New findings led by University of North Carolina Lineberger Comprehensive Cancer Center researchers will help lay the foundation for developing highly personalized immune therapies for acute myeloid leukemia patients.
In the journal Blood Advances, UNC Lineberger’s Ben Vincent, MD, Paul Armistead, MD, PhD, and their collaborators reported early findings from a study that could aid in the development of immune-based treatments that are tailored to individual leukemia patients who are undergoing stem cell transplantation.
“If you could identify and activate the immune cells from the stem cell donor that only target leukemia cells, and not normal, healthy cells, that would be a big win,” said Vincent, who is an assistant professor in the UNC School of Medicine Division of Hematology/Oncology and was co-senior author of the paper along with Armistead.
The researchers’ approach relies on the fact that a patient’s cells can have unique genetic signatures that produce proteins that are distinct from any proteins found in the stem cell donor. The patient’s proteins can serve as markers for the cancer cells’ destruction by the donor’s natural defense system, which is activated in the process of stem cell transplantation. The researchers reported in their study they were able to validate their method of using genetic sequencing and computer software to predict which of those patient sequences resulted in unique surface markers, or minor histocompatibility antigens. They confirmed this approach in a group of patients with myeloid leukemia who were undergoing stem cell tranplant.
In their retrospective study, the researchers tested whether their software could predict antigenic targets in a group of 101 leukemia patients who had undergone stem cell transplant. Using the software, they correctly identified 16 of 18 minor histocompatibility antigens that are known to occur in AML. In addition, they predicted more than 100 new minor histocompatibility antigen targets that could be expressed on an individual’s AML cells.
Because AML does not have one clear immune target, the validation of multiple potential targets is crucial. Based upon their computational predictions, the researchers confirmed a new minor histocompatibility antigen that is commonly presented on AML cells, and subsequently identified immune responses to this antigen in four of nine AML patients who had undergone stem cell transplant. Given these properties, this antigen could serve as a new target for immunotherapies across a wide range of AML patients.
Looking ahead, the researchers want to optimize their software to predict the most common AML-associated minor histocompatibility antigens present in the U.S. population, and then confirm these predicted antigens as valid immunotherapy targets. They could potentially use their predictions to engineer donor immune cells to specifically target the cancer cell antigens while preventing graft-versus-host disease, in which the donor’s immune cells attack healthy tissues.
“We’ve developed a software package that predicts leukemia-specific immune targets in any leukemia patient undergoing a stem cell transplant based on DNA and RNA sequencing and demonstrated that these data can lead to actual targets expressed on leukemia cells,” Vincent said. “The next step of our work is to use that information for patient-specific therapies to try to improve cure rates without making graft-versus-host disease worse.”
In addition to Vincent and Armistead, other authors from UNC-Chapel Hill involved in the study included: Jefferson L Lansford, UNC School of Medicine; Udara Dharmasiri, formerly of UNC Lineberger; Shengjie Chai, UNC School of Medicine Curriculum in Bioinformatics and Computational Biology; Sally A. Hunsucker and Dante S. Bortone, UNC Lineberger; James E. Keating, Ian Schlup and Gary Glish, UNC-Chapel Hill Department of Chemistry, and Edward J. Collins, formerly of the UNC School of Medicine Department of Microbiology and Immunology.
The research was supported by the National Institutes of Health, the National Cancer Institute as well as an ASCO Young Investigator Award. Individual researchers were also supported by the University Cancer Research Fund and the Scott Neil Schwirck Fellowship.