Researchers have identified factors that could determine whether donor lymphocyte infusion—a type of adoptive cell therapy—will result in remission among patients with acute myeloid leukemia (AML) who have relapsed following allogeneic hematopoietic stem cell transplant (HSCT), according to a recent study published by Maurer et al in Science Immunology.
Background
Among patients with AML, a stem cell transplant holds the potential for a cure. The goal of the transplant is to replace the patient’s hematopoietic stem cells—cells that rejuvenate supplies of blood and immune cells—with nonmalignant donor stem cells. The donor cells also include active immune cells that can attack leukemia cells that remain in the patient following the stem cell transplant, known as the graft-vs-leukemia effect. Although approximately 33% of patients with AML relapse following allogeneic HSCT, donor lymphocyte infusion is a standard follow-up therapy that can help prevent or treat relapse. The treatment involves an infusion of lymphocytes from the donor of the stem cell transplant into the patient.
“Relapse of AML after stem cell transplant is a major challenge,” explained lead study author Katie Maurer, MD, PhD, of Dana-Farber Cancer Institute. “There are few effective therapies, and patient outcomes after relapse are poor,” she explained.
Nonetheless, donor lymphocyte infusion is successful in just 15% to 20% of the patients with AML. Currently, the mechanism by which the cells in the donor lymphocyte infusion product help move leukemia into remission are unknown, making it difficult for researchers to improve the treatment.
Study Methods and Results
In the study, the researchers sought to better understand the factors contributing to the success of donor lymphocyte infusion. They examined cells from the bone marrow of 25 patients with relapsed leukemia who had received an allogeneic HSCT and donor lymphocyte infusion. The sample included both patients who responded and didn’t respond to donor lymphocyte infusion.
The researchers employed single-cell sequencing techniques to deeply profile multitudes of cells from each patient, enabling them to uncover the range of cell types in the bone marrow and better understand how those cells were interacting and driving immune responses in the patients.
The researchers found that a key cell type that originated in the donor lymphocyte infusion product—which was present in the donor’s original graft and reinfused during donor lymphocyte infusion—and features of patients’ tumor microenvironments both played a role. Notably, the patients who responded to donor lymphocyte infusion therapy had different cellular populations in their bone marrow compared with those who did not respond. The researchers suggested that there may be types of AML that respond to immune therapy, termed “hot,” and those that don’t, termed “cold.” This was similar to the “hot” and “cold” paradigm seen in some solid tumors.
Further, the researchers identified a single immune cell type that appeared to mediate the graft-vs-leukemia effect in patients who responded to donor lymphocyte infusion. The cell type—CD8-positive, cytotoxic T lymphocytes that expressed a transcription factor called ZNF683/Hobit at high levels—was shown to coordinate with other immune cells to expand and attack leukemia cells. In patients who did not respond, these T cells had lower levels of expression of ZNF683/Hobit and higher levels of markers that inhibited their activity.
Conclusions
“The goal of our research is to identify the ways in which some patients respond in the hopes that uncovering these mechanisms can help us create improved therapies that are more effective for a greater number of patients,” underscored Dr. Maurer. “In this project, we identified a specific subset of activated T cells that have antileukemic activity. This discovery paves the way for creation of T-cell therapies with improved efficacy in treating AML,” she concluded.
Disclosure: The research in this study was funded by the National Institutes of Health, the National Cancer Institute, Columbia University, the American Society of Hematology, the Lubin Family Foundation, the Berlin Institute of Health at Charité, Deutsche Krebshilfe, the Else Kröner-Fresenius-Stiftung, the Cancer Prevention and Research Institute of Texas, the Be the Match Foundation, the Lavine Family Foundation, and the Leukemia and Lymphoma Society. For full disclosures of the study authors, visit science.org.
