Improved Overall Survival, Relapse-Free-Survival, and Less Graft-vs.-Host-Disease in Patients With High Immune Reconstitution of TCR Gamma Delta Cells 2 Months After Allogeneic Stem Cell Transplantation

Abstract

T-cell receptor (TCR) γδ cells are perceived as innate-like effector cells with the possibility of mediating graft-vs. -tumor (GVT) without causing graft-vs.-host disease (GVHD) in the setting of hematopoietic allogeneic stem cell transplantation (HSCT). We conducted a prospective study to assess the clinical impact of TCR γδ cell immune reconstitution on overall survival, relapse-free-survival, relapse and GVHD. The impact of CD3, CD4, and CD8 T cells together with NK cells including subtypes were analyzed in parallel. A total of 108 patients with hematological malignancies transplanted with HLA-matched, T cell replete stem cell grafts were included for analyses of absolute concentrations of CD3, CD4, and CD8 positive T cells and NK cells together with a multi-color flow cytometry panel with staining for TCRαβ, TCRγδ, Vδ1, Vδ2, CD3, CD4, CD8, HLA-DR, CD196, CD45RO, CD45RA, CD16, CD56, CD337, and CD314 at 28, 56, 91, 180, and 365 days after transplantation. Immune reconstitution data including subsets and differentiation markers of T and NK cells during the first year after transplantation was provided. Patients with TCR γδ cell concentrations above the median value of 21 (0–416) × 10 6 cells/L 56 days after transplantation had significantly improved overall survival ( p = 0.001) and relapse-free survival ( p = 0.007) compared to patients with concentrations below this value. When day 56 cell subset concentrations were included as continuous variables, TCR γδ cells were the only T cell subsets with a significant impact on OS and RFS; the impact of TCR γδ cells remained statistically significant in multivariate analyses adjusted for pre-transplant risk factors. The risk of death from relapse was significantly decreased in patients with high concentrations of TCR γδ cells 56 days after transplantation ( p = 0.003). Also, the risk of acute GVHD was significantly lower in patients with day 28 TCR γδ cell concentrations above the median of 18 × 10 6 cells/L compared to patients with low concentrations ( p = 0.01). These results suggest a protective role of TCR γδ cells in relapse and GVHD and encourage further research in developing adaptive TCR γδ cell therapy for improving outcomes after HSCT.

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

“…Tables 5A,B shows univariate and multivariate associations between cell subset concentrations in peripheral blood during Figure 5. Associations for T cell subsets were similar to previously published data (27).…”

“…By day 56, patients with concentrations above the median value of total NK cells (p = 0.04) and CD56dim cells (p = 0.03) had lower cumulative incidence of relapse compared to patients with values below the median of these cell types, Figure 8. Associations to remaining cell subsets where similar to those presented for the original cohort (27).…”

“…There was a trend toward an increased incidence of aGVHD in patients with day 28 CD56bright NK cell concentration below the median of 60 × 10 6 /L, p = 0.08. Associations to remaining cell subsets where similar to those presented for the original cohort (27).…”

“…Our original study included 111 patients transplanted with peripheral blood stem cells or bone marrow and data on immune reconstitution and clinical outcomes in all patients are recently published (27). Here, data on healthy donors together with data from stem cell grafts in patients transplanted with PBSC are presented and correlated with data on immune reconstitution and clinical outcomes.…”

“…Here we report data on stem cell grafts, immune reconstitution, and clinical outcomes in HSCT patients transplanted with PBSC. Details on immune reconstitution and the impact on clinical outcomes for the included patients is recently published as part of a larger cohort (27) why results in this report are focused on stem cell grafts and their impact on immune reconstitution and clinical outcomes.…”