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Fall 2013

This issue includes articles about progress on two fronts in treating the most challenging pediatric malignancies:

Taking Aim at Deadliest Childhood Cancers

Mortality rates for many childhood cancers have declined by more than 50 percent over the past three decades.

But this overall positive trend can’t hide the stubbornly high mortality rates still seen in certain pediatric malignancies. Much of our highest-powered pediatric research in bone marrow transplantation (BMT), genomics, and immunotherapy is now aimed at these lethal cancers.

This issue of Pediatric Bone Marrow Transplant Update, includes articles about progress on two fronts in treating the most challenging pediatric malignancies:

First, a new Seattle Cancer Care Alliance (SCCA) clinical trial is testing a long-sought form of immunotherapy: T-cell engineering for relapsed acute lymphocytic leukemia (ALL) where survival is typically less than 40 percent. Based on the research of Michael Jensen, MD, director of the Ben Towne Center for Childhood Cancer at Seattle Children’s Research Institute and professor of hematology-oncology at the University of Washington School of Medicine (UW), this new form of adoptive immunotherapy aims to reprogram the child’s own T cells to destroy the leukemia cells before the child goes on to have a transplant.

Seattle researchers have been carefully developing these methods of T-cell therapy for more than two decades, and their techniques are finally ready for clinical testing. The long-term potential for this new therapy is tremendous for pre-transplant pediatric ALL as well as patients of all ages with all types of cancer. But first it must be tested. The newly initiated Phase I trial led by Rebecca Gardner, MD, acting assistant professor in the department of pediatrics at UW, and Dr. Jensen will determine the appropriate dose of these modified T cells. Another trial for children who relapse after transplant will open later this year.

Our other update involves neuroblastoma and a new form of targeted radiation now available at Seattle Children’s Hospital, an SCCA founding institution. As described by Julie Park, MD, UW professor of pediatrics, researchers have identified several new genetic indicators of risk for neuroblastoma, and these markers may soon point the way to more targeted therapy. Until these new therapies become available, high-intensity chemotherapy and autologous BMT remain the standard of care.

Also newly available through SCCA and Seattle Children’s Hospital is targeted radiation with I-131-MIBG (metaiodobenzylguanidine) for neuroblastoma patients with relapsed or refractory disease. Park is the chair of the Neuroblastoma Scientific Committee of Children’s Oncology Group, where she is leading the development of studies with even wider applications for MIBG.

“Today at SCCA and Seattle Children’s, we are dedicated to improving options for children with the most unfavorable outcomes,” said K. Scott Baker, MD, MS, director of pediatric blood and marrow transplantation and survivorship programs at SCCA and Seattle Children’s. “I encourage referring physicians to learn more about these high-priority research protocols and consider referring appropriate patients for these novel therapies. Participation in research has clearly helped improve survival rates over the past 30 years. Further progress is ahead—and your continued participation will hasten these improvements.”

For questions about new treatments at SCCA and Seattle Children’s, or to discuss the management of patients with relapsed ALL or high-risk neuroblastoma, contact Dr. K. Scott Baker at

Fighting Leukemia with Engineered T Cells

After more than two decades of dogged immunological research, researchers at SCCA have optimized the strategies and techniques for reprogramming a patient’s own T cells to hunt down and eliminate cancer cells.

Late in 2012, SCCA received approval from the U.S. Food and Drug Administration (FDA) to begin human testing in adults. And in June 2013, a young man with relapsed high-risk ALL became the first patient to enroll in the initial trial of this novel immunotherapy at Seattle Children’s.

The new pediatric study will eventually enroll, treat, and monitor about 20 patients who have B-cell leukemias and who have developed resistance to chemotherapy. Another adoptive immunotherapy study scheduled to start in fall 2013 will treat children with ALL who have relapsed after BMT.

Engineered T Cells: Hard-Wired to Find and Kill Leukemia Cells

Clinician-researchers and others at SCCA have been working toward the goal of targeted T-cell therapy for more than 20 years. To reach this milestone clinical trial, Michael Jensen, MD, pediatric cancer researcher at Seattle Children’s, partnered with several SCCA researchers including Stanley R. Riddell, MD, professor of medical oncology at UW; Cameron Turtle, MD, acting instructor at UW, and Philip Greenberg, MD, researcher at Fred Hutchinson Cancer Research Center.

Figuring out how to retrain T cells to fight malignant B cells was no easy task. Most previous victories with cancer immunotherapy to date—cytokines, monoclonal antibodies, cancer vaccines—have been partial at best. That’s why early hints of clinical efficacy here and at a few other U.S. research centers have spawned so much excitement about engineered T cells.

One breakthrough for researchers was the newfound ability to arm T cells with a chimeric antigen receptor (CAR)—half monoclonal antibody and half T-cell receptor. For ALL, the extracellular tip of this receptor is a portion of a monoclonal antibody specific for CD19, a molecule expressed exclusively on B cells (both malignant and normal). This antibody fragment is fused to a cluster of normal T-cell receptor signaling components, which remain positioned inside the cell.

Combining these two immune features into one membrane-spanning receptor removes the requirement for human leukocyte antigen (HLA ) while still triggering the killing of tumor cells. Normally, the HLA molecule must present the tumor antigen before triggering cytotoxicity.

“Recognition and signaling is based only on the surface tumor antigen,” Riddell said. “The patient’s HLA allele doesn’t matter.” This absence of major histocompatibility complex (MHC) restriction makes it easier to use a single pre-engineered receptor to target tumor cells in a variety of patients displaying a diversity of MHC patterns.

“We are coupling the exquisite specificity of the antibody to the potent effector function of the T cell,” Riddell said. “We target the tumor with the antibody and kill it with the T cell. Moreover, since this is a living therapy, the engineered cells can grow in the patient until the tumor is eradicated.”

High-Risk Relapsed Patients Need New Options

“Less than 40 percent of patients with relapsed ALL typically survive,” said Rebecca Gardner, MD, acting assistant professor in the department of pediatrics at UW who leads the new pediatric trial.

She explains that residual leukemia is unlikely to respond to further chemotherapy, and children who have relapsed soon after their initial diagnosis or multiple times after repeated chemotherapy have especially low chances of long-term cure. Unfortunately, the presence of residual disease also reduces the chance of success with a BMT— often the main hope for cure. That’s why new options are urgently required.

“In many cases, if these patients who have relapsed after first-line chemotherapy don’t get a transplant, their cancer will almost certainly come back,” Gardner says. “But outcomes after transplant are much improved if you don’t have any detectable disease going into the transplant. Our hope with this trial is to offer relapsed patients something new to induce remission and ultimately improve their chance of a life-long remission.”

Wiping the slate clean of leukemia with T-cell therapy will allow many more of these children to go on to receive a successful transplant. That’s the ultimate goal of the new therapy.

How Patients in the Trial will be Treated

After the patient enrolls in the trial, a blood sample is drawn and T cells are purified. The smaller volume of blood in children can make this step challenging. Also, a history of intensive chemotherapy may further limit the number of viable T cells available. On the other hand, chemotherapy may actually enrich the T cell central memory subsets, which are ideal for generating longer-lasting cells.

Assuming an adequate blood draw, the purified T cells are then reprogrammed with recombinant DNA techniques to recognize CD19, which is expressed on over 90 percent of pre B-cell ALL in children. The gene encoding the CAR is inserted with a unique lentiviral vector that was constructed by researchers at the Hutchinson Center.

The transduced cells are nurtured with cytokines. They grow for about three weeks in a special laboratory—an FDA-certified Therapeutic Cell Production Core, located at Seattle Children’s Research Institute—until billions of the CAR-studded T cells are available. After returning to Seattle Children’s for two days of cyclophosphamide treatment for lymphodepletion, the child receives an infusion of the reprogrammed cells.

“The chimeric receptors recognize CD19 on the leukemia cells,” Gardner said. “Once the T cell binds to the leukemia cell, it kills it.”

Since the patient’s noncancerous, functioning B cells also express CD19, they are also eliminated. Thus, the patient also must receive treatment with intravenous immunoglobulin (IVIG) as protection against infections.

The patients are monitored closely for six weeks with serial blood tests and bone marrow aspirates. Then they are returned to the care of their primary oncologist with annual checks for 15 years. As appropriate, they will receive additional chemotherapy or a BMT.

Measuring Safety and Demonstrating T Cell Viability

The main purpose of the clinical trial is to determine the safety of the new therapy and the dose that can be tolerated. Based on previous studies with T cells, a short period of side effects related to revved-up immune reactions is expected.

“This is called a cytokine storm,” Gardner said. “It makes sense since we are redirecting part of the immune system to recognize cancer cells. Some patients have a one- to three-week period of being sick with fevers and possibly needing hospitalization for supportive care. Once the cytokine storm is over we don’t know of any long-term side effects. Obviously that’s why we will follow these patients for a long time.”

After treatment, researchers also monitor the patient’s burden of leukemia and the persistence of the engineered T cells in the blood. To gauge T cell viability, researchers measure a cell surface protein marker, a truncated version of the epidermal growth factor receptor (EGFR) that was added along with the CAR during the genetic reengineering of the T cell. The EGFR acts as a tracer and offers a potential way to “recall” the engineered T cells.

“If the patient is having severe side effects attributableto the engineered T cells, we want to have an effective strategy to selectively eliminate them,” Gardner said. “Because of the EGFR tag, we can give the patient an antibody to EGFR (cetuximab, Erbitux®). It’s very well tolerated and our preclinical testing shows it should allow us to eliminate all of the T cells we have engineered.”

The EGFR tag might also prove useful in the upcoming ALL clinical trial with children who have relapsed after a BMT.

“For the post-transplant trial, we will purify the engineered donor T cells before infusion so only donor cells containing the EGFR tag will be infused,” Gardner said. “Most post-transplant patients are already tolerized to their donor T cells, so they likely won’t have graft-versus-host disease (GVHD). But, if the patient does develop severe GVHD,we can use Erbitux to get rid of all their reprogrammedT cells.”

A Potential Turning Point in Cancer Treatment

While other research groups have also reported preliminary success with reengineered T cells in ALL trials, SCCA/Seattle Children’s researchers have now developed a sophisticated tool kit of reprogramming, manufacturing, and monitoring methods that have the potential for superior antitumor activity and enhanced safety.

These powerful new approaches to immunotherapy could be a game-changer in cancer treatment. Initially, as in the pediatric trial described here, the therapies will be carefully tested in patients with very specific forms of high-risk leukemia or lymphoma either before or after BMT. Eventually, if early tests go as expected, a growing array of T cell treatments may be created for other patients, including those with lower risk disease or patients with other types of hematological or solid cancers.

“In some cases, we may be able to cure cancer with side effects no worse than having a cold for a couple days,” said Michael Jensen, MD, director of the Ben Towne Center for Childhood Cancer at Seattle Children’s Research Institute and professor of hematology-oncology at UW. “Our ultimate goal is to reprogram a child’s immune defense system to attack and kill cancer cells without chemotherapy or radiation—or their debilitating side effects.”

Whether deployed in conjunction with BMT or used asa stand-alone cancer therapy, genetically modified T cells are clearly a very promising treatment for patients who have few other options.

The clinical trials now underway at SCCA/Seattle Children’s will define the safety and efficacy of these immunotherapies — and possibly set a course for a whole new direction in cancer therapy.

Overview of Cancer Immunotherapy with Engineered T Cells

(1) Peripheral Blood T Cells or T-Cell Subsets
(2) Gene transfer to introduce a chimeric antigen receptor
(3) Administration of CAR T Cells to the patient

In T-cell immunotherapy, a patient’s own T cells are purified, reprogrammed with recombinant DNA, and grown in a special laboratory. The reprogramming instructs the T cells to make a chimeric antigen receptor that recognizes a tumor-specific protein. When the engineered cells are infused back into the patient, they hunt down and eradicate the cancer cells and remain in the bloodstream as memory cells to provide long-term protection.

Seattle Children's Leukemia Cancer Trial with Engineered T Cells

Phase I Study Design

  • Treatment with genetically modified autologous T cells directed against CD19
  • For patients with relapsed ALL
  • Open label, interventional, single group
  • Primary outcomes: safety, maximum tolerated dose
  • Secondary outcomes: Anti-leukemic activity; persistence of engineered T cells

Key Enrollment Criteria

  • Young adults or children with relapsed B-cell ALL
    • First six patients will be 18 to 26 years of age (typically higher risk)
    • Additionally, at least a dozen patients, age one to 26 years
  • Patients with poor prognosis
    • Two or more relapses after chemotherapy
    • First marrow relapse with minimal residual disease
  • CD19-positive leukemia cells

For more information, visit:

New Targeted Radiation for High-Risk Neuroblastoma

Neuroblastoma is a strikingly heterogeneous tumor. Many infants with low- and intermediate-risk forms of the cancer have a good prognosis; the five-year survival rate is about 90 percent and many patients have spontaneous regression of localized tumors. But about half of patients have high-risk neuroblastoma, which tends to be rapidly progressive and resistant to therapy.

Every year, about a dozen patients with neuroblastoma come to Seattle Children’s and SCCA to receive treatment. About half of these receive an autologous transplant as part of their therapy.

Over the past two decades, outcomes for patients with the worst forms of this rare cancer of the sympathetic nervous system have steadily improved. A new type of targeted radiation treatment now available at Seattle Children’s—the first facility in the Pacific Northwest to offer it—may provide the next advance in neuroblastoma therapy.

In this update, we discuss evolving neuroblastoma management strategies and the potential therapeutic role of metaiodobenzylguanidine (MIBG) radiolabeled with iodine-131.

Identifying High-Risk Patients is the First Step

According to Julie R. Park, MD, professor of pediatrics at UW who oversees the neuroblastoma program, international pediatric oncology researchers have made great strides in identifying patients with the high-risk form of this disease. Being older than 18 months of age and having tumors that have already spread at the time of diagnosis are still the red flags of elevated risk. But in recent years, a variety of genetic, epigenetic, and molecular biomarkers have been linked with poor prognosis.

This improved up-front risk stratification is important because it allows for risk-adjusted therapy: markedly reduced therapy for the half of patients with lower-risk neuroblastoma and earlier and more aggressive therapies for those patients with high-risk disease.

Today’s most aggressive approaches for high-risk neuroblastoma typically involve a sequence of chemotherapy followed by surgery, high-dose chemotherapy, and autologous stem cell transplantation. This final step of myeloablative therapy, now standard for most high-risk patients, is thought to be necessary to overcome the strong resistance of the tumor cells to chemotherapy. Additional therapies include local radiation, administration of biologic agents such as 13-cis-retinoic acid, and use of immunotherapy targeting the tumor.

“Randomized international trials have shown that autologous transplantation reduces the risk of relapse and increases survival,” Park said. “That was a big gain. And more recently Seattle Children’s was part of a national trial showing that immunotherapy after transplant further improves the outcome.”

“Overall, we’ve gone from only about a third of these patients with high-risk neuroblastoma surviving, to about half of them surviving,” Park said. “So, we’ve made advances, but it’s not enough. Now we need better therapies that target this aggressive cancer. That’s where MIBG may fit in.”

New Facility Ready for Safe MIBGAdministration

MIBG labeled with radioiodine (I-131 or I-123) was developed in the 1980s to visualize neuroendocrine tumors such as pheochromocytomas and neuroblastomas. This synthetic analogue of norepinephrine is taken upand concentrated inside about 90 percent of these cells, allowing for scintigraphic imaging of the tumors.

More recently, oncologists have experimented with high doses of MIBG labeled with I-131 as targeted therapy for neuroblastoma. The labeled MIBG is infused over one to two hours via an intravenous line. Based on published evidence of activity in patients with refractory or recurrent disease, the FDA now allows use of I-131 MIBG through a compassionate use protocol and most insurance companies will cover the treatment.

Although taken up by tumor cells in a relatively selective fashion, the radiation still impacts nearby cells, and presents a danger to staff or others who come into close contact with the patient in the week after therapy. These potential risks have led to upgraded safety procedures and highly specialized facilities for I-131 MIBG administration.

To reduce staff exposure to radiation during administration, a new tungsten-shielded injector was developed. The other major investment in MIBG safety was a lead-lined room where the child is isolated after treatment until the radiation is excreted—generally about five days. The room is comfortable and parents can stay nearby and communicate with their child at all times with video-conferencing equipment. Seattle Children’s was one of the first sites in the country to build such an infrastructure to deliver MIBG therapy.

“This facility took about a decade of planning and work,” Park said. “MIBG was one of the main reasons for building it, but FHCRC investigators are evaluating other such targeted therapies—such as radiolabeled monoclonal antibodies against CD45 in acute myeloid leukemia—so we were able to partner with these other SCCA groups.

“Today, after all this careful testing of MIBG and all this time getting the room ready,” she said, “we are ready to begin treating patients with neuroblastoma.”

Who Should Receive MIBG and When?

While the first patients to receive MIBG in Seattle will likely be those who have recurrent or refractory high-risk neuroblastoma, Park is also leading the Children’s Oncology Group (COG) Neuroblastoma Scientific Committee in designing national clinical studies aimed at determining the best use of MIBG in combination with other agents and/or earlier in the disease course.

“Within the COG research consortium we will eventually do a randomized national trial asking if MIBG therapy improves outcomes for all kids with high-risk neuroblastoma—not just those with recurrent disease,” Park said.

The agent will also be tested as a possible addition to induction therapy before high-dose chemotherapy in newly diagnosed neuroblastoma.

“The radiation delivered by high-dose I-131-MIBG has a bystander effect on nearby tissues,” Park said. “It doesn’t ablate the marrow but it suppresses the marrow significantly, and so we also use peripheral blood stem cells as a rescue to enhance the recovery of blood cells after MIBG treatment.”

Other Targeted Treatments in the Pipeline

Beyond the new availability of MIBG—both as a compassionate use agent and within clinical trials—Park emphasizes that Seattle Children’s and SCCA are developing a breadth of other new therapies for patients with recurrent or refractory neuroblastoma.

“Our new options will increasingly include molecularly targeted agents and novel combinations of drugs and biological agents,” she said. “Over the next year, we also will continue our work with Dr. Mike Jensen, [pediatric cancer researcher at Seattle Children’s], to create an immune-directed therapy using T cells genetically modified to attack neuroblastoma tumor cells.” [See accompanying story in this issue about Dr. Jensen’s pioneering work on T-cell engineering.]

“MIBG is not the only new thing we have to offer patients with recurrent or refractory neuroblastoma,” Park said. “It’s just one more tool in our fight against this deadly cancer.”

For a list of active clinical trials for patients with neuroblastoma see:

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.