Improved Relapse-Free Survival in Patients With High Natural Killer Cell Doses in Grafts and During Early Immune Reconstitution After Allogeneic Stem Cell Transplantation

Abstract

Mature immunocompetent cells from the stem cell graft as well as early robust immune reconstitution are essential for the graft-vs.-tumor (GVT) effect to eliminate residual malignant cells after allogeneic hematopoietic stem cell transplantation (HSCT). In this prospective study we characterized graft composition of T-and NK cell subsets in 88 recipients of peripheral blood stem cell grafts with multicolor flowcytometry. Our primary aim was to analyze the impact of graft composition on immune reconstitution and clinical outcomes after transplantation. Patients transplanted with graft NK cell doses above the median value of 27 × 10 6 /kg had significantly increased relapse-free-survival compared to patients transplanted with lower doses, HR 2.12 (95% CI 1.01-4.45, p = 0.04) Peripheral blood concentrations of NK cells obtained from donors before G-CSF mobilization were significantly correlated to graft NK cell doses (Spearman's ρ 0.53, p = 0.03). The dose of transplanted NK cells/kg correlated significantly with NK cell concentrations in patients early after transplantation (Spearman's ρ 0.26, p = 0.02, and ρ = 0.35, p = 0.001 for days 28 and 56, respectively). Early immune reconstitution above median values of NK cells was significantly associated with improved relapse-free survival (HR 2.84 [95% CI 1.29-6.28], p = 0.01, and HR 4.19 [95% CI 1.68-10.4], p = 0.002, for day 28 and 56, respectively). Early concentrations above the median value of the mature effector CD56dim NK cell subset were significantly associated with decreased relapse incidences at 1 year, 7% (95% CI 1.8-17) vs. 28% (95% CI 15-42), p = 0.04, and 7% (95% CI 1.8-18) vs. 26% (95% CI 14-40) %, p = 0.03, for days 28 and 56, respectively. The results suggest a protective effect of high doses of NK cells in grafts and during early immune reconstitution and support the perception of NK cells as innate effector cells with anti-tumor effects in the setting of allogeneic stem cell transplantation.

Granulocyte Colony-Stimulating Factor Effectively Mobilizes TCR γδ and NK Cells Providing an Allograft Potentially Enhanced for the Graft-Versus-Leukemia Effect for Allogeneic Stem Cell Transplantation

“…On the contrary, our results indicate preservation of the CD56dim subtype, as the subset distribution was not altered by G-CSF. High doses of CD56dim NK cells in PBSC graft ( 30 ) as well as during early immune reconstitution ( 11 ) have been associated with reduced relapse rates in clinical studies, indicating a favorable effect of G-CSF in preserving this subset.…”

“…Samples from these 14 BM grafts where included in this study for comparison between PBCS and BM graft types. Patient data (including complete graft data and immune reconstitution) and outcomes from the original study are presented in two previous publications ( 10 , 11 ).…”

“…In addition, TCR γδ cells and NK cells play an important role in the protection against infections, primarily cytomegalovirus (CMV), after HSCT ( 8 , 9 ). Recently, we found higher doses of TCR γδ cells and NK cells in the stem cell graft and during immune reconstitution to be associated with reduced relapse rates and improved survival in patients after HSCT ( 10 , 11 ). PBSC are being increasingly applied as graft source for HSCT and granulocyte colony-stimulating factor (G-CSF) is used for mobilization of peripheral blood stem cells in healthy donors ( 12 , 13 ).…”

Associations between the Gut Microbiota, Immune Reconstitution, and Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation

“…Enhanced neutrophil recovery provides innate immune defense against bacterial and fungal infections and can shorten hospital stay, yet has been associated with a risk of potentiating GvHD [12]. Likewise, increased natural killer (NK) cell recovery at days 28 and 56 decreases the risk of relapse, but may come at the expense of increased risk of GVHD [13,14]. Although early monocyte recovery is associated with decreased risk of relapse and improved overall survival, [15][16][17] early recovery of immune regulatory myeloid derived-suppressor cells at day 14 increases the risk of both relapse and paradoxically severe acute GVHD [18].…”

“…Protects against opportunistic infection [30] Early recovery associated with increased risk of GVHD [30] Monocyte Early recovery associated with less relapse in certain subsets [31] Timing of recovery not clearly associated with aGVHD [15] Dendritic cell Low plasmacytoid dendritic cell recovery associated with relapse and infection [32] High plasmacytoid and myeloid dendritic cell recovery associated with less incidence of severe aGVHD [32,33] NK cell Early recovery associated with less relapse [13,14] Early recovery associated with increased risk of aGVHD [13,14] Immunometabolism. 2021;3(1):e210004.…”