Allogeneic hematopoietic stem cell transplantation, while proven as an effective therapy for a number of cancers and other diseases, remains limited by high morbidity and mortality after the procedure. Although patient outcomes have improved over the past few decades, possible adverse effects still include graft-versus-host disease, infection, and relapse.
A new retrospective study has found the immune cell content of granulocyte colony-stimulating factor-mobilized peripheral blood stem cell grafts may have an effect on how well transplants are tolerated by patients. The analysis indicated a higher dose of invariant natural killer T (iNKT) cells is associated with an improved outcome in terms of graft-versus-host disease and relapse/progression.
Allogeneic stem cell transplantation from an HLA-matched or unrelated donor was performed in 80 patients whose diagnoses included both myeloid and lymphoid malignancies. The researchers identified subsets of immune cells in each graft to determine any possible influence in terms of patient outcomes. A larger number of donor iNKT cells in the graft, while having no impact on overall survival, did correlate with improved graft-versus-host disease-free, progression-free survival.
The study, published online by the journal Blood in February, suggests new interventions could be developed to manipulate the graft content to up the dose of iNKT cells and lower the risk of complications related to allogeneic stem cell transplantation.
“Our observation is quite strong and could pave the way for future developments. For instance, you can start tailoring the graft that you are going to infuse to the patient, which we know from the technological point of view is feasible,” said study author Mohamad Mohty, MD, PhD, Professor of Hematology and Head of the Hematology and Cellular Therapy Department at the Saint-Antoine Hospital and University Pierre & Marie Curie. “If these iNKT cells have a positive impact, then why not tailor the graft to make it richer in terms of this substance?”
Although researchers have begun to scratch the surface, much still remains unknown about how much immune cell subsets matter in terms of allogeneic hematopoietic stem cell transplantation. Also, most studies tend to focus on a specific immune cell population rather than a large collection of immune subpopulations. For instance, one recent publication found higher graft CD8 dose predicts better survival in patients undergoing reduced-intensity conditioned transplant.
“This is quite a long ago idea I had, along with many investigators in this field, that the content of the graft that we infuse to patients should be able to modulate or at least have some significant influence on the outcome of the patient—whether that be disease relapse, survival, or complications,” said Mohty.
In 2004, Mohty and his colleagues discovered that a greater dose of CD8+ T cells in the allograft was associated with a higher likelihood of developing acute graft-versus-host disease in 57 patients who received allogenic peripheral blood stem cells from HLA-identical siblings. As an updated version of that study, they decided to use today's advanced technology to look deeper into the content of allografts and build upon that previous work.
The study used frozen aliquots of peripheral blood stem cell grafts from 80 patients who underwent allogeneic transplantation at the University Hospital of Nantes in France between 2010 and 2013. Their diagnoses included acute myeloid leukemia (n = 33), non-Hodgkin lymphoma (n = 17), acute lymphoblastic leukemia (n = 8), myelodysplastic syndrome (n = 8), and other myeloid or lymphoid malignancies.
A wide range of immune cells were analyzed by either flow cytometry or intranuclear staining techniques: naïve and memory T-cell subsets, B cells, regulatory T cells, iNKT cells, natural killer cells, and dendritic cell subsets.
For a median follow-up of 37 months among surviving patients, two-year overall survival was 58 percent. However, none of the cell subsets—including iNKT cells—had a significant association with this endpoint. The researchers also calculated another primary endpoint called graft-versus-host disease-free and progression-free survival (GPFS), defined as survival with no evidence of relapse/progression, grade III-IV acute graft-versus-host disease, and systemic therapy-requiring chronic graft-versus-host disease. The two-year GPFS was significantly higher for patients who received greater than the median number of iNKT cells (49%) versus those who did not (22%).
“To go away from the traditional cells, we analyzed cell subsets that had not been very much looked at in the literature,” he said. “We were very keen on including iNKT cells because this is a very rare subset of cells which is not very easy to identify and quantify, but there was some strong scientific rationale that they would have an effect on patient outcome.”
Previous research had suggested iNKT cells could play a role in reducing the incidence of graft-versus-host disease or even the incidence of immunological conflict between the donor and recipient. Because these can initiate complications after transplant, Mohty hopes his findings on iNKT cell dose could reduce adverse effects without favoring disease relapse.
After additional confirmatory studies, possible interventions that would harness these findings include tailoring the graft to include a higher dose of iNKT cells, or giving a pill after transplant that would spur an in vitro proliferation and expansion of iNKT cells.
Meeri Kim is a contributing writer.