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Issue 23

Winter 2012

In this Issue:

Ground-Breaking Gene Therapy Study for Fanconi Anemia in Adults Begins

By Paul Courter, Science Writer

The world’s first-ever clinical trial of lentiviral vector gene transfer for adult patients with Fanconi anemia (FA) is now underway at Seattle Cancer Care Alliance.

Patients with this rare inherited disease often develop bone marrow failure along with other serious multi-organ problems. Medications such as androgens (male hormones) and growth factors are used to manage the marrow disorders and many patients also require hematopoietic cell transplantation. Today, more FA patients reach adulthood thanks to the coordinated multidisciplinary care available in specialized centers, but many of them still develop severe aplastic anemia or leukemia.

Allogeneic bone marrow transplantation can be a life-saving option for these patients developing signs of severe FA-related bone marrow failure. However, because the abnormal FA gene prevents DNA repair, FA patients require reduced intensity or radiation-free protocols.

“When we can transplant patients earlier, before they have transfusions or infections, patients with a sibling matched donor do extremely well with these special low-intensity conditioning protocols,” says Hans-Peter Kiem, MD, an FA researcher and gene therapy expert at Fred Hutchinson Cancer Research Center and UW Medicine. “That’s why our new FA gene therapy trial is only for patients with no matched sibling donor.”

For those FA patients who lack an HLA-matched donor, researchers hope the new form of gene correction using a lentiviral vector will be a safe and effective alternative.

Initial efforts to insert a normal gene into a patient’s blood stem cells used a gammaretroviral vector and were unsuccessful. Other gene therapy studies using gammaretroviral vectors produced undesired side effects when the virus vehicle triggered oncogene activation and leukemia.

The lentiviral vector has two main advantages. First, its apparent ability to insert the gene without triggering new problems (like mutations) in the patient’s cells, and second, the shorter period (compared to the gammaretrovirus) needed to insert the gene into the patient’s cultured cells (transduction). This shorter transduction period is important because FA patient blood cells are notoriously fickle in culture.

The study procedure is basically a variation on autologous transplantation. Patients undergo stem cell stimulation (with filgrastim and plerixafor) and leukapheresis. If this mobilization fails, bone marrow is harvested. The cells are cultured with the lentiviral vector overnight. This lentiviral vector contains the corrected FA gene and has been modified with the intent of making the vector safer. The following day the patient’s genetically modified cells are reinfused. Patients do not receive any conditioning regimen such as those used in allogeneic transplantation. Researchers hope that evidence indicating the gene modified cells are working will be observed within a few months of the cell infusion.

Safety will be measured by adverse event monitoring, periodic clinical laboratory testing, and special genetic and cellular analysis of cells. As an extra precaution in this first test of the lentiviral vector in FA patients, the FDA has recommended that only adults (≥18 years of age) be enrolled initially. Kiem says he and his Seattle team hope to expand enrollment soon from adult to pediatric patients.

Although gene therapy may alleviate many of the problems related to anemia in FA patients, all non-blood cells in the body still harbor the faulty FA gene and thus the patient remains prone to cardiovascular, gastrointestinal, orthopedic, and other problems. The support of a full team of specialists in a comprehensive care center will remain critical.

Still, the new trial of lentiviral vector gene transfer for FA brings one new ray of hope to families struggling with this complex multi-organ disease—and it also represents a potential milestone in the march toward safe and effective gene-based therapy for all types of genetic diseases.

For more information about the new Phase I gene therapy study, visit:

It will also be published in the Spring 2012 issue of the SCCA Pediatric BMT Update in print and on the web at

New Genomic Test Links 12 Mutations to Ovarian Cancer Risk

(Excerpt from an Oct. 25, 2011 UW Today article by Leila Gray)

A new and low-cost method for genomic screening has identified mutations in 12 genes that predispose women to cancers of the ovary, fallopian tubes, and peritoneum.

Seattle researchers who developed the test say that more patients with ovarian carcinoma carry cancer-predisposing mutations, and in more genes, than previously thought.

More than one-fifth of ovarian cancers arise in women with a familial predisposition, but relying on family history alone for screening would have missed one-third of the cases, says Elizabeth M. Swisher, MD, senior author of a paper on these findings published in the Proceedings of the National Academy of Sciences.

Swisher is an associate professor of obstetrics and gynecology at the University of Washington. She directs the Breast and Ovarian Cancer Prevention program at Seattle Cancer Care Alliance and the UW School of Medicine, and is an affiliate researcher at Fred Hutchinson Cancer Research Center. The results of her most recent study have implications far beyond those related to ovarian cancer.

The speedy, low-cost method her team developed could soon be applied to genome testing for a broad range of breast, colon, pancreatic, and melanoma gene mutations. A single test might even be able to screen a patient for susceptibility to all these cancers.

Also, because the new method lends itself to simultaneous analysis of great numbers of specimens, it could lead to large-scale population screening for cancer-causing mutations. Such screenings would predict who is at risk for certain cancers and allow clinicians to target prevention efforts more effectively.

The BROCA sequencing method employed by Swisher and colleagues was named after Paul Broca, a 19th century medical scientist who was among the first to describe inherited breast and ovarian cancer. The method is highly sensitive and can find all classes of genetic mutations, including single substitutions, small insertions and deletions, and large rearrangements of genes. According to the Seattle researchers, the BROCA test is not patented and designs for its use in genetic studies are freely available.

Swisher and her team concentrated on ovarian cancer in their recent study because it is one of the most deadly of all malignancies as it typically begins quietly, presents with symptoms that mimic those of various benign conditions, and has thus become widespread once it is finally diagnosed.

“Most women are not diagnosed until the cancer has advanced to the point where the chances of a cure are small,” Swisher says. “Women with early stage ovarian cancer have a better survival rate than those diagnosed with late stages, but current methods of detection are not effective.”

And this is precisely why Swisher and her research team are looking for a more complete genetic picture of ovarian and related cancers. Finding the group of genetic mutations most often associated with these cancers, and developing a simple test to detect these mutations, could lead to earlier identification of the women most prone to malignancies.

Microsphere-Based Internal Radiation Treatment Study for Patients with Non-Resectable Colorectal Cancer Metastases to the Liver

Seattle Cancer Care Alliance is conducting a study for untreated colon cancer patients who have non-resectable metastases to the liver. In the treatment arm of the SIRFLOX trial, a single dose of irradiated microspheres is administered directly into an artery that supplies the liver metastases; patients also receive systemic (IV) chemotherapy.

The SIR-Spheres® technology links a beta-particle radiation source (yttrium-90) to a small resin microsphere that measures just 20 to 40 micrometers in diameter. In the trial, patients first undergo preparatory studies to ensure safety and guide delivery. Next, a UW Medicine interventional radiologist infuses about 50 million spheres into the tumor-feeding hepatic artery.

The spheres “follow the blood flow to the tumor(s) and do two things,” explains Samuel H. Whiting, MD, PhD, medical oncologist at SCCA. “They deliver lethal doses of radiation to the tumors from the inside while mostly sparing healthy liver tissue (the radiation penetrates no more than 1.1 cm) and they also compromise blood flow to the cancer by clogging the arteries.” The radiation within the spheres has a half-life of two days and is gone from the body in about 10 days. The microspheres (provided by Sirtex Medical) are not metabolized or excreted and remain in the liver permanently.

“T here have been a large number of patients treated worldwide with yttrium-90 microsphere therapy, and the cumulative data suggest a treatment-related improvement in tumor response, disease control, and survival duration,” says Whiting. “But much of the efficacy data come in the form of small trials and retrospective reports of patient outcomes. This trial is looking to rigorously test the treatment in a large randomized trial. Additionally, we are looking carefully at the option of combining microsphere radioembolization of liver metastases with the best available systemic chemotherapy in order to provide the best of both worlds to patients.”

In the SIRFLOX trial, Whiting and his colleagues will determine if newly diagnosed patients with stage IV colorectal cancer that is predominantly in the liver and is non-resectable will benefit from the combination of microsphere radioembolization plus best available first-line chemotherapy (oxaliplatin + leucovorin + 5- fluorouracil [FOLFOX] with or without bevacizumab [Avastin] versus receiving the same chemotherapy given alone. “The growth of cancer in the liver is probably the most dangerous-to-survival event that a stage IV colorectal cancer patient can experience,” says Whiting. “This trial tests whether treating the cancer in the liver more aggressively and more effectively than chemotherapy alone will provide patients with improved survival.”

This randomized trial opened at SCCA in December 2011. For more information about the study, visit:

SCCA Spotlight: Michael S. Mulligan, MD — National Leader in Cardiothoracic Surgery

When Michael Mulligan, MD went off to medical school at the University of Connecticut he was on a path to becoming a general practitioner. But his natural inclinations and abundant energy soon focused on surgery. Recognizing his skill and enthusiasm, his professors and mentors eventually steered him toward a specialty in thoracic surgery.

“You have to be passionate about what you do,” Mulligan says. “You can be good at it, but if you aren’t passionate about it, you can’t bring the same level of care to your patients.”

After completing a general surgery residency at Columbia-Presbyterian Medical Center in New York City and receiving advanced surgical training at the University of Michigan Medical Center, Mulligan soon became a leader in cardiothoracic surgery. He has now performed hundreds of lung transplants and thousands of other thoracic surgeries at University of Washington Medical Center, an SCCA founding organization.

He is the director of Minimally Invasive Thoracic Surgery and regularly performs and teaches video-assisted thoracic surgery (VATS), a much less invasive technique than traditional open-chest surgery. VATS anatomic lung resections are available only at about 30 centers in the country, including UW Medical Center.

Mulligan is a full professor in cardiothoracic surgery at the University of Washington. He has earned numerous teaching and research awards, belongs to a variety of professional associations for thoracic surgeons, and is among the youngest members ever elected to the American Surgical Association.

More on Michael Mulligan, MD can be found at

Upcoming CME Events

2nd Annual Pacific Northwest Head, Neck & Thyroid Cancer Symposium
April 6, 2012 at the Orin Smith Auditorium, UW Medicine South Lake Union campus, Seattle

Bringing up-to-date information to clinicians who care for patients with head, neck, and thyroid cancer, a multidisciplinary panel of experts will discuss clinical innovations in a variety of treatment areas pertinent to head, neck, and thyroid cancers. Topics will include minimally invasive laser and robotic surgery, management of side effects of current chemoradiation protocols, innovations in radiation delivery, and new paradigms in the understanding and management of thyroid cancers. Participants will be able to apply the newly acquired knowledge, techniques, and protocols to maximize benefits for their head, neck, and thyroid cancer patients.

For more information visit:

Adult Bone Marrow Transplant News

The SCCA Adult Bone Marrow Transplant News is a publication presenting the latest information on bone marrow transplant research at SCCA, providing up-to-date information for all health care professionals caring for transplant patients.

Pediatric Bone Marrow Transplant News

Read about important outcomes research at the Fred Hutch that may benefit your patients.

Clinical Trials Monthly

Each issue of Clinical Trials Monthly highlights several of the more than 200 clinical trials that are currently recruiting patients at SCCA.

The Leading Edge Newsletter

Each quarterly Leading Edge newsletter will highlight a new topic to give you the latest news on leading-edge therapies that SCCA physicians are offering.