Adult Bone Marrow Transplant Update - Summer 2013
- Engineered T-Cell Trials Underway at SCCA
- New Adult Blood and Marrow Transplant Program Medical Director
- Filling a Gap in Post-Transplant Care: The Transitional Transplant Clinic
Several new strategies for genetically engineering T cells to treat high-risk leukemia and lymphoma have recently advanced from laboratory testing to human clinical trials. Three separate clinical trials of genetically modified T cells are now underway within Seattle Cancer Care Alliance (SCCA), and two more will open in coming months.
Recently, using related T-cell techniques, researchers at the University of Pennsylvania and Memorial Sloan-Kettering Cancer Center made headlines after reporting encouraging results in patients with chemotherapy-refractory acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL). In these small trials, patients achieved remission after treatment with modified T cells.
Although these early phase studies at SCCA and elsewhere share the same goal—to test the safety and efficacy of T cells that have been genetically modified to target specific cancer cells—each trial employs unique methods.
In Seattle, after more than two decades of dogged immunological research, researchers have optimized special methods for modifying T cells to hunt down and eliminate cancer cells. Based on preclinical studies demonstrating encouraging antitumor activity, these special techniques for genetic modification and manufacturing of engineered T cells are now ready for testing in humans.
Today, SCCA clinician-scientists are drawing from their tool kit of sophisticated methods to test their T-cell therapies in a series of clinical trials. Seeking to improve previous attempts to harness the immune system for cancer therapy (e.g., with cytokines, monoclonal antibodies, or cancer vaccines), their goals are to bolster anti-tumor effects and maximize the duration and safety of T-cell immunotherapy.
Each of the active or planned SCCA trials described in this update provide insights into the special techniques and applications of this emerging class of therapy.
These new T-cell therapies are being tested mainly in patients with high-risk leukemia or lymphoma before or after bone marrow transplant (BMT). The entry criteria and timelines for these trials may change, and several new trials are still being designed, so referring physicians with high-risk leukemia or lymphoma patients who may benefit should contact SCCA for up-to-date information.
Trial 1: Preventing Relapse in Adults After Allogeneic BMT
The U.S. Food and Drug Administration (FDA) approved the SCCA trial of engineered T cells, CD19-specific Donor T Cells for B-Cell Malignancies After Allogeneic Transplant (FH 2494), late last year. The goal of this Phase I/II trial is to boost the graft-versus-tumor effect in subgroups of adults with ALL, advanced CLL, or diffuse large B-cell lymphoma who have received an allogeneic BMT from a matched related donor, thereby reducing the risk of post-transplant relapse. Up to 30 patients will receive engineered T cells after their transplant.
For this trial, T cells are generated from the donor’s blood. A lentiviral vector inserts a gene that encodes a chimeric antigen receptor (CAR), which is half monoclonal antibody and half T-cell receptor that targets the CD19 molecule expressed exclusively on B cells (both malignant and normal). CARs are hard-wired to bind to the tumor cell without regard to the patient’s HLA status (See details in the May 2012 issue of Adult BMT Update). This is important because it allows a single pre-constructed CAR to target tumors in patient populations with diverse HLA patterns. Once they bind to the target, the T cells automatically trigger cytotoxicity.
“We are coupling the exquisite specificity of the antibody to the potent effector functions of the T cell,” said Stanley R. Riddell, MD, oncologist and immunology researcher at Fred Hutchinson Cancer Research Center (Hutchinson Center). “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.”
To encourage the T cells to persist in the patient, SCCA researchers take steps to enrich the donor’s T-cell population with longer-lasting central memory cell subsets.
Cameron Turtle, MD, PhD, is the hematologist-oncologist and researcher at SCCA who is the principal investigator for this trial. “Engineered T-cell therapy certainly has potential for the treatment of patients with B-cell malignancies, but more work is needed to make the responses durable,” Turtle said. “We believe that using central memory cells as a starting population for expansion might enable transferred T cells to provide long lasting anti-tumor effects.”
Click here for more details about the trial.
Upcoming Related Trials: Researchers at SCCA have received FDA approval to open a new trial of autologous therapy with T cells modified with CD19-specific CARs. This autologous trial will enroll up to 63 adult patients with ALL, CLL, and lymphoma. The core techniques vary from those employed in the allogeneic trial just described. The CAR is different and the T cells selected for engineering will be a combination of CD4+ and CD8+ central memory cells. [www.seattlecca.org/clinical-trials/ lymphoma-NCT01865617.cfm] An additional leukemia trial will utilize CAR-modified T cells to target the CD20 antigen.
Trial 2: Treating Chemotherapy-Resistant ALL in Adolescents and Children
The Pediatric Trial of Genetically Modified Autologous T Cells Directed Against CD19 for Relapsed CD19+ Acute Lymphoblastic Leukemia is a trial that was just initiated at Seattle Children’s Hospital, an SCCA founding institution. It will enroll, treat, and monitor approximately 20 patients, six between 18 and 26 years of age and then at least another dozen between one and 26 years of age. All patients will have B-cell ALL that has developed resistance to chemotherapy. The first patient was enrolled in May 2013.
“Less than 40 percent of patients with relapsed ALL typically survive,” said Rebecca Gardner, MD, acting assistant professor in the Department of Pediatrics at the University of Washington, who leads this trial. Residual leukemia is unlikely to respond to further chemotherapy, so wiping the slate clean of leukemia with T-cell therapy will allow many more children to receive a successful transplant. That’s one ultimate goal of the new therapy.
In this trial, the patient’s own T cells are reprogrammed with a CAR that recognizes CD19, which is expressed on more than 90 percent of pre B-cell ALL in children. The transduced cells are grown for about three weeks in a special laboratory, the FDA-certified Therapeutic Cell Production Core at Seattle Children’s Research Institute. They are then infused into the child. Since the patient’s healthy B cells also express CD19, they are eliminated along with the tumor cells. The patient must also receive treatment with intravenous immunoglobulin to protect against infections.
The main purpose of this trial is to determine the safety of the new therapy and the dose that can be tolerated. Based on previous studies with T cells, researchers expect a short period of flu-like side effects related to revved-up immune reactions. A severe form of this feverish reaction, called a “cytokine storm,” sometimes requires hospitalization for supportive care.
To monitor the persistence of T cells in the blood, researchers will measure a cell surface protein marker, a truncated version of the epidermal growth factor receptor (EGFR) added with the CAR during the genetic reengineering of the T cell. The EGFR acts as a tracer and as a potential way to recall the engineered T cells.
Click here for more information.
Upcoming Related Trial: The EGFR tag may also prove useful in a pediatric adoptive immunotherapy study scheduled to start in Fall 2013. This trial of anti-CD19 engineered T cells will treat children with ALL who have relapsed allogeneic BMT. Most post-transplant patients are already tolerized to their donor T cells, but if they do develop graft-versus-host disease (GVHD), the Erbitux can get rid of the reprogrammed T cells.
Trial 3: Preventing or Treating Relapse After BMT for Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myeloid Leukemia
This new Phase I/II trial has two arms: (1) prophylactic T-cell therapy for acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myeloid leukemia (CML) patients with high risk of relapse after BMT, and (2) treatment with T cells for AML/MDS/CML patients with either minimal residual disease or full hematologic relapse after BMT. The first two patients were enrolled and started treatment in May 2013. The target for enrollment is 55.
The strategy of this trial involves genetically engineering donor-derived T-cells to express a T-cell receptor that is specific to Wilm’s Tumor Antigen (WT1), a protein that is highly expressed on leukemia cells. The magnitude of WT1 expression correlates with the cancer’s aggressiveness. The gene that encodes the high affinity WT1 T-cell receptor has been isolated from a healthy individual with human leukocyte antigen (HLA)-A*0201 and cloned into a lentiviral vector, which is then used to transduce donor-derived T-cells. For this to work, the patient must have the proper matching HLA-A*0201 marker.
“We selected this HLA marker because it is common in the overall population—seen in about a third of Caucasians,” said Merav Bar, MD, assistant professor of medical oncology at the University of Washington, and the SCCA lead investigator for this trial. “Using this HLA marker allows us to treat the most patients with a single T-cell receptor product.” “Eventually we hope to create an array of lentiviral vectors that will allow us to treat patients with any HLA type,”Bar said, “But we don’t have these virus libraries yet.”
Researchers targeted the WT1 antigen based on a recent SCCA study (Science Translational Medicine 2013;5:174ra27; PubMed: 23447018) showing antileukemic activity without significant GVHD in patients receiving WT1-specific donor-derived CD8+ cytotoxic T cells after BMT for high-risk leukemia. These were not engineered T cells but naturally occurring anti-WT1 T cells that were carefully removed from the donor’s lymphocytes, grown in culture, and then given to the patient. At the time of the study’s publication, four patients with the best responses were still alive with no recurrence of their cancer more than two years after transplant.
“In this study, there was great variability in the efficacy of the different T cells,” Bar said. “So for our new study, Dr. Philip Greenberg, head of the Immunology Program at Fred Hutch, and his team cloned the gene of the anti-WT1 T-cell receptor from a donor whose T cells led to the best anti-leukemic activity in the laboratory. They cloned that gene into a lentiviral vector and that’s what we now use to engineer donor T cells in our new trial. We believe our new treatment will be as consistently effective as the best donor’s treatment in our previous trial.”
To boost persistence of the therapeutic T cells in the body, Bar said they start with T cells active against cytomegalovirus or Epstein-Barr virus since those are usually primed central memory cells. The researchers also culture the engineered T cells with the cytokine interleukin-21 (IL-21) to promote expansion and improve in vivo persistence. Evidence from their published trial confirms that generating T cells in the presence of IL-21 leads to a greatly extended T-cell life span in the bloodstream and longer-lasting anti-leukemic effect.
Click here for more information on the trial.
Upcoming Related Trials: Since the WT1 antigen is also highly expressed on a range of solid tumors, SCCA researchers are also developing new T-cell therapies directed at several other specific tumors.
Variations on the T-Cell Theme
The array of immunotherapy approaches now being developed at SCCA could provide important new options for many patients with difficult-to-treat cancers.
As illustrated in the trials just described, each specific clinical setting dictates a slightly different engineering approach in terms of antigen target selection, T-cell source and preparation, vector choice, manufacturing protocols, administration, monitoring, and follow-up treatment.
In other words, there are hundreds of variations on the engineered T-cell theme, and more emerge every day. That’s why, as in the relatively mature but equally complex area of stem-cell transplantation, expertise with the entire range of techniques and strategies will be essential to achieving the best outcomes. Developing that expertise with all the most powerful T-cell methods is the goal of SCCA researchers and clinicians.
Initially, as in several of the trials just described, the T-cell therapies will be carefully tested in patients with specific forms of high-risk leukemia or lymphoma either before or after BMT. If early tests go as expected, a growing number of T-cell treatments may be created for other patients, including those with lower-risk disease or other types of hematological or solid cancers.
Whether deployed in conjunction with stem-cell transplantation or used as a stand-alone cancer therapy, genetically modified T cells are clearly a promising treatment for patients who have few other options.
The growing number of clinical trials now underway at SCCA will define the safety and efficacy of these immunotherapies and possibly set a course for a whole new direction in cancer therapy.
This past July, Marco Mielcarek, MD, was appointed as the new medical director of the Adult Blood and Marrow Transplant Program at SCCA and the Hutchinson Center.
After training in internal medicine and hematology/oncology at the Free University of Berlin from 1987 to 1993, Mielcarek accepted a two-year research fellowship in the laboratory of Beverly Torok-Storb, PhD, at the Hutchinson Center. He eventually decided to stay on as a researcher, but also to become fully credentialed as a clinician in the United States.
“I was not originally a laboratory person,” he explained. “I was an internal medicine doctor. I didn’t want to give that up. I wanted to take care of patients.”
Dividing his time between patient care and research ever since completing his internal medicine residency and medical oncology fellowship at UW Medical Center in 2003, Mielcarek is an associate professor of medicine (Medical Oncology) at the UW School of Medicine and associate member of the Clinical Research Division at the Hutchinson Center.
A Focus on Graft-Versus-Host Disease
Mielcarek specializes in blood stem cell transplantation and BMT for hematologic malignancies. His research is aimed at preventing and treating graft-versus-host-disease (GVHD). “Severe acute GVHD is potentially life-threatening,” he said. “Patients with chronic GVHD may need to take immunosuppressive drugs for years, putting them at risk of infection and compromising their overall quality of life.”
Mielcarek is currently testing statins as a potential GVHD preventive. “In our large retrospective studies,” he said, “we found that if the donor was taking a statin, the grade III-IV acute GVHD was almost nonexistent.”
Compared to current grade III-IV acute GVHD rates of 10 to 15 percent, those results were stunning. Mielcarek then initiated two SCCA prospective trials to determine if giving atorvastatin to donors for two weeks before their final stem cell collection would reduce GVHD rates. He teamed with basic scientists to define the molecular mechanism that might explain how statins prevent GVHD.
In other studies, Mielcarek is evaluating low-dose prednisone as a less toxic yet still effective treatment for GVHD, and whether the use of carefully timed infusions of high-dose cyclophosphamide after a BMT is safe and effective in preventing GVHD.
Dramatic Changes Past and Future
Advances in transplantation over the past decade—many invented or refined at SCCA and the Hutchinson Center—have led to dramatic changes in the typical BMT procedure and outcome.
“In particular, our reduced-intensity conditioning regimens are relatively well tolerated even by most of our patients in their 60s or 70s—exactly the older population that tends to get leukemia and lymphoma,” Mielcarek said. “With less toxic conditioning regimens, many patients spend very little time in the hospital.”
Mielcarek sees further reductions in the pre-transplant conditioning intensity and increasingly effective targeted treatments against the leukemia or lymphoma in the future which can make the transplantation procedure safer and reduce relapse rates.
Mielcarek said: “Research is the backbone for improving cancer care. For this we rely on our patients and our referring physicians. By participating in appropriate clinical trials, they help us increase our understanding of diseases, improve our treatments, and achieve better cure rates.”
The Long-Term Follow-Up (LTFU) Clinical Program at SCCA has expanded its scope of services to assist in the hands-on management of patients who develop complex conditions more than 100 days after their peripheral blood hematopoietic stem cell or BMT procedure.
Started in September 2012, the Transitional Transplant Clinic (TTC) offers specialized post-transplant care from a dedicated team of SCCA physicians and nurses. The TTC takes pressure off the early post-transplant care teams and referring physicians by providing temporary care for patients with complex medical conditions until they are ready to return to the care of their local oncologists or primary care physicians. The TTC also opens up capacity at SCCA, ensuring that new patients get access to life-saving transplants without delay, and improving the continuity of care for patients with lingering complications.
How the LTFU Clinical Program Works
Most patients who have a BMT at SCCA initially receive care in a dedicated post-transplant clinic for two to three months and then return to the care of their primary physician. Once patients are discharged from this early post-transplant service they become LTFU patients. The LTFU Clinical Program provides telemedicine and onsite clinical consultation to its patients. If a patient develops a typical, mild transplant-related problem or if the primary provider has a question, clinicians in the LTFU Program consult with them over the phone to provide advice or, if needed, coordinate a return to SCCA for an evaluation or clinical care.
Today, the LTFU program has approximately 4,000 patients who were transplanted between 100 days and 40 years ago at either the Hutchinson Center or SCCA. This growing LTFU population attests to the expanding use and improved long-term outcomes of modern BMT techniques used at SCCA.
Helping Primary Physicians
Even with safer and more effective transplants, some patients will develop severe post-transplant complications that prevent them from being discharged to their primary provider at the expected 100 days after transplant. Other patients who have already been discharged also sometimes experience new or recurrent post-transplant complications that are difficult for a primary provider to handle.
“These are often recipients of allogeneic transplants with new or poorly controlled late acute or chronic GVHD,” said Mary Flowers, MD, medical director of the LTFU Clinical Program. “Or they might be patients with serious or recurrent infections, poor graft function, or other— perhaps multiple—medical conditions that require extensive ongoing management. These types of patients require prolonged and frequent clinic visits which are hard for a busy oncology clinic to handle. The TTC at SCCA provides this complex level of post-transplant care.”
The LTFU Clinical Program continues to offer its full range of services. “What’s new is that the TTC now fills the gap in continuity of care for the high-acuity patients with complex post-transplant-related problems beyond two to four months after transplantation,” Flowers said.
According to Paul V. O’Donnell, MD, PhD, past medical director of SCCA’s Adult Transplant Service, the TTC provides an essential backup service to referring physicians. “A private oncologist in the community may see three patients every hour, so caring for one of these patients with chronic or complicated issues can be extremely difficult,” O’Donnell said. “The TTC will take care of these patients and help them transition back to the referring physician over a period of a few months.”
Ensuring Capacity for New Transplant Patients
Until recently, BMT patients with late-developing chronic or serious problems typically received care at SCCA’s early post-transplant clinic or the hematological clinic, located at UW Medical Center and Seattle Children’s. But increasing demand for BMTs has reduced the capacity of these core clinics to keep or re-admit patients with chronic problems.
“If these patients with late acute problems stay too long in the allogeneic or the autologous post-transplant care clinics, the clinic volumes build and build,“ O’Donnell said. “We need those inpatient clinics for about five new patients each week.” If our transplant team is overloaded with complex patients, it makes it difficult to take new patients,” he said. “The TTC was designed to help us maintain this capacity for new incoming patients.”
Providing Continuity of Expert Care
Another primary motivation for creating the TTC was to establish a seamless continuity of care from a dedicated, expert medical team. Flowers said the acute post-transplant team’s monthly staff rotation hampered their ability to provide continuity of care to patients with lingering complications beyond three months after transplant.
“The TTC has solved this problem,” Flowers said. “It’s another novel aspect of our transplant program here at SCCA.”
The TTC team consists of two attending physicians, Merav Bar, MD, assistant member, Hutchinson Center, Laura S. Connelly-Smith, MBBCh, DM, SCCA staff physician, one dedicated mid-level practitioner, one dedicated nurse, and one support staff. The TTC team goal is to improve or stabilize the patient’s post-transplant medical conditions and eventually transfer their primary medical care back to their referring physicians with periodic follow-up by the LTFU team.
“Our dedicated team of experts in the TTC makes this goal achievable,” Flowers said.
The TTC at Work
To date, 50 patients have received care at the TTC, which is more than originally projected. Approximately half of these patients required hospital admissions. The average duration of medical care received by TTC patients is three months.
Case Study: A Seattle resident developed late acute GVHD one month after returning to care with his referring physician.
His local physician referred him back to SCCA. In the TTC, the patient’s situation was stabilized over a couple of months. Eventually, the TTC team tapered his steroids and returned him to the care of his referring physician. The immunosuppression was ongoing, but the patient had responded nicely and there was no further need for intense monitoring.
“It was a short intervention,” Merav Bar, MD says. “It gave comfort to the patient and also to the physician.”
Case Study: A newly transplanted patient from Bellingham, Wash. struggled with severe acute GVHD in the SCCA post-transplant clinic.
The patient required heavy immunosuppression and experienced several severe infections. Instead of staying in the main post-transplant unit or going back to his referring physician, the patient was discharged to the TTC. Some of his infections and complications required admission to UW Medical Center, and at certain points he stayed in Seattle to be seen once or twice a week.
This patient had several post-transplant complications, which required close monitoring and intense treatment. Over a period of months, he slowly improved and returned to Bellingham. The TTC established dual care with his physician, once-a-week visits at the TTC, and once-a-week visits with his own physician. Eventually he graduated from our program and was seen only by his referring physician with the support of the LTFU Program.
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