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Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy.

ABSTRACT: PR1, an HLA-A*0201 epitope shared by proteinase-3 (PR3) and elastase (ELA2) proteins, is expressed in normal neutrophils and overexpressed in myeloid leukemias. PR1-specific T cells have been linked to graft-versus-leukemia (GVL) effect. We hypothesized that lymphopenia induced by chemo-radiotherapy can enhance weak autoimmune responses to self-antigens such as PR1. We measured PR1-specific responses in 27 patients 30-120 days following allogeneic stem cell transplant (SCT) and correlated these with ELA2 and PR3 expression and minimal residual disease (MRD). Post-SCT 10/13 CML, 6/9 ALL, and 4/5 solid tumor patients had PR1 responses correlating with PR3 and ELA2 expression. At day 180 post-SCT, 8/8 CML patients with PR1 responses were BCR-ABL-negative compared with 2/5 BCR-ABL-positive patients (P = 0.025). In contrast, PR1 responses were detected in 2/4 MRD-negative compared with 4/5 MRD-positive ALL patients (P = 0.76). To assess whether the lymphopenic milieu also exaggerates weak T-cell responses in the autologous setting, we measured spontaneous induction of PR1 responses in 3 AML patients vaccinated with WT1-126 peptide following lymphodepletion. In addition to WT1-specific T cells, we detected PR1-specific T cells in 2 patients during hematopoietic recovery. Our findings suggest that lymphopenia induced by chemo-radiotherapy enhances weak autoimmune responses to self-antigens, which may result in GVL if the leukemia expresses the relevant self-antigen.

SUBMITTER: Rezvani K

PROVIDER: S-EPMC4163946 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy.

Rezvani Katayoun K Yong Agnes S M AS Mielke Stephan S Savani Bipin N BN Jafarpour Behnam B Eniafe Rhoda R Le Robert Quan RQ Musse Laura L Boss Carole C Childs Richard R John Barrett A A

Cancer immunology, immunotherapy : CII 20111224 7

PR1, an HLA-A*0201 epitope shared by proteinase-3 (PR3) and elastase (ELA2) proteins, is expressed in normal neutrophils and overexpressed in myeloid leukemias. PR1-specific T cells have been linked to graft-versus-leukemia (GVL) effect. We hypothesized that lymphopenia induced by chemo-radiotherapy can enhance weak autoimmune responses to self-antigens such as PR1. We measured PR1-specific responses in 27 patients 30-120 days following allogeneic stem cell transplant (SCT) and correlated these ...[more]

PMID: 22198310

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Project description:Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease. Identifying AML patients with t(8;21) who have a poor prognosis despite achieving remission is important for determining the best subsequent therapy. This study aimed to evaluate the impact of Wilm tumor gene-1 (WT1) transcript levels and cellular homolog of the viral oncogene v-KIT receptor tyrosine kinase (C-KIT) mutations at diagnosis, and RUNX1-RUNX1T1 transcript levels after the second consolidation chemotherapy cycle on outcomes.Eighty-eight AML patients with t(8;21) who received chemotherapy only or allogeneic hematopoietic stem cell transplantation (allo-HSCT) were included. Patients who achieved remission, received two or more cycles of consolidation chemotherapy, and had a positive measureable residual disease (MRD) test result (defined as <3-log reduction in RUNX1-RUNX1T1 transcript levels compared to baseline) after 2-8 cycles of consolidation chemotherapy were recommended to receive allo-HSCT. Patients who had a negative MRD test result were recommended to receive further chemotherapy up to only 8 cycles. WT1 transcript levels and C-KIT mutations at diagnosis, and RUNX1-RUNX1T1 transcript levels after the second consolidation chemotherapy cycle were tested.Patients who had a C-KIT mutation had significantly lower WT1 transcript levels than patients who did not have a C-KIT mutation (6.7% ± 10.6% vs. 19.5% ± 19.9%, P < 0.001). Low WT1 transcript levels (?5.0%) but not C-KIT mutation at diagnosis, a positive MRD test result after the second cycle of consolidation chemotherapy, and receiving only chemotherapy were independently associated with high cumulative incidence of relapse in all patients (hazard ratio [HR] = 3.53, 2.30, and 11.49; 95% confidence interval [CI] 1.64-7.62, 1.82-7.56, and 4.43-29.82; P = 0.002, 0.034, and <0.001, respectively); these conditions were also independently associated with low leukemia-free survival (HR = 3.71, 2.33, and 5.85; 95% CI 1.82-7.56, 1.17-4.64, and 2.75-12.44; P < 0.001, 0.016, and <0.001, respectively) and overall survival (HR = 3.50, 2.32, and 4.34; 95% CI 1.56-7.82, 1.09-4.97, and 1.98-9.53; P = 0.002, 0.030, and <0.001, respectively) in all patients.Testing for WT1 transcript levels at diagnosis in patients with AML and t(8;21) may predict outcomes in those who achieve remission. A randomized study is warranted to determine whether allo-HSCT can improve prognosis in these patients.

Dataset Information

Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy.

Publications

Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy.

Similar Datasets

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