What This Project Does
Acute myeloid leukemia (AML) accounts for 25% of all childhood leukemias with nearly 1,000 children and adolescents diagnosed each year. The current treatment for AML is aggressive chemotherapy followed by a stem cell transplant. The procedure is called an allogeneic (from a donor) hematopoietic stem cell transplantation (allo-HSCT). In this procedure, blood stem cells found in the bone marrow of a matched donor are infused into the AML patient’s blood. The therapeutic benefit of allo-HSCT is killing of the leukemia by T-lymphocytes in the donor blood, known as graft versus leukemia (GvL). However, a highly undesirable side effect of allo-HSCT is known as Graft versus Host Disease (GvHD). This condition is often fatal and is a leading cause of patient mortality. GvHD is commonly associated with stem cell or bone marrow transplant. Immune cells (white blood cells) in the tissue (the graft) recognize the recipient (the host) as “foreign.” The transplanted immune cells then attack the host’s body cells.
Dr. Maria-Grazia Roncarolo and her collaborator, Dr. Rosa Bachetta, at Stanford University, recently received a CureSearch Acceleration Initiative grant to improve the odds for patients with AML following a stem cell transplant. The Stanford team has developed a method to optimize GvL and minimize GvHD. Their approach is to engineer donor T regulatory lymphocytes as a supplement to standard allo-HSCT therapy. The engineered cells allow for killing of the leukemia while at the same time reduce or eliminate GvHD. The researchers will test their approach by infusing donor T-regulatory lymphocytes that overproduce a molecule called interleukin 10 (IL-10) into the patient (TR IL10 cells). T-regulatory lymphocytes modulate the patient’s immune system and facilitate organ transplant while IL-10 helps support T-regulatory lymphocyte function. The TR-IL10 cells will be tested for their ability to promote GvL in AML patient blood samples and to promote GvL and prevent GvHD in mouse models of AML. The ultimate goal of the research is to develop a cell-based therapy that will be tested in a clinical trial. The hope of Dr. Roncarolo and her team is that this new therapy will dramatically reduce mortality and improve the long-term survival of pediatric AML patients.
12 Month Research Update
Dr. Roncarolo and her team have spent the first year of the study developing the tools needed to conduct their novel cell therapy protocol for treating AML patients. To accomplish this, they have produced and characterized 7 novel cell lines that produce the IL-10 cytokine. They are now confirming the phenotype of these cells, and will then assess the ability of cell lines to kill AML samples obtained from bone marrow, blood, or cerebrospinal fluid of AML pediatric patients. They will test a panel of 40 pediatric patient AML samples which are immediately available through the Bass Center Leukemia Tissue Bank at Stanford.
To better determine the molecules that direct the cells to kill AML, they are developing a flow cytometry panel based on known AML surface markers. Identified markers will be “knocked-out” using “gene editing” to determine which markers mediate cell killing. The data generated from these in vitro experiments will direct characterization of patient AML samples so that gene expression can be correlated to susceptibility to cell therapy-mediated killing.