Bone Marrow Transplant Update - Spring 2012
- New Multi-Center Haplo and Cord-Blood Transplant Trial
- Paul V. O’Donnell, MD, PhD—BMT Expert
- Engineered T Cells to Treat Leukemia and Lymphoma
—By Sally James
A new trial that will randomize patients between two alternative donor stem cell protocols will be recruiting Seattle Cancer Care Alliance (SCCA) patients soon. Paul O’Donnell, MD, PhD, medical director of the Adult Stem Cell Transplant Service describes the trial as a comparison of two alternative donor types, haploidentical (HLA-mismatched) family members (including parents, children, and about half of a patient’s siblings) versus unrelated umbilical cord blood. This study is being coordinated nationwide by the Blood and Marrow Transplant Clinical Trial Network.
Patients who may not have been able to find a matched donor will have new opportunities through the growth of these alternative donor options, O’Donnell says. In some cases, patients of mixed ethnic heritage can have the most difficulty finding matches, and may benefit the most from these studies.
Looking for alternativesOnly 30 percent of bone marrow transplant patients have matched sibling donors. Another 35 percent will find matched unrelated donors, leaving the remaining 35 percent looking for alternatives. “For a long time, matched unrelated donors have been the alternative donors of choice,” O’Donnell says. “Our outcomes using such donors consistently outperform many other centers. Now we are able to offer patients who can’t find a matched unrelated donor with the option of transplants using a haploidentical donor or unrelated cord blood.”
Across the country, findings indicate that transplant outcomes using haploidentical or cord blood donors are very similar to matched donors, according to O’Donnell. “The incidences of acute or chronic graft versus host disease are surprisingly similar or less than matched donors using current protocols,” he says.
O’Donnell is one of three principal investigators and the trial is hoping to include about 40 centers around the nation enrolling 410 leukemia and lymphoma patients. The trial will be open for four years and patients will be followed for three years after their transplant. Because the trial is opening across the country at many centers, O’Donnell is hoping that doctors and potential patients will hear about it and know that patients can enroll within a reasonable distance of their own home state. More information is on the SCCA website at: https://web.emmes.com/study/bmt2/protocol/1101_protocol/1101_protocol.html
Paul O’Donnell, MD, PhD began his career studying chemistry and earned graduate degrees in biochemistry and molecular biology that led to a 20-year research scientist position at Memorial Sloan-Kettering Cancer Center in New York, where he studied retroviruses that cause leukemia in mice.
At the age of 42, O’Donnell felt the need to become more involved in the study of human diseases. He enrolled in Johns Hopkins School of Medicine where he later pursued an oncology fellowship and joined the faculty.For many, beginning medical school in the midst of one’s career is more than a daunting task. “You just have to decide what you’re going to do and do it,” he said. “When you can make decisions like that, it frees up enormous amounts of internal energy to accomplish what you want to do.”
O’Donnell worked at Johns Hopkins for over 10 years and moved to Seattle to join the faculty of the bone marrow transplantation program at Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance in 2001. He became the medical director of the Adult Blood and Marrow Transplant Service, overseeing about 45 medical staff members, attending physicians, mid-level providers, and oncology fellows, and is a researcher in the Clinical Research Division at the Hutchinson Center, working on leading-edge research using alternative donors for bone marrow transplantation.
Traveling to south Lake Union from Bainbridge Island, O’Donnell says he can’t wait to get to work each day. “I feel fortunate to have a rewarding job that is so engaging and intellectually stimulating,”
he says. “I want to provide the best evidence-based clinical care to our oncology patients. I want them to be as well-informed as possible about their disease so that treatment decisions can be shared and realistic.
“The purpose of SCCA is to improve how things are done and to really expand the option of treatment for the widest possible audience. The patients who are willing to be participants in clinical research are very special. They’re unique in being willing to take risks. They want to be helped, of course, but they’re also helping advance knowledge.”
—By Paul Courter, Science Writer
The U.S. Food and Drug Administration has given SCCA researchers approval to begin a new clinical trial using immunotherapy with genetically engineered T cells for leukemia and lymphoma patients. Modified receptors on T cells will recognize a specific antigen on cancerous blood cells. When infused into a patient, these engineered lymphocytes bind to the tumor antigen, triggering potent cytotoxic effects that lyse the cancer cells.
This SCCA trial, led by Cameron Turtle, MD, aims to reduce relapse rates in patients having allogeneic bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL), advanced chronic lymphocytic leukemia (CLL), and diffuse large cell lymphoma. Even with current best practices, nearly half of patients with these advanced forms of cancer will eventually relapse after BMT.
“The results of allogeneic BMT have improved, but cancer recurrence remains a significant problem,” says Stanley R. Riddell, MD, oncologist and immunology researcher at the Hutchinson Center.
“The graft-versus-leukemia effect that occurs with an allogeneic BMT is simply insufficient to eliminate all of the tumor in all patients. “The primary goal of administering engineered T cells,” he says, “is to boost the graft-versus-tumor effect and reduce leukemia and lymphoma relapse rates after transplant.”
The quest for improved cancer immunotherapy
To create this promising immunotherapy, Drs. Turtle and Riddell partnered with Michael Jensen, MD, pediatric cancer researcher at Seattle Children’s Hospital, and several other SCCA researchers. This trial culminates years of work. The Seattle team is not the first to engineer T cell receptors in an attempt to sharpen these spearheads of the immune system against cancer. In late 2011, a report of complete remissions in two of three patients with refractory CLL who were treated with this approach at the University of Pennsylvania (Porter et al. N Engl J Med 2011; 365:725-733; Kalos et al. Sci Transl Med 2011;3:95ra73) generated headlines and raised hopes that years of laboratory research into developing immunotherapy will soon benefit patients with cancer.
Fighting cancer with the immune system has become a goal for many clinician-researchers. Harnessing the body’s own immune mechanisms theoretically targets malignant cells for a relentless search-and-destroy mission. If immunotherapy becomes a reality, the side effects of chemotherapy and radiation might be lessened or avoided entirely.
But the immune system is incredibly complex. So far, researchers have exploited only a fraction of its potential protective energy. Most victories using cancer immunotherapy—cytokines, monoclonal antibodies, cancer vaccines—have been partial at best. That’s why preliminary evidence of efficacy with engineered T cell receptors has spawned so much excitement.
The engineered chimeric antigen receptor: Why it may work better
In most previous attempts at adoptive T cell transfer immunotherapy, lymphocytes with anti-tumor activity were isolated from a patient, stimulated to grow in the laboratory, and re-introduced into the patient. Although helpful in certain diseases (e.g. melanomas), this approach is limited by the difficulty of isolating the ideal antitumor cells and because the T cells still require the proper HLA (human leukocyte antigen) molecule to present the tumor antigen before triggering cytotoxicity.
To get around these problems, Riddell and Jensen armed donor T cells obtained easily from the blood with a chimeric antigen receptor—half monoclonal antibody and half T cell receptor. The extracellular tip of the 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, explains Riddell, overcomes the inherent limitations of each separate element, removing the requirement for HLA, and still triggering killing of tumor cells.
“W e know that monoclonal antibody therapies have been very useful in treating B cell tumors,” Riddell says. “These antibodies given passively will target the tumor but they can be ineffective in killing all of the tumor cells.” Rituximab, which targets CD20 on B lymphocytes, is one classic example of monoclonal antibody therapy that zeros in on the tumor. While the agent is clinically effective, having been used by more than a million patients with lymphoma, it is thought to produce its cytotoxic activity via antibody-dependent or complement pathways—which are considered relatively weak or indirect antitumor mechanisms.
By contrast, a monoclonal antibody linked directly to the T cell receptor requires no activation of immune mediators or attraction of other immune cells to trigger cytotoxicity. When the antibody is hard-wired in the chimeric receptor, binding to the tumor cell automatically flips the switch on the lethal effector functions inside the T cell. This leads to the release of molecules that poke holes in the target cell membrane and cause it to explode.
In addition, T cell activation no longer requires recognition of the HLA molecule on the target cell. “Recognition and signaling is based only on the surface tumor antigen,” says Riddell. “The patient’s HLA allele doesn’t matter.” This absence of major histocompatibility complex 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 says. “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.”
Clinical trial specifics
The SCCA clinical trial, when underway in a few months, will be open to subgroups of adult ALL, advanced CLL, and diffuse large cell lymphoma patients who are getting an allogeneic BMT from a matched donor. (Plans for a protocol for children using similarly engineered T cells will be submitted to the FDA later this year.) Patients who have relapsed after a previous transplant will also be eligible.
“For this trial, we generate the engineered T cells from donor blood cells,” says Riddell. “A lentiviral vector inserts the gene that encodes the chimeric receptor. The receptor is then expressed on the T cell’s surface, retargeting it to the CD19 molecule.”
The whole process for making the T cells takes a few weeks. The patient receives the engineered cells after the allogeneic BMT. For those patients who have relapsed after a previous transplant, stored cells from the original donor can be retrieved, engineered, and then given as a donor lymphocyte infusion.
“Our first goal is to show safety; however, we also hope to see antitumor activity. Because tumors are susceptible to mutation, we also need to see if the tumors lose expression of the molecule we’re targeting,” Riddell says.
“In animal models these cells are extremely effective and completely eliminate tumors,” Turtle says. “If proven effective in trials, this is a treatment that could expand very rapidly to help patients who are unable or choose not to receive a transplant.”
Potential applications for engineered T cell receptors
Other studies employing engineered T cells are planned at SCCA. In one new trial expected to start later this year, Riddell and Turtle are working with David G. Maloney, MD, PhD, oncologist and fellow researcher at the Hutchinson Center, to test chimeric antigen receptor therapy in non-transplant populations. Meanwhile, Drs. Elizabeth Budde, Brian Till, and Oliver Press have developed chimeric receptors that target CD20 on B cell malignancies and are also planning a clinical trial in nontransplant patients. These combined efforts hope to provide new effective treatment options for patients with B cell tumors.
Philip Greenberg, MD, an immunology researcher at the Hutchinson Center, is engineering whole T cell receptors (not chimeric) with specificity against a tumor antigen called Wilms tumor protein (WT1), which is highly expressed in myeloid malignancies and many solid tumors. Greenberg has conducted an early phase trial using WT1-specific T cells, and plans to launch a larger trial using donor T cells that express an optimized T cell receptor later this year.
Results from these multiple clinical research efforts may pave the way for a new era in cancer therapy—an era where immunotherapies are finally powerful enough to significantly improve patient survival and quality of life while limiting, or perhaps even entirely supplanting, the need for harsh chemotherapies or radiation.
“It’s an exciting time to be involved in T cell immunotherapy,” says Turtle. “We’re hopeful that recent advances in the lab will lead to better treatments for our patients in the clinic.”
More information about the Phase I/II study of cellular immunotherapy with donor central memory-derived virus-specific CD8+T cells engineered to target CD19 for CD19+ malignancies after allogeneic hematopoietic stem cell transplantation can be found online at www.seattlecca.org/clinical-trials/clinical-trials.cfm.
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