cancer Care Alliance, Fred Hutch’s patient-care arm. Pancreatic cancer patients elsewhere who may be interested in participating in the upcoming phase 3 trial should contact trial sponsor Halozyme Therapeutics, he said, or talk to their oncologist about the availability of the trial in their area.

The Phase 1b trial enrolled 28 patients with untreated stage 4 metastatic pancreatic cancer. Its results, published last week in Clinical Cancer Research, “further substantiate that this strategy should be pursued” in further trials, Hingorani said. The study also provided some insights into additional measures of enzyme activity in tumors that the team is considering incorporating into the new trial, he said.

Halozyme’s PEGPH20 program in pancreatic cancer was granted fast-track status by the U.S. Food and Drug Administration in 2014 to speed the development and review of the drug for this malignancy, which is notoriously difficult to treat. Since then, clinical trials have proceeded swiftly.

“The train’s moving very rapidly, and in many respects, more rapidly than I would have anticipated,” Hingorani said.

PEGPH20 is a version of a naturally occurring enzyme called hyaluronidase. Hyaluronidase breaks down a substance called hyaluronic acid, or HA, which absorbs the shock of everyday activity in the knees and other joints. But some tumors, including many pancreatic cancers, produce it in high amounts, and high HA correlates with a poor prognosis. The water-loving HA inside tumors draws in and binds the moisture from surrounding tissues, which results in such high pressures that blood carrying anticancer drugs cannot readily get in.

— By Susan Keown / Fred Hutch News Service

Dr. Joshua Schiffer
Dr. Joshua Schiffer Fred Hutch file

Novel mathematical model could transform dosage selection for clinical trials

Fred Hutch researchers have developed a new mathematical model that factors in the body’s immune system to more accurately simulate clinical trial conditions and help researchers select the optimal dosing regimen to test in the final phase of a clinical trial.

In a study published Feb. 3 in the journal Science Translational Medicine, the researchers reported that the model successfully predicted the results in a trial of the drug pritelivir to treat herpes simplex virus-2, or genital herpes. The model may have applications for testing drugs against other infectious diseases as well as some cancers, said Dr. Joshua Schiffer, an assistant member of Fred Hutch’s Vaccine and Infectious Disease and Clinical Research divisions and the study’s lead author.

“I believe that this technique can be used to help develop the best dosing strategy for different infections,” Schiffer said in an interview. “Potentially, it could have relevance for cancers, particularly liquid tumors. A handful of cancers are now being monitored with molecular methods similar to viral loads to infections.”

The technique could also be applicable to CAR-T-cell therapy and therapeutic vaccination, Schiffer said.

The new model was developed to address a lack of precision in choosing dosage levels to test in large, time-consuming, and expensive Phase 3 trials, saving the money and time that would be wasted in testing less than optimal doses.

The federal Food and Drug Administration now requires scientists conducting clinical trials that seek to license a drug to use two types of modeling: pharmacokinetics, which models the way drug concentration changes over time in the body, and pharmacodynamics, which models the drug’s effect on the target, in this case HSV-2. The new model combines these two approaches with a third type of model, which characterizes the immune system’s response to the virus.

Other models have captured complex viral immune interactions but have not synthesized the three approaches into a working model.

“When you do that, you can more accurately simulate clinical trial conditions,” Schiffer said.

For HSV-2, the model successfully predicted the dosage of pritelivir that would be needed to suppress shedding — the period in which the virus is contagious — in a majority of patients. It also identified a more general requirement of any drug against HSV-2 or other rapidly replicating viruses:  The drug would need to have a long half-life to fully suppress shedding because even a three- to four-hour window allows enough time for transmission.

Schiffer cautioned that the model doesn’t replace Phase 3 trials. However, helping select the optimal dosage to test, it can make them more efficient.

“Phase 3 randomized controlled clinical trials are the gold standard for proving therapeutic efficacy but are expensive and labor intensive. Accurate dose selection is crucial,” the authors concluded.

Other authors on the paper included Drs. David A. Swan, Amalia Margaret, Larry Corey, and Anna Wald from Fred Hutch, as well as researchers from AiCuris, a pharmaceutical company in Wuppertal, Germany; the Institute for Clinical Pharmacodynamics in Latham, New York; and the School of Pharmaceutical Sciences, University at Buffalo, The State University of New York. 

The National Institutes of Health, the National Institute of Allergy and Infectious Diseases and AiCuris provided funding for the study.

— By Mary Engel / Fred Hutch News Service


Today, World Cancer Day, marks the launch of Breast Cancer Initiative 2.5, a Seattle-based global campaign to reduce disparities in breast cancer.

New global initiative for breast cancer has roots in Seattle

Today, World Cancer Day, marks the launch of a new global campaign to reduce disparities in breast cancer outcomes for 2.5 million women by 2025. Called Breast Cancer Initiative 2.5 (BCI2.5), the campaign is spearheaded by two internationally renowned, Seattle-based breast cancer physicians: Drs. Julie R. Gralow and Benjamin O. Anderson, both faculty members at Fred Hutch and the University of Washington who treat patients at Seattle Cancer Care Alliance.

BCI2.5 today launched its website, www.bci25.org, which will serve as a platform and resource for policy makers, clinicians and health advocates from across the world.

Breast cancer is the most prevalent cancer in women worldwide. Estimates suggest 5.8 million women will die from breast cancer by 2025, with a disproportionate number of these deaths occurring in low-resource settings around the world. Not only is BCI2.5 engaging partners from around the world to make breast cancer a global priority, the campaign is also leveraging expertise from Fred Hutch, SCCA, UW and other Seattle global health organizations to act as the global coalition’s administrator, or secretariat.

“The world needs a roadmap to success to improve breast cancer outcomes. It’s complicated but doable. BCI2.5 can provide that framework to help ensure the right decisions are made in the right place,” said Anderson, co-chair of the BC12.5 secretariat. Anderson is also a member of the Fred Hutch Public Health Sciences Division, director of the Hutch-based Breast Health Global Initiative and a professor of surgery and global health at UW School of Medicine.

“We have clear strategies for prevention, detection and treatment of cervical cancer,” said Gralow, SCCA’s director of breast medical oncology and BCI2.5 secretariat co-chair. “We can expect to see reductions in the burden of disease, but we lack the same clarity for breast cancer. It is clear that breast cancer is poised to become an increasing problem for women in low- and middle-resource countries. We need metrics, models and strategies to help ministries of health decide how to address breast cancer.” Gralow is also the Jill Bennett Endowed Professor of Breast Cancer and a professor of global health at UW School of Medicine and is a member of Fred Hutch’s Clinical Research Division

The initiative began as a call for action in 2014, supported by the American Cancer Society, Susan G. Komen and the Union for International Cancer Control. Since that initial pledge, BCI2.5 has been engaging partners around the world, assessing need, identifying priorities and defining a strategy to meet this goal. Its consensus-based approach empowers regional champions to bring about change with the aid of BCI2.5 analytic, assessment and planning tools, educational materials and implementation science research methodology.

— Adapted from a Seattle Cancer Care Alliance news release

Dr. Colin Correnti
Dr. Colin Correnti Fred Hutch file

Dr. Colin Correnti speaks at inaugural SHIFT 2016 

Dr. Colin Correnti, director of Protein Sciences in the Olson Lab at Fred Hutch, was one of three featured speakers on Jan. 19 at the inaugural SHIFT 2016, a student-run scientific research symposium held at the University of North Texas Health Science Center in Fort Worth.

The symposium, hosted by the university’s Medical Sciences Community Service Organization, focused on exploring new paradigms in the development of cancer therapies.

Dr. Correnti talked about developing new, targeted cancer therapies and how the Olson Lab’s work in developing Tumor Paint for imaging cancers has introduced a novel and inspiring approach to funding translational cancer research. Click here for a short film about Tumor Paint called “Bringing Light.”

Other cancer experts who spoke at the free community event were Dr. Eugenie Kleinerman of MD Anderson Cancer Center, who spoke about new therapeutic strategies for altering cancer microenvironments; and Dr. Christopher Jordan of the University of North Texas Health Science Center, who talked about the economics of treating cancer.

— By Kristen Woodward / Fred Hutch News Service

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