No immature cells allowed – removing naïve T-cells in hematopoietic stem cell transplants

From the Bleakley Lab, Clinical Research Division

Hematopoietic stem cell transplantation (HCT) is a procedure commonly performed for patients with hematologic malignancies, and in some instances can eliminate the cancer of the patient receiving HCT. However, one of the most common side effects of HCT is graft-versus-host disease (GVHD), a complicated disease state whereby the cells of the transplant donor attack and kill the normal healthy cells of transplant recipient causing serious side effects such as fatigue, chronic pain and tissue damage that greatly reduce quality of life and can increase mortality risk. Dr. Marie Bleakley, an Associate Professor in Fred Hutch’s Clinical Research Division, Dr. Warren Shlomchik and colleagues have worked to overcome the challenge of GVHD by manipulating the T-cell component of peripheral blood stem cell transplant donor grafts.

In their previous research, they observed that of the different T-cell subtypes circulating after engraftment, naïve T-cells (antigen-inexperienced T-cells that do not recognize previous infections) were the most likely to cause GVHD in mouse models by attacking the host (mouse) endogenous cells as well as the foreign pathogens. Conversely, memory T-cells (cells, that as their name suggest recall antigens present on the surface of pathogens as well as cancerous cells) had a much-decreased likelihood of causing GVHD and instead promoted the continued positive effect of the transplant graft on the recipient. Capitalizing on this finding, the authors developed a method that enables the effective depletion of naïve T-cells from the transplant donor stem cell graft. The method is characterized by targeting a marker, CD45RA, present on the surface of naïve T-cells but absent on most memory T-cells. This method greatly reduces the numbers of naïve T-cells that will be part of the transplant procedure, while retaining memory T-cells. Their most recent work in three phase I clinical trials for patients undergoing allogeneic transplants, published in Journal of Clinical Oncology, utilizes this naïve T-cell depletion methodology and describes a significant decrease in the risk of developing chronic GVHD, demonstrating the potential of this approach in improving quality of life outcomes for patients. 

Decreasing the number of naïve T-cells reduces risk of chronic graft-versus-host disease in hematopoietic stem cell transplantation recipients.
Decreasing the number of naïve T-cells reduces risk of chronic graft-versus-host disease in hematopoietic stem cell transplantation recipients. Image provided by Dr. Bleakley.

The authors enrolled patients into one of three phase I clinical trials and subjects (n=138) received a naïve T-cell depleted peripheral blood stem cell graft. The intent of the trial was to ascertain the impact of naïve T-cell depleted grafts on reducing chronic GVHD and to assess the impact on overall survival and relapse rates. Incidence of serious acute GVHD, was observed at very low levels among naïve T-cell depleted transplant recipients and, excitingly, rates of chronic GVHD were only observed in 6% (mild), 1% (moderate) and 0% (severe) of trial participants after three years observation, a drastic reduction from rates of 30-60% routinely reported from traditional standard of care HCT. Further, the authors did not observe any increased risk of relapse or reduction in overall survival rates attributed to this novel transplant method, supporting their preliminary observations that naïve T-cell depleted HCT procedures can greatly aid in reducing risk of severe side effects for HCT recipients. Support from the Fred Hutch/University of Washington/Seattle Children's Cancer Consortium has enabled this research to continuously advance in the clinical trial realm. The Consortium “supports 'Clinical Research Support (CRS)' which provides essential infrastructure to conduct our clinical trials, including managing the investigational new drug application and ongoing regulatory requirements,” said Dr. Bleakley.

Moving forward, Dr. Bleakley and colleagues are further investigating their findings from single-arm phase II clinical trials by expanding to randomized phase II trials in patients undergoing HCT. “We are conducting two randomized controlled trials comparing the naive T cell-depletion technique that we developed and have tested in the three single-arms trials to 1) standard bone marrow transplantation in pediatrics and young adults (NCT03779854) and to, 2) another promising GVHD reduction strategy (NCT03970096),” summarized Dr. Bleakley.

This work was supported by funding from the National Institutes of Health, the Damon Runyon Cancer Research and Richard Lumsden Foundations, the National Cancer Institute, a Special Fellowship in Clinical Research from the Leukemia and Lymphoma Society and the Burroughs Wellcome Fund.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Dr. Marie Bleakley, Dr. Melinda A. Biernacki, Dr. Elizabeth F. Krakow, Dr. Anne Dahlberg, Dr. Paul J. Martin, Dr. Paul A. Carpenter, Dr. Mary E. Flowers, Dr. Ted A. Gooley, Dr. Keith Loeb, Dr. Brent L. Wood and Dr. Stanley R. Riddell contributed to this work.

Bleakley M, Sehgal A, Seropian S, Biernacki MA, Krakow EF, Dahlberg A, Persinger H, Hilzinger B, Martin PJ, Carpenter PA, Flowers ME, Voutsinas J, Gooley TA, Loeb K, Wood BL, Heimfeld S, Riddell SR, Shlomchik WD. Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease. J Clin Oncol. 2022 Apr 10;40(11):1174-1185. doi: 10.1200/JCO.21.01755. Epub 2022 Jan 10. PMID: 35007144; PMCID: PMC8987226.