Donor Lymphocyte Infusion Induces Polyspecific CD8<sup>+</sup> T-Cell Responses With Concurrent Molecular Remission in Acute Myeloid Leukemia With <i>NPM1</i> Mutation

Hofmann, Susanne; Götz, Marlies; Schneider, Vanessa; Guillaume, Philippe; Bunjes, Donald; Döhner, Hartmut; Wiesneth, Markus; Greiner, Jochen

doi:10.1200/jco.2011.41.1116

Cited by 41 publications

(36 citation statements)

References 12 publications

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“…The presence of LAAs‐specific T cells may be at least partially involved in the maintenance of the CR of the patients. Functional WT1‐specific CTLs were detected in AML patients by ELISPOT in accordance with other hematological disease studies . This population vanished in the peripheral blood of patients after they had received chemotherapy and at the time of relapse.…”

Section: Discussionsupporting

confidence: 85%

Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation

Casalegno-Garduño

Schmitt

Spitschak

et al. 2015

Intl Journal of Cancer

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Wilms' tumor gene 1 (WT1) is overexpressed in leukemia and WT1-derived CD8 1 T-cell epitopes for immunotherapies targeting WT1 have been defined. Here, we analyzed expression of WT1 in 226 peripheral blood and bone marrow samples from patients with acute myeloid leukemia or myelodysplastic syndrome (AML/MDS) before and after allogeneic stem cell transplantation (SCT). Transcripts were assessed by quantitative polymerase chain reaction, and WT1-specific CD81 cytotoxic T cells (CTL) were monitored by tetramer staining and enzyme-linked immunospot (ELISPOT) assays. Reduction of WT1 levels correlated with a longer survival (p < 0.01). Increment of WT1 transcripts eventually resulted in relapse and subsequent death of the patients. In patients with longer survival and continuous complete remission (cCR) after SCT, higher and enduring frequencies of WT1-specific CTL than in patients developing a relapse were detected. These cells were effector T cells secreting interferon gamma and granzyme B. In summary, WT1 is a suitable marker for the detection of minimal residual disease after SCT or chemotherapy. A rising WT1 signal correlated with a dismal prognosis of the patients. WT1-specific CD8 1 T cells might contribute to the maintenance of a cCR. Targeting WT-1 by peptide/protein vaccination as well as adoptive transfer of genetically modified T cells are future options in the individualized therapy for AML/MDS patients.

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Section: Discussionsupporting

confidence: 85%

Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation

Casalegno-Garduño

Schmitt

Spitschak

et al. 2015

Intl Journal of Cancer

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“…In an AML patient with NPM1 mut and molecular relapse, a polyspecific CTL response against several known LAAs, including an epitope derived from NPM1 mut , was demonstrated after pre-emptive donor lymphocyte infusion [81]. Especially when considering patients harboring a low tumor burden, represented by MRD without hematological relapse, this subgroup would be especially suited to NPM1 mut peptide vaccination to expand NPM1 mut -specific CD8 + T-cells and prolong remission or remove MRD.…”

Section: Mutated Epitopes (Neoantigens)mentioning

confidence: 99%

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Hofmann

Mead

Malinovskis

et al. 2015

Cancer Immunol Immunother

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“…The major therapeutic benefit of allogeneic HSCT results from the so-called graft-versus-leukemia (GVL) effect, namely, the recognition by donor-derived T cells of antigens expressed on host malignant cells. The existence of a GVL effect is underpinned by the evidence that infusion of donor lymphocytes can induce disease remission in patients who have relapsed following allogeneic HSCT [3, 4]. These findings imply that the stimulation of anti-leukemia immunity may be crucial to improve the clinical outcome of patients with AML.…”

Section: Introductionmentioning

confidence: 99%

Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia

et al. 2013

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Microenvironmental factors contribute to the immune dysfunction characterizing acute myeloid leukemia (AML). Indoleamine 2,3-dioxygenase 1 (IDO1) is an interferon (IFN)-γ-inducible enzyme that degrades tryptophan into kynurenine, which, in turn, inhibits effector T cells and promotes regulatory T-cell (Treg) differentiation. It is presently unknown whether childhood AML cells express IDO1 and whether IDO1 activity correlates with patient outcome.We investigated IDO1 expression and function in 37 children with newly diagnosed AML other than acute promyelocytic leukemia. Blast cells were cultured with exogenous IFN-γ for 24 hours, followed by the measurement of kynurenine production and tryptophan consumption. No constitutive expression of IDO1 protein was detected in blast cells from the 37 AML samples herein tested. Conversely, 19 out of 37 (51%) AML samples up-regulated functional IDO1 protein in response to IFN-γ. The inability to express IDO1 by the remaining 18 AML samples was not apparently due to a defective IFN-γ signaling circuitry, as suggested by the measurement of signal transducer and activator of transcription 3 (STAT3) phosphorylation. Co-immunoprecipitation assays indicated the occurrence of physical interactions between STAT3 and IDO1 in AML blasts. In line with this finding, STAT3 inhibitors abrogated IDO1 function in AML blasts. Interestingly, levels of IFN-γ were significantly higher in the bone marrow fluid of IDO-expressing compared with IDO-nonexpressing AMLs. In mixed tumor lymphocyte cultures (MTLC), IDO-expressing AML blasts blunted the ability of allogeneic naïve T cells to produce IFN-γ and promoted Treg differentiation. From a clinical perspective, the 8-year event-free survival was significantly worse in IDO-expressing children (16.4%, SE 9.8) as compared with IDO-nonexpressing ones (48.0%, SE 12.1; p=0.035).These data indicate that IDO1 expression by leukemia blasts negatively affects the prognosis of childhood AML. Moreover, they speak in favor of the hypothesis that IDO can be targeted, in adjunct to current chemotherapy approaches, to improve the clinical outcome of children with AML.

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Donor Lymphocyte Infusion Induces Polyspecific CD8⁺ T-Cell Responses With Concurrent Molecular Remission in Acute Myeloid Leukemia With NPM1 Mutation

Cited by 41 publications

References 12 publications

Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation

Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia

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Donor Lymphocyte Infusion Induces Polyspecific CD8+ T-Cell Responses With Concurrent Molecular Remission in Acute Myeloid Leukemia With NPM1 Mutation

Cited by 41 publications

References 12 publications

Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation

Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia

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Product

Resources

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Donor Lymphocyte Infusion Induces Polyspecific CD8⁺ T-Cell Responses With Concurrent Molecular Remission in Acute Myeloid Leukemia With NPM1 Mutation