A role of donor-specific HLA antibodies (DSA) in graft failure after SCT has been suggested, but the relevance of DSA in unmanipulated haploidentical SCT (haplo-SCT) remains unknown. We prospectively examined HLA antibodies using the Luminex-based single Ag assay for 79 adult patients undergoing unmanipulated haplo-SCT. Among them, 16 (20.2%) were HLA Ab-positive, including five patients with antibodies not corresponding to donor HLA Ags and 11 DSA-positive patients. Of the 11 DSA-positive patients, five received treatments to decrease DSA levels, including two, who received plasma exchange and rituximab, two who received platelet transfusions from healthy-related donors having DSAcorresponding HLA Ags and one who received bortezomib. Platelet transfusion was the most simple and effective treatment option for class I DSA. The cumulative incidence of neutrophil recovery was significantly lower in pretransplant (post-treatment) DSA-positive patients than in DSA-negative patients (61.9 vs 94.4%, P ¼ 0.026). Notably, three of five patients with high levels of DSA had graft failure. Donors should be selected on the basis of an evaluation of HLA antibodies. If haplo-SCT from donors with HLA Ags that correspond to high levels of DSA must be performed, then recipients should be treated for DSA to improve the chances of successful donor engraftment.
Expression of theThe Wilms' tumor gene WT1 was originally isolated as a tumorsuppressor gene responsible for Wilms' tumor, a kidney neoplasm of childhood. 1 However, we proposed that WT1 played an oncogenic role in leukemogenesis based on the following findings: 2 (i) the wild-type WT1 gene was expressed at high levels in leukemic blast cells, 3,4 (ii) there was a clear and inverse correlation between WT1 expression levels and prognosis in acute leukemia, 3 (iii) WT1 expression increased at relapse of acute leukemia, 5 (iv) growth of leukemic blast cells was inhibited by the treatment of WT1 antisense oligomers 6 and (v) constitutive expression of WT1 blocked differentiation and instead induced proliferation in response to granulocyte colony-stimulating factor in 32D cl3 myeloid progenitor cells 7 and normal myeloid progenitor cells. 8 Furthermore, we demonstrated that the wild-type WT1 as expressed in various types of cell line derived from lung cancer, gastric cancer, colon cancer and breast cancer and that growth of these WT1-expressing tumor cells was inhibited by the treatment of WT1 antisense oligomers. 9 These data suggested an oncogenic role of the WT1 gene in tumorigenesis. However, the involvement of the WT1 gene in de novo solid tumors remained unclear. In the present study, we examined WT1 expression in de novo lung cancer using quantitative real-time RT-PCR and immunohistochemistry and demonstrated that the wild-type WT1 was overexpressed in 54/56 (96%) de novo non-small cell lung cancers (NSCLCs) and 5/6 (83%) de novo small cell lung cancers (SCLCs) examined.
In acute-type leukemia, no method for the prediction of relapse following allogeneic stem cell transplantation based on minimal residual disease (MRD) levels is established yet. In the present study, MRD in 72 cases of allogeneic transplantation for acute myeloid leukemia, acute lymphoid leukemia, and chronic myeloid leukemia (accelerated phase or blast crisis) was monitored frequently by quantitating the transcript of WT1 gene, a "panleukemic MRD marker," using reverse transcriptase-polymerase chain reaction. Based on the negativity of expression of chimeric genes, the background level of WT1 transcripts in bone marrow following allogeneic transplantation was significantly decreased compared with the level in healthy volunteers. The probability of relapse occurring within 40 days significantly increased step-by-step according to the increase in WT1 expression level (100% for 1.0 ؋ 10 ؊2 -5.0 ؋ 10 ؊2 , 44.4% for 4.0 ؋ 10 ؊3 -1.0 ؋ 10 ؊2 , 10.2% for 4.0 ؋ 10 ؊4 -4.0 ؋ 10 ؊3 , and 0.8% for < 4.0 ؋ 10 ؊4 ) when WT1 level in K562 was defined as 1.0). WT1 levels in patients having relapse increased exponentially with a constant doubling time. The doubling time of the WT1 level in patients for whom the discontinuation of immunosuppressive agents or donor leukocyte infusion was effective was significantly longer than that for patients in whom it was not (P < .05). No patients with a short doubling time of WT1 transcripts (< 13 days) responded to these immunomodulation therapies. These findings strongly suggest that the WT1 assay is very useful for the prediction and management of relapse following allogeneic stem cell transplantation regardless of the presence of chimeric gene
The Wilms' tumor gene WT1 is overexpressed in most types of leukemias and various kinds of solid tumors, including lung and breast cancer, and participates in leukemogenesis and tumorigenesis. WT1 protein has been reported to be a promising tumor antigen in mouse and human. In the present study, a single amino-acid substitution, M-->Y, was introduced into the first anchor motif at position 2 of the natural immunogenic HLA-A*2402-restricted 9-mer WT1 peptide (CMTWNQMNL; a.a. 235-243). This substitution increased the binding affinity of the 9-mer WT1 peptide to HLA-A*2402 molecules from 1.82 x 10(-5) to 6.40 x 10(-7) M. As expected from the increased binding affinity, the modified 9-mer WT1 peptide (CYTWNQMNL) elicited WT1-specific cytotoxic T lymphocytes (CTL) more effectively than the natural 9-mer WT1 peptide from peripheral blood mononuclear cells (PBMC) of HLA-A*2402-positive healthy volunteers. CTL induced by the modified 9-mer WT1 peptide killed the natural 9-mer WT1 peptide-pulsed CIR-A*2402 cells, primary leukemia cells with endogenous WT1 expression and lung cancer cell lines in a WT1-specific HLA-A*2402-restricted manner. These results showed that this modified 9-mer WT1 peptide was more immunogenic for the induction of WT1-specific CTL than the natural 9-mer WT1 peptide, and that CTL induced by the modified 9-mer WT1 peptide could effectively recognize and kill tumor cells with endogenous WT1 expression. Therefore, cancer immunotherapy using this modified 9-mer WT1 peptide should provide efficacious treatment for HLA-A*2402-positive patients with leukemias and solid tumors.
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