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Fall 2012

Welcome from the Director 

For Challenging Cases of Childhood Leukemia:
Three Emerging Transplantation Strategies

For many children with high-risk or chemotherapy-refractory leukemia, allogeneic hematopoietic stem cell transplantation is the standard of care. Over the past decade, transplantation techniques have advanced and more patients than ever are now completely cured of their cancer. But the procedure is still an ordeal for many young patients and their families, often involving a long tense wait for a bone marrow match, substantial complications, and no guarantee of success.

That’s why researchers here at Seattle Cancer Care Alliance (SCCA) and Fred Hutchinson Cancer Research Center (FHCRC) are continually refining transplantation methods for leukemia. In this issue of Pediatric BMT News we update you on emerging strategies that promise to improve transplant outcomes in three key areas:

Ensuring Patient Access

New methods to expand the number of hematopoietic stem cells from donated umbilical cord blood may soon allow all patients in need—including those with no matched donor—to receive an immediate transplant. 

Reducing the Risk of Graft Versus Host Disease (GVHD)

By selectively removing specific T cell subsets from donor stem cell products, many patients may soon avoid the serious complications caused by chronic GVHD and related immunosuppressive therapy.

Improving Treatment of Relapse

A novel form of immunotherapy that targets minor histocompatibility proteins on leukemia cells may eventually allow more potent treatment of post-transplant relapses.

Pediatric BMT Clinical Trials

There are many clinical trials going on at Seattle Cancer Care Alliance involving pediatric bone marrow transplantation. Read the current list of open trials,  from acute myelogenous leukemia to graft-versus-host disease to systemic sclerosis.

These are just three examples of SCCA/FHCRC research on childhood leukemia. Clinical trials for two of these will be opening soon. As our scientific knowledge grows, other new trials are sure to open in the coming year.

Even for my colleagues and me here in Seattle, it can be challenging to stay up to date on transplantation options for our patients. 

To help our team—pediatric hematologists/oncologists, leukemia specialists, and transplantation specialists—understand all the newest options, we now meet every other week to review our most challenging cases. This SCCA Leukemia Transplantation Team is a collaborative team effort where we discuss how transplantation or other novel therapies might fit into a particular patient’s treatment plan. The meeting has become our essential forum for learning about the latest leukemia protocols. Even more importantly, it helps us map out the best course of therapy for our sickest patients, smoothing the treatment path for these patients and their referring physicians.

Our goal at SCCA is not only to create better therapy options—but also to ensure that you and your patients take advantage of new opportunities as soon as they become available. That’s the whole point of our Leukemia Transplantation Team.

Please let me know if you have any questions about the new strategies described in this newsletter—or if you would like to discuss the management of a patient with high-risk or chemotherapy-resistant leukemia.

K. Scott Baker, MD, MS

Director, Pediatric Blood and Marrow Transplantation Director, Survivorship Programs, Fred Hutchinson Cancer Research Center and Seattle Children’s Hospital Professor of Pediatrics, University of Washington School of Medicine



Umbilical Cord Blood Grown in Culture May Provide “Universal Donor” Stem Cells for Transplantation

A new method of preparing and transplanting stem cells from umbilical cord blood will soon be tested at Seattle Cancer Care Alliance (SCCA)/Fred Hutchinson Cancer Research Center (FHCRC) and six other cancer centers in the U.S. The new clinical trial, scheduled to open by January 2013, will enroll patients aged six months to 46 years who have acute leukemia, myelodysplasia, or chronic myelogenous leukemia and who lack an HLA-matched marrow donor.

Hematopoietic stem cell transplants using alternative donors are important because many patients—about 40 percent overall and as many as 80 percent of African Americans or patients of mixed ethnicities—are unable to find a match from a family member or in the donor registry.

The principal investigator for the multicenter trial, which is funded by the National Heart, Lung, and Blood Institute, is Colleen S. Delaney, MD, pediatric oncologist, transplantation specialist, and researcher at SCCA/FHCRC.

The new trial is the latest in a series of SCCA/FHCRC clinical studies employing pre-transplantation culture, or “expansion,” of stem cells from umbilical cord blood—a technique that employs discoveries made by Delaney’s mentor Irwin D. Bernstein, MD, a stem cell researcher at Fred Hutchinson Cancer Research Center.
 

Expanding stem cells in cord blood: Why and how

Using umbilical cord blood as a source of stem cells for transplantation has been an option at a few transplant centers for about 25 years. For many patients lacking an HLA-matched bone marrow or peripheral blood stem cell donor, these cord blood transplants have offered a life-saving alternative.  It is the relative immaturity of the immune system in cord blood that allows the less stringent matching requirements (only four of six HLA proteins need to match in cord blood, versus 10 of 10 for bone marrow).

Theoretically, this advantage guarantees a suitable stem cell source for nearly every patient needing a transplant. In reality, only a limited number of stem cells can be harvested from the placental cord blood and this paucity of progenitor cells slows the post-transplant recovery of white blood cells (WBC), which can put patients at a higher risk of infection.

“Even in pediatric patients,” says Delaney, “once you hit 60 to 80 pounds, finding a large enough unit of cord blood is difficult.”

To overcome this hurdle, Delaney and her colleagues started experimenting with double doses of cord blood and with ex vivo expansion of cord blood stem cells. Employing Bernstein’s breakthrough, which identified the Notch-signaling pathway as important in stem cell fate decisions, the researchers used a specific protein to prevent dividing CD34+ stem and progenitor cells from maturing (or differentiating) as they are cultured in the laboratory. 

“It’s amazing,” says Delaney. “When this Notch-signaling pathway is activated in the cord blood stem cells, they do not mature. We believe we have successfully recapitulated what happens in the bone marrow where these proteins activate Notch signaling within the stem cell and other blood forming cells.”

In a study published in Nature Medicine, the SCCA/FHCRC group revealed that use of these expanded stem cells led to more rapid WBC recovery (engraftment) after transplantation. 

The vision: Huge banks of “universal donor” cord blood 

In addition to documenting potential clinical benefits, the early SCCA trials with expanded cord blood highlighted a key challenge—plus an exciting opportunity.

The challenge: real-time expansion was complex and time-consuming. The process, practically speaking, could not be ramped up to help all patients throughout the country.

The opportunity: because expansion involves isolating and growing only the stem cells—i.e., eliminating the immune T cells that cause GVHD—the expanded cell product could be used without any HLA matching requirement. This means that the expanded cord blood could be prepared and shipped ahead of time. 

“We generate many different cells in the expansion” explains Delaney, “but we don’t get the T cells that would cause problems in a mismatched transplant.”

“That’s where this whole direction for the new study came from. If we can develop a stem cell product that does not require a match, then we could manufacture this ahead of time and create a huge bank of expanded cells available for clinical use.”

In 2008, Delaney received a grant from a branch of the U.S. Department of Health and Human Services to develop this idea not as a cancer treatment but instead as a potential medical countermeasure following an acute radiation event.

“The government was interested in stockpiling the cord blood product in the event of a nuclear event,” says Delaney. “From my perspective, this study was also my chance to see if completely unmatched product would allow faster transplants and fewer infections.”

That initial test of completely unmatched transplants with “off-the-shelf” expanded cord blood proved successful and set the stage for the upcoming multicenter trial.

The new clinical trial

In the new trial, patients who need a transplant but have no matched donor will be randomized to receive a cord blood transplant with or without the expanded “off-the-shelf” product. All patients will receive a myeloablative conditioning regimen. The main outcomes to be measured will include speed of engraftment, rates of infection and graft versus host disease, and length of hospital stay.

Delaney emphasizes that the new trial, as well as the many other ongoing SCCA cord blood transplant trials, can help today’s patients who lack a matched donor.

“No patient needing a transplant should be denied because of the donor situation,” she says.  “Already today, we can find cord blood donors for 99 percent of patients who need it.”

In a few years, if Delaney’s hypothesis is confirmed, the process for cord blood transplantation may be even easier and safer.

For more information about the planned trial, visit http://www.seattlecca.org/clinical-trials/leukemia-NCT01690520.cfm.

 

Removing Naïve T Cells From Peripheral Blood Stem Cell Grafts to Reduce GVHD

The success of bone marrow transplantation (BMT) in treating leukemia relies on a delicate balance of donor T cell actions. The T cells must provide a strong graft-versus-leukemia effect and protect the recipient from pathogens—but the grafted T cells must also avoid provoking severe acute or chronic graft versus host disease (GVHD), which can be deadly.

For decades, the main clinical strategy for tipping T cell actions away from GVHD has involved pharmacologic immunosuppression. First perfected by Rainer F. Storb, MD, at Fred Hutchinson Cancer Research Center (FHCRC), immunosuppression to support transplantation is effective in preventing the most severe forms of GVHD in most patients but can have side effects including delayed immune reconstitution and increased infection risk. 

The complete removal (depletion) of T cells from the graft is more effective than pharmacologic immunosuppression for preventing GVHD, but this strategy makes patients even more vulnerable to infections.

In search of a better balance

The ideal mix of aggression and passivity in donor T cells is, as indicated by stubbornly high rates of GVHD, difficult to achieve. While exact frequencies of GVHD vary by age and by type of transplant, at least half of children receiving a myeloablative transplant still experience acute GVHD. About one in three children develop the even more problematic chronic GVHD, which may require a multi-year course of immunosuppression. The morbidity and mortality associated with GVHD can be significant.

“GVHD is always considered serious,” says Marie Bleakley, MD, PhD, pediatric oncologist and researcher at Seattle Cancer Care Alliance (SCCA). “It’s a big deal, particularly for a growing child.”

To prevent GVHD in children having a transplant for leukemia, Bleakley and her colleagues are now attempting a more selective form of T cell depletion.

“We try to achieve a better balance,” she says, “by removing the naïve T cells that cause GVHD but maintaining the memory T cells that prevent infection.”

Early results in adults indicate that the new strategy of selective T cell depletion may indeed reduce the frequency and severity of chronic GVHD compared to standard immunosuppression-based transplants. Importantly, the frequency of infection appears to be no higher than in a standard transplant.

Based on this encouraging preliminary evidence and with a grant from Hyundai Hope on Wheels, Bleakley is now finalizing a pediatric version of the protocol. She plans to open enrollment for children in early 2013.

Selective depletion of donor naïve T cells

Advances in immunological research over the past decade have led to keener understanding of T cell subsets. These newly refined concepts are at the heart of Bleakley’s hypothesis that certain groups of T cells are more or less likely to cause GVHD.

In her own laboratory work, Bleakley has shown that CD8+ cytotoxic T lymphocytes specific for recipient minor histocompatibility antigens (the usual target for GVHD on recipient tissue in HLA-matched transplants) are found mostly within the naïve T cell subset bearing the CD45RA+ surface marker. This key finding led to her ongoing SCCA/FHCRC study in adults—the first human trial of this nature.

“Our preliminary results with about 20 adult patients suggest that selectively removing these naïve T cells can reduce chronic GVHD,” she says. “But we leave behind the stem cells and memory T cells and because many donors have already been exposed to infectious agents like cytomegalovirus these memory cells protect the recipient against infection.”

Considering new infections for which no memory exists, according to Bleakley, patients eventually develop their own new naïve T cells—which pass through the recipient’s thymus where they learn not to react against the body they are in. In this “home-schooling” of the new naïve T cells, they become tolerized to avoid GVHD while being trained to fight new infections.

“This process take a little while,” she says. “But if the naïve T cells go through training in the recipient’s body then they know not to attack the recipient.”

To remove the donor naïve T cells, the cells in the stem cell product are exposed to microbeads covered with monoclonal antibodies to CD45RA+. A large magnet then pulls out the beads, which have become coated with the naïve T cells. This new separation technique, which Bleakley developed with colleagues at Yale University, has been more than 99.9 percent efficient in depleting the targeted cells.

The new SCCA/FHCRC trial of selective T cell depletion will enroll up to 20 pediatric patients with acute leukemia or myelodysplastic syndrome. The transplantation will involve HLA-identical unrelated or related donor peripheral blood stem cell grafts. Details on enrollment criteria will be available in early 2013.
 

Genetically Modified T Cells to Treat Leukemia Relapse

Leukemia that relapses after bone marrow transplantation (BMT) can be extremely difficult to treat. Resurgent cancer cells are often refractory to chemotherapy at this point. And while a lymphocyte infusion or a second transplant from a different donor may succeed in inciting a graft-versus-leukemia (GVL) effect, especially in chronic myelogenous leukemia, these options often cause severe graft versus host disease (GVHD) and are far from uniformly effective.

To improve outcomes in relapsed patients, or in those on the verge of relapse, researchers have tried for decades to develop specific immunotherapies that target the tumor. The twin goals are to re-boost the GVL effect of donor T cells while avoiding GVHD. The long-standing challenge with immunotherapy has been finding molecular targets specific for the cancer cell.

“The particular antigenic targets we are looking for are very, very rare,” says Marie Bleakley, MD, PhD, pediatric oncologist at Seattle Cancer Care Alliance (SCCA) and a researcher at Fred Hutchinson Cancer Research Center (FHCRC). “The vast majority of minor histocompatibility antigens are expressed on all body cells, including the skin and intestinal tract. In contrast, what we are looking for are antigens expressed only on cells of the recipient’s hematopoietic system, including their leukemia, but not on their other body cells, or on the donor’s hematopoietic cells. It is like looking for a needle in a haystack.”

But Bleakley and her fellow researchers at FHCRC recently successfully isolated T cells specific for a previously discovered antigen that is highly specific to hematopoietic cells called HA-1. They then started the painstaking task of engineering genetically-modified donor T cells that target this antigen and kill leukemic blasts. If all goes well, a SCCA clinical trial to test the safety and efficacy of this new form of immunotherapy will begin sometime in 2014.

Finding the target: minor histocompatibility antigen HA-1 

Minor histocompatibility proteins are essential cogs in the mechanism of allogeneic transplantation. These are the small cell surface antigens whose recognition by donor T cells triggers the GVL effect. Unfortunately, these antigens usually are also sprinkled on other cells throughout the recipient’s body and that’s why GVL effects go hand in hand with GVHD.

To separate GVL from GVHD, Bleakley’s group has focused on rare minor histocompatibility proteins as targets for immunotherapy. 

“Of a half dozen reasonable targets for immunotherapy,” she says, “HA-1 currently appears to be the best of the best, mainly because it is very specific to the hematopoietic system and is present in very low levels in the rest of the body. This antigen is present essentially only on cells of the patient’s blood system, including leukemia cells. Thus, after we get rid of all normal recipient blood cells in an allogeneic transplant and replace them with donor blood cells from donors that don’t express HA-1, the only cells that should have this protein are the hidden leukemia cells. This is how we introduce selectivity into adoptive immunotherapy.”

Hitting the target: T cells equipped with gene for HA-1-specific T-cell receptor

Bleakley’s colleagues Edus Houston Warren, MD, PhD, and Stan Riddell, MD, have already shown in a Phase I clinical trial that T-cell clones specific for certain minor histocompatibility antigens can infiltrate the marrow and mediate anti-leukemia activity. Now, to exploit the unique HA-1 target on leukemia cells, Bleakley’s team is hard at work creating gene-modified T cells that target this antigen. The goal is to begin clinical trials with modified donor T cells within two to three years.

The first step in this multi-year project is to create several T-cell receptor proteins that are specific for the HA-1 antigen. The genes for these receptors will then be cloned into a lentiviral vector—the same harmless virus used by Riddell and his FHCRC team to engineer chimeric T cells for lymphoma and leukemia therapy. See www.seattlecca.org/newsletters/spring-2012.cfm#fanconi-anemia. Once the viral delivery system is ready, it will be used to modify memory T cells from donors. This engineered product will then be tested in the prevention or treatment of relapsed leukemia following allogeneic BMT.

A first step toward individualized therapy

Bleakley explains that this new immunotherapy approach will only be appropriate for a fraction of relapsed patients—perhaps only 10 to 15 percent—because of the need for proper genotype discrepancy between recipient and donor. (Unlike the marrow HLA matching sought in allogeneic transplantation, minor histocompatibility antigen-directed immunotherapy requires an anti-match in order to elicit the desired GVL effect.) In addition, the donor and recipient must possess the proper HLA genotype for the HA-1 antigen-presenting molecule. 

 “We realize this HA-1 trial will only be suitable for a subset of patients,” says Bleakley. “But we selected this particular antigen for this first study because its antigen expression profile is near perfect and, of the currently available favored minor histocompatibility antigens, HA-1has the potential to help the largest possible group of relapsed patients.”

“The larger idea,” she says, “is to create an entire library of these molecules. Our study will be a proof of principle, the first step toward more individualized immunotherapy medicine."

Pediatric BMT Clinical TrialsPatients

DISEASE(S)

SCCA STUDY

REF. NO.

INVESTIGATOR

Leukemia and Other Hematologic Malignancies (6 mo to 45 years old)

Off-the-Shelf Expanded Cord Blood Cells to Augment Cord Blood Transplant

FHCRC 2378.00, NCT01175785

Colleen Delaney, MD, MSc

Ph+ Leukemia

Nilotinib and Imatinib Mesylate Post SCT for Patients with ALL or CML

FHCRC 2223, NCT00702403

Paul Carpenter, MD

GVHD Prevention in AML, ALL, MDS (14 to 55 years old)

Depletion of T-cells From Allogeneic Stem Cell Grafts for the Prevention of GVHD

FHCRC 2222, NCT00914940

Marie Bleakley, MD

Acute Myeloid Leukemia (1 year and older)

Clofarabine and Low-Dose Total-Body Irradiation for AML Patients Undergoing Donor Peripheral Blood Stem Cell Transplant

FHCRC 2430, NCT01252667

Boglarka Gyurkocza, MD

Leukemia (1 to 21 years old)

Clofarabine and Low Dose Total Body Irradiation as a Preparative Regimen for Stem Cell Transplant in Leukemia

FHCRC 2284, NCT00884572

Ann Woolfrey, MD

Leukemia or Lymphoma Relapsed After Non-Myeloablative BMT

Donor Lymphocyte Infusion in Treating Patients with Persistent, Relapsed, or Progressing Cancer After Donor Hematopoietic Cell Transplant

FHCRC 1803, NCT00068718

Brenda Sandmaier, MD

Acute Lymphoblastic or Biphenotypic Leukemia in Infants (up to 1 year)

Different Therapies in Treating Infants with Newly Diagnosed Acute Leukemia

CH 2006, NCT00550992

Blythe Thomson, MD

Acute Myeloid Leukemia, MDS

Treosulfan + Fludarabine + TBI for Allo HCT for AML and MDS

FHCRC 2272, NCT00860574

Boglarka Gyurkocza, MD

Leukemia, Lymphoma, MDS, Other Malig-nancies Not Eligible for Standard SCT

Unrelated Donor Cord Blood Transplant with Reduced-Intensity Preparative Regimen

FHCRC 2239, NCT00723099

Colleen Delaney, MD

Leukemia, Lymphoma, MDS, Other Malignancies (6 mo to 45 years old)

Cord Blood Transplant Cyclophosphamide / Fludarabine + TBI

FHCRC 2010, NCT00719888

Colleen Delaney, MD

Leukemia, Lymphoma, MDS, Other Malignancies (6 mo to 45 years old)

Fludarabine, Cyclophosphamide + TBI Followed by Cord Blood SCT

FHCRC 2044, NCT00343798

Colleen Delaney, MD

Leukemia, Lymphoma

Non-Myeloablative HCT for Hematologic Malignancies Using Related, HLA-Haploidentical Donors

FHCRC 2372, NCT01028716

Paul O’Donnell, MD, PhD

Leukemia, MDS

Treosulfan, Fludarabine + TBI with Cord Blood Transplant

FHCRC 2275, NCT00796068

Colleen Delaney, MD

Leukemia or MDS Relapse After BMT

Post-Transplant Relapse for MDS, CMML and AML with Azacitidine +/- Gemtuzumab

FHCRC 2240, NCT01083706

Bart Scott, MD

Leukemia, Lymphoma, Multiple Myeloma

Sequential Autologous HCT / Non-Myeloablative Allogeneic HCT Using Related, HLA-Haploidentical Donors for Patients with High-Risk Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

FHCRC 2241, NCT01008462

Mohammed Sorror, MD

Leukemia, Lymphoma, Multiple Myeloma, MDS, Myeloproliferative Diseases

Natural Killer Cell Therapy Post Non-Myeloablative BMT

FHCRC-2230, NCT00789776

Brenda Sandmaier, MD

Lymphoma

Autologous Stem Cell Transplant Followed by Donor Stem Cell Transplant in Treating Patients with Relapsed or Refractory Lymphoma

FHCRC 1409, NCT00005803

David Maloney, MD, PhD

CD-20+ B-Cell Malignancy

Rituximab for Patients Undergoing SCT for Relapsed B-Cell Cancer

FHCRC 2226, NCT00867529

Andrew Rezvani, MD

Lymphoma with HIV (15 years and older)

Autologous Transplant for Lymphoma Patients with HIV

FHCRC 2485, NCT01141712

Anne Woolfrey, MD

Untreated Myelodysplastic Syndrome or Myeloproliferative Disorder

Low-dose TBI Dose Escalation Before HCT for CMML, MDS or MPD

FHCRC 2056, NCT00397813

Brenda Sandmaier, MD

Multiple Myeloma

Stem Cell Transplant with Lenalidomide Maintenance in Patients With Multiple Myeloma

FHCRC 2434, NCT01109004

Bill Bensinger, MD

Neuroblastoma (Post SCT) (up to 30 years)

Isotretinoin with or without Monoclonal Antibody, Interleukin-2, and Sargramostim Post STM

COG ANBL0032, NCT00026312

Julie Park, MD



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 Hutchinson Center 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.