I am a cell-development biologist using genetic approaches in the model vertebrate zebrafish to study the regulation of myeloid blood cell development. My laboratory haematology research is in basic science and biology of haemopoiesism but is closely rel
Role Of Neutrophil Proteases In The Mobilisation Of Haemopoietic Progenitor Cells
Funder
National Health and Medical Research Council
Funding Amount
$318,279.00
Summary
Mobilisation is a procedure consisting in inducing the egress of blood forming cells (haemopoietic stem cells) from the bone marrow, where they normally reside, into the blood. The most common agent to induce mobilisation of haemopoietic stem cell is a cytokine called granulocyte - colony stimulating factor (G-CSF). In recent years, the number of transplantations performed with mobilised blood stem cells has exceeded those performed with bone marrow. Elements contributing to this success have be ....Mobilisation is a procedure consisting in inducing the egress of blood forming cells (haemopoietic stem cells) from the bone marrow, where they normally reside, into the blood. The most common agent to induce mobilisation of haemopoietic stem cell is a cytokine called granulocyte - colony stimulating factor (G-CSF). In recent years, the number of transplantations performed with mobilised blood stem cells has exceeded those performed with bone marrow. Elements contributing to this success have been the simplicity of the procedure (daily injections of a mobilising cytokines such as G-CSF), a more rapid recovery following high dose chemotherapy and transplantation, and lower costs. Despite its common use in clinics, the molecular mechanisms responsible for haemopoietic stem mobilisation following injection of cytokines are still unknown. A large body of experimental data demonstrate the critical role of adhesive interactions between blood forming cells and the bone marrow microenvironment These interactions control the lodgement of blood forming cells in the bone marrow, where they normally reside, and their egress into the blood during mobilisation. Experiments from this laboratory have shown that the mobilisation of blood forming cells that follows the administration of G-CSF, may be the consequence of the accumulation in the bone marrow of a class of leukocytes called neutrophils. These neutrophils subsequently release within the bone marrow a set of enzymes that specifically cleave a cell adhesion molecule expressed in the bone marrow, and therefore disrupt the adhesive interactions between the bone marrow and the blood forming cells resulting in their egress in the blood. This proposal aims to demonstrate this hypothesis and to provide tools to predict and improve the levels of mobilisation that can be achieved with healthy donors and cancer patients.Read moreRead less
Investigation Of Molecular And Cellular Determinants Of Immune Related Adverse Events Following Treatment With Immune Checkpoint Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$128,224.00
Summary
Novel immune-based treatments for advanced, incurable, cancer have significantly improved patient survival. Although these treatments have proven highly effective, they are associated with the unpredictable development of severe and sometimes life-threatening autoimmune disease. We aim to discover ways to predict and potentially prevent these complications by identifying genetic risk factors and markers in blood samples. If successful, this will be a ground breaking advance in cancer care.
Role Of Neutrophil Proteases And Their Inhibitors In Haematopoietic Stem Cell Mobilisation
Funder
National Health and Medical Research Council
Funding Amount
$472,750.00
Summary
Mobilisation is the enforced migration of blood forming cells (haemopoietic stem cells) from the bone marrow, where they normally reside, into the blood. The most common agent used to induce mobilisation of haemopoietic stem cells is a cytokine called G-CSF. In recent years, the number of transplantations performed with mobilised blood stem cells has exceeded those performed with bone marrow aspirates. The simplicity of the procedure (daily injections of G-CSF, absence of bone marrow aspiration) ....Mobilisation is the enforced migration of blood forming cells (haemopoietic stem cells) from the bone marrow, where they normally reside, into the blood. The most common agent used to induce mobilisation of haemopoietic stem cells is a cytokine called G-CSF. In recent years, the number of transplantations performed with mobilised blood stem cells has exceeded those performed with bone marrow aspirates. The simplicity of the procedure (daily injections of G-CSF, absence of bone marrow aspiration), better patient recovery and survival, lower costs have all contributed to the success of this procedure. Despite its common use in clinics to rescue cancer patients undergoing high-dose chemotherapy, the reasons why haemopoietic stem cells mobilise are still not fully understood. It is known that haemopoietic stem cells stay in the bone marrow because they express 'adhesive' molecules on their surface. In pioneering work, this laboratory has shown that cytokines such as G-CSF increases the number of neutrophils (a type of white blood cell) in the bone marrow. These neutrophils release enzymes (known as proteases) which cut into pieces the 'adhesive' molecules and other proteins responsible for the retention of blood forming cells within the bone marrow. This project aims to further these investigations to include both the role of proteases and their naturally-occurring inhibitors in the mobilisation of blood forming cells. Particularly, we will investigate how the expression of serpins and TIMPs, two families of protease inhibitors, is regulated in the bone marrow during mobilisation and how these inhibitors control the activity of proteases responsible for the mobilisation of blood forming cells. This knowledge may lead to the design of new treatments that induce more efficient mobilisation and ultimately improve the success of haemopoietic stem cell transplantation.Read moreRead less
Patient Tailored Anti-tumour T Cells To Prevent Relapse In Patients With Acute Myeloid Leukaemia Undergoing Allogeneic Haemopoietic Stem Cell Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$190,445.00
Summary
Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. Patients with high-risk AML have a 2-year survival of less than 20%. Blood or bone marrow transplant from a healthy donor is often the only chance of cure but the leukaemia frequently returns. Dr Blyth will perform a clinical trial giving leukaemia fighting immune cells from the transplant donor to patients with high risk AML to prevent relapse after transplant.
A Phase I Study Of Autologous CD19 Specific Chimeric Antigen Receptor T-cells For Therapy Of Relapsed And Refractory B-cell Leukaemia And Lymphoma (The Auto-CAR19 Trial).
Funder
National Health and Medical Research Council
Funding Amount
$584,666.00
Summary
Most people with leukaemia and lymphoma who relapse early after chemotherapy die of their disease. Inserting special genes into immune cells can enable them to kill leukaemia and lymphoma and has led to dramatic cures, but the cost of the viral vectors used to make these cells is prohibitively expensive. We will make leukaemia and lymphoma specific immune cells from patients using an inexpensive non-viral system, then administer the immune cells to patients to assess their safety and efficacy.
Develop New Approaches To Cancer Diagnosis And Treatment
Funder
National Health and Medical Research Council
Funding Amount
$4,000,000.00
Summary
Apoptosis is the dominant focus of our planned studies, because its impairment is both a critical step towards malignancy and a barrier to effective treatment. Arguably, the laboratory heads within our division and our collaborators from the Structure Biology Division at WEHI constitute the world’s strongest group with this focus. Our accumulated experience in this field from its renaissance in 1988 and the many unique materials they have created superbly position us to answer the fundamental qu ....Apoptosis is the dominant focus of our planned studies, because its impairment is both a critical step towards malignancy and a barrier to effective treatment. Arguably, the laboratory heads within our division and our collaborators from the Structure Biology Division at WEHI constitute the world’s strongest group with this focus. Our accumulated experience in this field from its renaissance in 1988 and the many unique materials they have created superbly position us to answer the fundamental questions and translate them into new therapeutic approaches. Our team’s second focus, the links of stem cells to cancer, is also of great importance, because the rare stem cells in the tumour may dictate therapeutic outcome. This Fellowship aims to addresses fundamental issues with enormous potential for medicine. It builds on productive ongoing research by a team with diverse complementary expertise, a record of effective interaction, high momentum and a history of path-breaking discoveries. I plan to maintain and further develop our Division (the Molecular Genetics of Cancer Division at WEHI) as one of the strongest teams for cancer research and development of cancer therapies in the world. Our division contains several laboratories that are highly interactive and complimentary in their approaches and research interests. I plan to strengthen the already highly productive laboratories in our division and to develop some new ones (see below under ‘proposed team’). I plan to increase work of our division to also include studies on other solid tumours (e.g. colon cancer, lung cancer, prostate cancer). This Fellowships aims to greatly enhance cancer research and hopefully also clinical practice in Australia. This should enhance the reputation of Australia as a country with recognized excellence in medical research and clinical practice. I am also confident that our division will continue to educate outstanding PhD graduates and postdoctoral fellows who will in due course become independent researchers and develop into future leaders in medical research in Australia and-or overseas.Read moreRead less
Prophylactic Early Parenteral Nutrition In Patients Undergoing Hematopoietic Cell Transplantation: A Multi-centre Randomised Controlled Trial.
Funder
National Health and Medical Research Council
Funding Amount
$1,131,673.00
Summary
We intend to conduct a multi-centre clinical trial in patients receiving bone marrow transplants to determine whether very early nutrition support improves overall survival.