Bachelor of Medicine & Surgery/MD, 1994:
Flinders University of South Australia, South Australia
Master of Medical Science (M.MSC.) in Clinical Epidemiology, 2000:
The University of Newcastle, New South Wales, Australia
The University of Sydney, New South Wales, Australia
Residency, Pediatrics, 1996-1999:The Children’s Hospital at Westmead, New South Wales, Australia
1. Pediatric Oncology, 1999-2001: The Children’s Hospital at Westmead, New South Wales, Australia
2. Pediatric Hematology-Oncology, 2002-2005: Fred Hutchinson Cancer Research Center and Seattle Children’s Hospital
Dr. Bleakley is a pediatric oncologist with expertise in hematopoietic (blood-forming) stem cell transplantation (HCT) to treat leukemia. The blood stem cells that are engrafted in donor (allogenic) HCT can be collected from bone marrow, peripheral blood or umbilical cord blood. T cells which are also present in the stem cell graft are a major part of the curative power of transplantation, but can also cause serious side-effects known as Graft-Versus-Host-Disease (GVHD). Dr. Bleakley is developing ways to optimize the use of T cells in transplantation and cell therapies given after transplantation to prevent and treat relapse of leukemia and other complications. .
Her research is focused on improving outcomes for patients with high-risk leukemia by developing new strategies that optimize the activities of T cells in the context of HCT. In particular, she is working to promote the advantageous Graft-Versus-Leukemia (GVL) effect and reduce the potentially dangerous GVHD that also can be caused by donor T cells after allogeneic transplantation.
T cells act by targeting specific proteins (antigens) on other cells, using highly specialized molecular complexes, called T cell receptors (TCRs). Dr. Bleakley is advancing one strategy that manipulates donor T cell responses to a group of antigens called minor histocompatibility (H) antigens. She established a new technique for isolating and expanding minor H antigen-specific T cells, which is now used for discovering novel hematopoietic-restricted minor H antigens expressed on leukemia that can be exploited as targets for vaccination and adoptive immunotherapy. She and her laboratory have already identified and characterized five novel human minor H antigens.
Dr. Bleakley’s lab is conducting a clinical trial using minor H antigen specific T cells to treat recurrent leukemia after transplantation. For this first clinical trial, she chose as a target the ‘gold standard’ highly hematopoietic-restricted minor H antigen, HA-1. This T cell immunotherapy was developed in her lab, where the team isolated HA-1-specific T cells, sequenced their TCRs, cloned several HA-1 TCRs into lentiviral vectors and evaluated the function of HA-1 TCR transduced CD4+ and CD8+ T cells.
Another strategy to prevent GVHD involves selectively removing GVHD-promoting T cells from hematopoietic stem cell grafts. An ongoing set of clinical trials was informed by laboratory studies which showed that a subset of allogeneic donor bone marrow (memory T cells, TM) could be purified and administered to produce immunity to a infections and tumor antigens, with little or no GVHD. The strategy involves removing another, potentially damaging subset of T cells (CD45RA+ naïve T cells, TN).
Dr. Bleakley is currently serving as the Principal Investigator of clinical trials of TN -depletion for recipients of peripheral blood stem cell grafts. The first two of these studies was completed for adult and pediatric acute leukemia patients, respectively. Dr. Bleakley and colleagues showed that TN-depleted PBSC grafts produced rapid immune reconstitution and transfer of pathogen-specific immunity, with a marked reduction of chronic GVHD relative to T cell replete HCT. Moreover, the duration of required immunosuppression after TN-depleted HCT was considerably shorter than with T cell replete HCT, providing a greatly improved platform for immunotherapy.
Two randomized control trials will compare TN-depleted HCT with standard HCT, starting in 2019.
A new phase I trial of HA-1 TCR-engineered T cell immunotherapy is now open and treating patients with relapse of leukemia after HCT. Ultimately, Dr. Bleakley plans to bring together this graft engineering for GVHD prevention in HCT, and T cell immunotherapies following transplantation, along with anti-tumor vaccination to develop a comprehensive treatment approach for patients with high-risk hematologic malignancies.
Ongoing trials, open to patients, include:
Phase I Study of Adoptive Immunotherapy with CD8+ and CD4+ Memory T cells Transduced to Express an HA-1-specific T cell Receptor (TCR) for Children and Adults with Recurrent Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation (HCT)
Dr. Marie Bleakley, a pediatric oncologist and stem cell transplant physician at the Fred Hutchinson Cancer Research Center, researches ways to manipulate and harness the power of the immune system in order to fight leukemia and other cancers.