High PR3 or ELA2 expression by CD34+ cells in advanced-phase chronic myeloid leukemia is associated with improved outcome following allogeneic stem cell transplantation and may improve PR1 peptide–driven graft-versus-leukemia effects

Abstract

phase (AdP), a higher expression of both PR3 and ELA2 in CD34 ؉ progenitors before SCT was associated with a lower incidence of relapse-related death, improved leukemia-free survival (LFS), and overall survival (OS); in chronic phase patients, no differences were observed. PR1-CTL responses were detected in 7 of 27 HLA-identical sibling donors, and associated with improved LFS and OS after SCT on follow-up. PR1-CTL responses detected in 7 of 28 CML patients before transplantation were not predictive of outcome and correlated inversely with PR3 and ELA2 expression. These findings suggest that assessment of PR3 and ELA2 expression in leukemic progenitors is useful for predicting posttransplantation outcome in AdP patients undergoing SCT. The presence of a donor immune response against PR1 may be advantageous and could be exploited therapeutically. (Blood. 2007;110:770-775)

Association between BMI-1 expression, acute graft-versus-host disease, and outcome following allogeneic stem cell transplantation from HLA-identical siblings in chronic myeloid leukemia

“…CD7, PR-3, and ELA-2 expression was not associated with OS. These data corroborate those from Yong et al, 8 where PR-3 and ELA-2 expression prior to allo-SCT was prognostic only in advancedphase CML but not in CP-CML. However, and in sharp contrast to our previous findings in the non-allo-SCT setting, 6 patients displaying a "high" BMI-1 expression level prior to allo-SCT had significantly better OS than those with low expression (P ϭ .005; Figure 1A).…”

“…4 We have recently shown in patients with CML who did not receive allo-SCT that the combination of CD7, proteinase-3 (PR-3), elastase-2 (ELA-2), and the polycomb group (PcG) gene BMI-1 expression levels at diagnosis can reflect the intrinsic molecular heterogeneity of the disease, especially disease aggressiveness and duration of chronic phase (CP). 5,6 As immune responses to both PR-3 and ELA-2 peptides have been implicated in the eradication of CML following allo-SCT, 7,8 we investigated whether these genes might also serve as biomarkers to predict outcome of patients with CP-CML receiving allo-SCT.…”

CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors

“…[20][21][22] A phase 1 trial (NCT02011945) of dasatinib and nivolumab, a PD-1 inhibitor, is recruiting, with MMR and DMR incidence as planned outcome measures. LAAs such as WT1, PRAME, PR3, and BMI-1 in CML patients represent attractive targets for immunotherapy, [23][24][25][26][27][28][29] with efficacy demonstrated in vaccination, including dendritic cell vaccination, [30][31][32][33] and, more recently, T-cell receptor-mimic antibodies. [34][35][36] In support of these studies, we observed maximal restoration of immune recovery, as demonstrated by increased effector NK cell and T-cell immune responses, reduced PD-1 inhibitory molecule expression on CD4 1 and CD8 1 T cells, and reduced numbers of Mo-MDSC in MR 4.5 only, suggesting DMR may be the preferred threshold for future TFR studies to benefit from the improved effector immune responses.…”

Prophylactic transfer of BCR-ABL–, PR1-, and WT1-reactive donor T cells after T cell–depleted allogeneic hematopoietic cell transplantation in patients with chronic myeloid leukemia

“…This immunotherapeutic strategy combines the antitumor effects mediated by both T-cell subsets and may induce more effective tumor-directed responses. 43 Furthermore, peptides derived from additional leukemia antigens, such as elastase, prame, and hyaluronic acid receptor, [44][45][46] can be used to generate specific T cells. Purifying antigen-specific T cells by their secretion of interferon-␥ or their binding to peptide/human leukocyte Ag complexes may increase the specificity of adoptive cellular therapy and thereby decrease the risk for acute and chronic GVHD.…”