An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML

Lee, Dyantha I. van der; Koutsoumpli, Georgia; Reijmers, Rogier M.; Honders, Willy M.; Jong, Rob C. M. de; Remst, Dennis F. G.; Wachsmann, Tassilo L. A.; Hagedoorn, Renate S.; Franken, Kees L. M. C.; Kester, Michel G.D.; Harber, Karl J.; Roelofsen, Lisanne M.; Schouten, Annemiek M.; Mulder, Arend; Drijfhout, Jan W.; Veelken, Hendrik; Veelen, Peter A. van; Heemskerk, Mirjam H.M.; Falkenburg, F.; Griffioen, Marieke

doi:10.3390/cancers13215390

Cited by 5 publications

(3 citation statements)

References 44 publications

(53 reference statements)

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“…For example, Lee et al reported a novel InDel within the KIT gene, a commonly mutated gene in AML patients, in a clinical sample from a 35 year old female [64]. Two neoantigens derived from NPM1 mutations have been identified [65, 66]. Variant calling was performed on TCGA-LAML samples using a consensus approach in which each variant had to be detected by at least two separate variant callers (for SNVs) or three separate variant callers (InDels) to be considered.…”

Section: Resultsmentioning

confidence: 99%

LENS: Landscape of Effective Neoantigens Software

Vensko

Olsen

Bortone

et al. 2022

Preprint

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Elimination of cancer cells by T cells is a critical mechanism of anti-tumor immunity and cancer immunotherapy response. T cells recognize cancer cells via engagement of T cell receptors with peptide epitopes presented by major histocompatibility complex (MHC) molecules on the cancer cell surface. Peptide epitopes can be derived from antigen proteins coded for by multiple genomic sources. Bioinformatics tools used to identify tumor-specific epitopes via analysis of DNA and RNA sequencing data have largely focused on epitopes derived from somatic variants, though a smaller number have evaluated potential antigens from other genomic sources. We report here an open-source workflow utilizing the Nextflow DSL2 workflow manager, Landscape of Effective Neoantigen Software (LENS), which predicts tumor-specific and tumor-associated antigens from single nucleotide variants (SNVs), insertions and deletions (InDels), fusion events, splice variants, cancer testis antigens (CTAs), overexpressed self-antigens, viruses, and human endogenous retroviruses (hERVs). The main advantage of LENS is that it extends the breadth of genomic sources of tumor antigens that may be discovered using genomics data. Other advantages include modularity, extensibility, ease of use, incorporation of phasing and germline variant information in epitope identification, and harmonization of relative expression level and immunogenicity prediction across multiple genomic sources. Current limitations include lack of support for class II MHC epitope predictions and advanced visualization features. To demonstrate the utility of LENS, we present an analysis of predicted antigen landscape in 115 acute myeloid leukemia (AML) samples. We expect that LENS will be a valuable platform and resource for T cell epitope discovery bioinformatics, especially in cancers with few somatic variants and increased importance of tumor-specific epitopes from alternative genomic sources.

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Section: Resultsmentioning

confidence: 99%

LENS: Landscape of Effective Neoantigens Software

Vensko

Olsen

Bortone

et al. 2022

Preprint

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“…CD33 is expressed in the majority of leukemic blasts, but the driver mutation dNPM1 is only found in approximately 30% of all AML patients. 18 , 19 Although another dNPM1-TCR specific for HLA-A∗11:01 has already been described, 44 further expansion of the available dNPM1-TCR selection is required to enable flexible therapy adjustments according to the patient’s HLA haplotype.…”

Section: Discussionmentioning

confidence: 99%

CAR’TCR-T cells co-expressing CD33-CAR and dNPM1-TCR as superior dual-targeting approach for AML treatment

Teppert,

Yonezawa Ogusuku,

Brandes

et al. 2024

Molecular Therapy: Oncology

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“…Tetramer-positive CD8+ T cells were isolated and their activity towards primary AMLs investigated. The TCR was then isolated from a clone with high anti-leukemic reactivity and its capability to specifically recognize and lyse HLA-A*02:01-positive ΔNPM1 AML demonstrated after retroviral transduction of CD8+ and CD4+ T cells [145]. Moreover, T cells transduced with TCR for HLA-A*02:01-binding CLAVEEVSL efficiently killed AML cells and prolonged OS of NSG mice engrafted with HLA-A*02:01-positive NPM1-mutated OCI-AML3 human cells [145] (Fig.…”

Section: Antibodies Against Cd33 and Cd123mentioning

confidence: 99%

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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An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML

Cited by 5 publications

References 44 publications

LENS: Landscape of Effective Neoantigens Software

LENS: Landscape of Effective Neoantigens Software

CAR’TCR-T cells co-expressing CD33-CAR and dNPM1-TCR as superior dual-targeting approach for AML treatment

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

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