Cell Therapy Methods to Improve AML Patient Outcome Post Allo-HSCT

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, received a CureSearch Acceleration Initiative grant to improve the odds for patients with AML following a stem cell transplant. The Stanford team 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 reducing or eliminating GvHD. The researchers are testing 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 alter the patient’s immune system and facilitate organ transplant while IL-10 helps support T-regulatory lymphocyte function. The TR-IL10 cells are being 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.

As of the conclusion of her CureSearch-funded project, Dr. Roncarolo has developed a potential modification to standard of care that should improve outcomes for patients with AML:

• 1 cell therapy method in preclinical testing to improve AML patient outcome after allo-HSCT
• 4 classes of sensitivity to Tr1(CD4^IL-10) identified
• 301 potential biomarkers of AML sensitivity identified
• 2 novel targets identified that can potentially be manipulated to modify the pediatric AML blast sensitivity to killing