Enhanced stimulation of <scp>antigen‐specific</scp> immune responses against nucleophosmin 1 mutated acute myeloid leukaemia by an anti‐programmed death 1 antibody

Greiner, Jochen; Goetz, Marlies; Schuler, Patrick J.; Bulach, Christiane; Hofmann, Susanne; Schrezenmeier, Hubert; Döhner, Hartmut; Schneider, Vanessa; Guinn, Barbara

doi:10.1111/bjh.18326

Cited by 10 publications

(17 citation statements)

References 33 publications

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“…These include novel exportin-1 inhibitors [50,51], the nucleolar stress-inducing agent dactinomycin [52], the NPM1c protein-degrader arsenic trioxide and ATRA combination [28,53], and the BH3 mimetic venetoclax based combinations [54]. Immunotherapy of AML expressing mtNPM1 with anti-CD33 or CD123 strategies [55][56][57], anti-PD1 or PD-L1 antibodies-based combinations [58,59], or anti-CD123 directed chimeric antigen receptor (CAR-T) cells are also being investigated [60]. However, which of these therapies will be safe and improve clinical outcome in elderly AML expressing mtNPM1 remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1

et al. 2023

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In AML with NPM1 mutation causing cytoplasmic dislocation of NPM1, treatments with Menin inhibitor (MI) and standard AML chemotherapy yield complete remissions. However, the causal and mechanistic linkage of mtNPM1 to the efficacy of these agents has not been definitively established. Utilizing CRISPR-Cas9 editing to knockout (KO) or knock-in a copy of mtNPM1 in AML cells, present studies demonstrate that KO of mtNPM1 from AML cells abrogates sensitivity to MI, selinexor (exportin-1 inhibitor), and cytarabine. Conversely, the knock-in of a copy of mtNPM1 markedly sensitized AML cells to treatment with MI or cytarabine. Following AML therapy, most elderly patients with AML with mtNPM1 and co-mutations in FLT3 suffer AML relapse with poor outcomes, creating a need for novel effective therapies. Utilizing the RNA-Seq signature of CRISPR-edited AML cells with mtNPM1 KO, we interrogated the LINCS1000-CMap data set and found several pan-HDAC inhibitors and a WEE1 tyrosine kinase inhibitor among the top expression mimickers (EMs). Additionally, treatment with adavosertib (WEE1 inhibitor) or panobinostat (pan-HDAC inhibitor) exhibited synergistic in vitro lethal activity with MI against AML cells with mtNPM1. Treatment with adavosertib or panobinostat also reduced AML burden and improved survival in AML xenograft models sensitive or resistant to MI.

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Section: Discussionmentioning

confidence: 99%

Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1

et al. 2023

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“…With the advent of next generation immunotherapeutic strategies including Boolean gating, reversing T cell exhaustion, and split/SUPRA CARs (recently reviewed in [115]), we see an opportunity to address the current challenges limiting the safety and efficacy of CAR-T cells for cancer treatment. It is likely that a combinational approach can provide a safe delivery method for immunotherapeutic targeting of AML, and, indeed, recent studies suggest the combination of an immune checkpoint inhibitor and antigen targeting, as well as immune modulation, could further enhance anti-leukaemic responses [116,117].…”

Section: Discussionmentioning

confidence: 99%

A Direct Comparison, and Prioritisation, of the Immunotherapeutic Targets Expressed by Adult and Paediatric Acute Myeloid Leukaemia Cells: A Systematic Review and Meta-Analysis

Morris

Ghazi

Fletcher

et al. 2023

IJMS

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Acute myeloid leukaemia (AML) is characterized by impaired myeloid differentiation resulting in an accumulation of immature blasts in the bone marrow and peripheral blood. Although AML can occur at any age, the incidence peaks at age 65. The pathobiology of AML also varies with age with associated differences in incidence, as well as the frequency of cytogenetic change and somatic mutations. In addition, 5-year survival rates in paediatrics are 60–75% but fall to 5–15% in older AML patients. This systematic review aimed to determine whether the altered genes in AML affect the same molecular pathways, indifferent of patient age, and, therefore, whether patients could benefit from the repurposing drugs or the use of the same immunotherapeutic strategies across age boundaries to prevent relapse. Using a PICO framework and PRISMA-P checklist, relevant publications were identified using five literature databases and assessed against an inclusion criteria, leaving 36 articles, and 71 targets for therapy, for further analysis. QUADAS-2 was used to determine the risk of bias and perform a quality control step. We then priority-ranked the list of cancer antigens based on predefined and pre-weighted objective criteria as part of an analytical hierarchy process used for dealing with complex decisions. This organized the antigens according to their potential to act as targets for the immunotherapy of AML, a treatment that offers an opportunity to remove residual leukaemia cells at first remission and improve survival rates. It was found that 80% of the top 20 antigens identified in paediatric AML were also within the 20 highest scoring immunotherapy targets in adult AML. To analyse the relationships between the targets and their link to different molecular pathways, PANTHER and STRING analyses were performed on the 20 highest scoring immunotherapy targets for both adult and paediatric AML. There were many similarities in the PANTHER and STRING results, including the most prominent pathways being angiogenesis and inflammation mediated by chemokine and cytokine signalling pathways. The coincidence of targets suggests that the repurposing of immunotherapy drugs across age boundaries could benefit AML patients, especially when used in combination with conventional therapies. However, due to cost implications, we would recommend that efforts are focused on ways to target the highest scoring antigens, such as WT1, NRAS, IDH1 and TP53, although in the future other candidates may prove successful.

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“…More recently, the anti-PD-1 antibody, nivolumab, was found to increase leukemia-associated antigen-stimulated cytotoxic T cells and cytotoxicity against stem cell-like cells, especially those carrying NPM1 mutations [128]. These findings provide a rationale for the treatment of NPM1-mutated AML, combining anti-PD-1 and anti NPM1-mutation specific immunotherapy (see below).…”

Section: Antibodies Against Cd33 and Cd123mentioning

confidence: 94%

Current status and future perspectives in targeted therapy of NPM1-mutated AML

et al. 2022

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Nucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which is predominantly located in the nucleolus and exerts multiple functions, including regulation of centrosome duplication, ribosome biogenesis and export, histone assembly, maintenance of genomic stability and response to nucleolar stress. NPM1 mutations are the most common genetic alteration in acute myeloid leukemia (AML), detected in about 30–35% of adult AML and more than 50% of AML with normal karyotype. Because of its peculiar molecular and clinico-pathological features, including aberrant cytoplasmic dislocation of the NPM1 mutant and wild-type proteins, lack of involvement in driving clonal hematopoiesis, mutual exclusion with recurrent cytogenetic abnormalities, association with unique gene expression and micro-RNA profiles and high stability at relapse, NPM1-mutated AML is regarded as a distinct genetic entity in the World Health Organization (WHO) classification of hematopoietic malignancies. Starting from the structure and functions of NPM1, we provide an overview of the potential targeted therapies against NPM1-mutated AML and discuss strategies aimed at interfering with the oligomerization (compound NSC348884) and the abnormal traffic of NPM1 (avrainvillamide, XPO1 inhibitors) as well as at inducing selective NPM1-mutant protein degradation (ATRA/ATO, deguelin, (-)-epigallocatechin-3-gallate, imidazoquinoxaline derivatives) and at targeting the integrity of nucleolar structure (actinomycin D). We also discuss the current therapeutic results obtained in NPM1-mutated AML with the BCL-2 inhibitor venetoclax and the preliminary clinical results using menin inhibitors targeting HOX/MEIS1 expression. Finally, we review various immunotherapeutic approaches in NPM1-mutated AML, including immune check-point inhibitors, CAR and TCR T-cell-based therapies against neoantigens created by the NPM1 mutations.

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Enhanced stimulation of antigen‐specific immune responses against nucleophosmin 1 mutated acute myeloid leukaemia by an anti‐programmed death 1 antibody

Cited by 10 publications

References 33 publications

Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1

Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1

A Direct Comparison, and Prioritisation, of the Immunotherapeutic Targets Expressed by Adult and Paediatric Acute Myeloid Leukaemia Cells: A Systematic Review and Meta-Analysis

Current status and future perspectives in targeted therapy of NPM1-mutated AML

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