CureSearch Acceleration Initiative Award, 2016-2018
Maria-Grazia Roncarolo, MD
Research Focus: Acute Myeloid Leukemia
What This Project Does
Acute myeloid leukemia (AML) accounts for 25 percent 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 transplantation (allo-HSCT)—the transfer of stem cells from a donor to the patient. 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 that the T-cells in the donor blood kill the leukemia cells, in a process 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 occurs when immune cells in the donor 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 are developing a novel cell-based therapy for AML patients that aims to reduce GvHD while maintaining the beneficial effects of GvL. Their approach is to engineer donor T-regulatory lymphocytes to be added to standard allo-HSCT therapy. The researchers will test their approach by infusing donor T-regulatory lymphocytes that overproduce a molecule called interleukin 10 (IL-10), called TR-IL10 cells, into the patient. 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.
30 Month Research Update
Dr. Roncarolo and collaborators have selected a TR-IL10 cell development method that produces cells that impair AML growth in vivo in three different models of AML. Importantly, they have also validated that these cells retain their anti-GvHD effect. In an effort to advance these cells into clinical trials, Dr. Roncarolo’s team has established a defined protocol to generate them and is working with the Stanford Laboratory for Cell and Gene Medicine (LCGM) to adapt the protocol to produce cells that adhere to Good Manufacturing Practice (GMP) regulations for use in humans. In addition, they are testing a method of cell preparation that will improve the reproducibility of cell generation. Dr. Roncarolo anticipates the beginning of TR-IL10 cell scale-up experiments and preparation of a pre-IND by the end of this year.
In parallel to the development of these specialized cells, Dr. Roncarolo’s group is determining what molecular changes confer sensitivity of AML to their cell-based therapy. Some pediatric AML samples are resistant to killing while others are susceptible and an understanding of genes whose expression correlates with cell killing could aid in the proper selection of patients for this therapy. The Roncarolo lab has observed specific killing in 60 percent of the AML samples that they have tested and have identified four subgroups of AML: (1) high sensitivity to killing, (2) intermediate sensitivity to killing, (3) resistant to killing, and (4) variable killing. Assessment of transcriptomic sequencing (RNA) in the high sensitivity, intermediate sensitivity, and resistant groups has yielded 573 genes that are related to specific killing.