Leukemic stem cells of acute myeloid leukemia patients carrying NPM1 mutation are candidates for targeted immunotherapy

Schneider, Vanessa; Zhang, Li; Bullinger, Lars; Rojewski, Markus; Hofmann, Susanne; Wiesneth, Markus; Schrezenmeier, Hubert; Götz, Marlies; Botzenhardt, Ursula; Barth, Thomas F.E.; Döhner, Konstanze; Döhner, Hartmut; Greiner, Jochen

doi:10.1038/leu.2014.116

Cited by 19 publications

(22 citation statements)

References 15 publications

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“…recently investigated the influence of nivolumab and ipilimumab, agents targeting PD-1 and CTLA-4, respectively, on antigen-specific immune responses against AML blasts in functional T-cell assays [31]. Interestingly, the authors documented that the addition of nivolumab to CTL cultures for several days increased both specific T-cell responses against various leukemia-associated antigens, mainly PRAME, RHAMM and WT1, as well as T cell cytotoxic effects against primary AML blasts [31–33]. Furthermore, high PD-L1 expression has recently been documented in NPM1 -mutated AML cells, especially in leukemic progenitor/stem cell compartments, suggesting that NPM1 -mutated AML patients may potentially be candidates for immune checkpoint PD-1/PD-L1-driven immunotherapy [34].…”

Section: Discussionmentioning

confidence: 99%

Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia

et al. 2019

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Nucleophosmin(NPM1)-mutated protein, a leukemia-specific antigen, represents an ideal target for AML immunotherapy. We investigated the dynamics of NPM1-mutated-specific T cells on PB and BM samples, collected from 31 adult NPM1-mutated AML patients throughout the disease course, and stimulated with mixtures of 18 short and long peptides (9-18mers), deriving from the complete C-terminal of the NPM1-mutated protein. Two 9-mer peptides, namely LAVEEVSLR and AVEEVSLRK (13.9–14.9), were identified as the most immunogenic epitopes. IFNγ-producing NPM1-mutated-specific T cells were observed by ELISPOT assay after stimulation with peptides 13.9–14.9 in 43/85 (50.6%) PB and 34/80 (42.5%) BM samples. An inverse correlation between MRD kinetics and anti-leukemic specific T cells was observed. Cytokine Secretion Assays allowed to predominantly and respectively identify Effector Memory and Central Memory T cells among IFNγ–producing and IL2–producing T cells. Moreover, NPM1-mutated-specific CTLs against primary leukemic blasts or PHA-blasts pulsed with different peptide pools could be expanded ex vivo from NPM1-mutated AML patients or primed in healthy donors. We describe the spontaneous appearance and persistence of NPM1-mutated-specific T cells, which may contribute to the maintenance of long-lasting remissions. Future studies are warranted to investigate the potential role of both autologous and allogeneic adoptive immunotherapy in NPM1-mutated AML patients.

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Section: Discussionmentioning

confidence: 99%

Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia

et al. 2019

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“…Markedly, genes with immunological functions seem to play an important role in the NPM1 mut AML subtype, 5 and as such could also induce immune responses against subclones without NPM1 mutation. These facts might explain why the existence of NPM1 mut clones could mirror the overall immunogenicity of a genetically unstable underlying disease.…”

Section: Letters To the Editormentioning

confidence: 99%

“…Nevertheless, microarray analysis comparing enriched LSC populations of NPM1 wt and NPM1 mut AML patients underlined the potential relevance of the immune system in NPM1 mut AML patients, as highly immunological regulatory pathways are differentially regulated in NPM1 mut compared to NPM1 wt samples. 5 However, aside from the PD-L1 expression in this patient population, a high number of other relevant factors e.g., other molecular markers, different characteristics of subclones, the microenvironment and niche of leukemic and normal stem cells, and other immune checkpoint molecules may influence immune reactions against NPM1 mut AML cells and hence, the outcome of the patients.…”

mentioning

confidence: 99%

Acute myeloid leukemia with mutated nucleophosmin 1: an immunogenic acute myeloid leukemia subtype and potential candidate for immune checkpoint inhibition

Greiner¹,

Hofmann²,

Schmitt³

et al. 2017

Haematologica

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“…Earlier studies identified candidate NPM1 mut -derived epitopes predicted to bind HLA-A * 02:01 (106)(107)(108), against which the authors elicited CD8 + T cells responses in patients and healthy donors after ex vivo stimulation. CD8 + T cells specific for two epitopes (AIQDLCLAV and AIQDLCVAV) identified in these publications lysed an NPM1 mut AML sample (106), suggesting that these epitopes were naturally processed and presented.…”

Section: Neoantigens In Specific Hematologic Malignancies Acute Myelomentioning

confidence: 99%

Neoantigens in Hematologic Malignancies

Biernacki

Bleakley

2020

Front. Immunol.

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T cell cancer neoantigens are created from peptides derived from cancer-specific aberrant proteins, such as mutated and fusion proteins, presented in complex with human leukocyte antigens on the cancer cell surface. Because expression of the aberrant target protein is exclusive to malignant cells, immunotherapy directed against neoantigens should avoid "on-target, off-tumor" toxicity. The efficacy of neoantigen vaccines in melanoma and glioblastoma and of adoptive transfer of neoantigen-specific T cells in epithelial tumors indicates that neoantigens are valid therapeutic targets. Improvements in sequencing technology and innovations in antigen discovery approaches have facilitated the identification of neoantigens. In comparison to many solid tumors, hematologic malignancies have few mutations and thus fewer potential neoantigens. Despite this, neoantigens have been identified in a wide variety of hematologic malignancies. These include mutated nucleophosmin1 and PML-RARA in acute myeloid leukemia, ETV6-RUNX1 fusions and other mutated proteins in acute lymphoblastic leukemia, BCR-ABL1 fusions in chronic myeloid leukemia, driver mutations in myeloproliferative neoplasms, immunoglobulins in lymphomas, and proteins derived from patient-specific mutations in chronic lymphoid leukemias. We will review advances in the field of neoantigen discovery, describe the spectrum of identified neoantigens in hematologic malignancies, and discuss the potential of these neoantigens for clinical translation.

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Leukemic stem cells of acute myeloid leukemia patients carrying NPM1 mutation are candidates for targeted immunotherapy

Cited by 19 publications

References 15 publications

Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia

Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia

Acute myeloid leukemia with mutated nucleophosmin 1: an immunogenic acute myeloid leukemia subtype and potential candidate for immune checkpoint inhibition

Neoantigens in Hematologic Malignancies

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