Anti-leukemia potential of interleukin-2 activated natural killer cells after bone marrow transplantation for chronic myelogenous leukemia

Abstract

The anti-leukemia potential of natural killer (NK) cells has been evaluated in 40 patients transplanted for chronic myelogenous leukemia (CML) to determine whether differences in NK cell function were correlated with subsequent leukemic relapse. Cells from patients and their donors were tested in 51Cr release assays against fully allogeneic CML targets and against cultured K562 targets; cells from 26 patients were tested against host-derived CML targets that were cryopreserved before transplantation. Cultured CML targets (K562) were highly susceptible to lysis by freshly isolated peripheral blood lymphocytes (PBL) and to a greater degree by PBL cultured in medium containing interleukin-2 (IL-2) in all assays performed. In contrast, noncultured CML targets were lysed only by IL-2-activated cells from a subset of patients. When present, lytic activity to CML targets was detectable as early as 3 weeks after bone marrow transplantation, and remained positive throughout the posttransplant period. Optimal lytic activity developed within the first week of culture and required greater than or equal to 250 U/mL of IL-2 in the culture medium. Lytic activity to fully allogeneic and host-derived CML targets appeared to be mediated by CD16+ and CD56+ cells but not by CD3+ cells. Lysis of allogeneic CML targets was variable, but patients could be divided into two groups: those with and those without lytic activity to the majority of targets tested. The basis for the differences in lytic activity could not be ascribed to target susceptibility to lysis, the proportion of NK cells in the cultures, or to the phenotype of the NK cell subsets in the cultures. When tested in parallel, the lytic activity of donor and recipient cultures against host-derived CML targets was highly correlated, suggesting that there may be inherent differences in the ability of NK cells to recognize CML targets. The risk of relapse for patients who failed to generate lytic activity against host-derived CML targets was significantly increased over that for patients with lytic activity against host leukemia. These data indicate that posttransplant immunotherapy with IL-2 designed to activate NK cells will likely augment the graft-versus-leukemia potential of the graft.

The allogeneic graft‐versus‐cancer effect

“…Therefore, it seems that NK‐cells have an antileukaemic effect against AML but not ALL (Ruggeri et al , 2002; Aversa et al , 2005). Furthermore, an anti‐leukemic effect by IL‐2‐activated NK‐cells was previously reported after HSCT in patients with CML (Hauch et al , 1990).…”

Harnessing graft-versus-malignancy: non-myeloablative preparative regimens for allogeneic haematopoietic transplantation, an evolving strategy for adoptive immunotherapy

“…In patients transplanted for CML, several recent studies have identified CD4 1 T-cell lines or clones that either inhibit the growth of leukaemia progenitors or are directly lytic (Sosman et al, 1990;Van der Harst et al, 1994;Jiang & Barrett, 1995;Jiang et al, 1996). Natural killer cells have also been implicated as mediators of GVL effects (Hauch et al, 1990;Okunewick et al, 1995;Zeis et al, 1995;Glass et al, 1996;Jiang et al, 1997).…”

Donor Selection for Killer Immunoglobulin-like Receptors B Haplotype of the Centromeric Motifs Can Improve the Outcome after HLA-Identical Sibling Hematopoietic Stem Cell Transplantation

“…In allogeneic HSCT, donor NK cells attack the allogeneic cells if the recipient HLA class I ligands do not sufficiently engage their inhibitory receptors. Alloreactive donor-derived NK cells are thought to promote engraftment [3][4][5][6], reduce GVHD [7,8], mediate a graft-versus-leukemia effect, and decrease leukemic relapse [4,9,10], resulting in an antileukemic response with lower relapse rates, fewer graft failures, and less GVHD, ultimately leading to improved overall survival (OS) [11,12]. Some recent studies have indicated that KIR interactions of donor and recipient can influence the outcomes of haploidentical [13][14][15], matched-unrelated donor [3,16,17], and matched-related donor [2,5,[18][19][20][21][22] allogeneic HSCT, particularly in patients with acute myeloid leukemia (AML).…”