A perspective of immunotherapy for acute myeloid leukemia: Current advances and challenges

Chen, Ying; Wang, Jishi; Zhang, Fengqi; Liu, Ping

doi:10.3389/fphar.2023.1151032

Cited by 3 publications

(1 citation statement)

References 194 publications

(208 reference statements)

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“…Checkpoint inhibition targeting the Programmed cell death protein 1 (PD-1)/Programmed cell death 1 ligand 1 (PD-L1), PDx axis have successfully achieved responses in a number of tumor types, including hematopoietic malignancies (reviewed in [77]). However, responses in AML have shown fewer promising results perhaps reflecting their lower mutation burden.…”

Section: The Immune Checkpoint Inhibitors -αPd-1 and αPd-l1mentioning

confidence: 99%

Immunotherapeutic Potential of Mutated NPM1 for the Treatment of AML

Greiner,

Mohamed,

Fletcher

et al. 2024

Preprint

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Acute myeloid leukemia (AML) is a malignant disease of the blood and bone marrow that is characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells. Nucleophosmin 1 (NPM1) gene mutations are the most common genetic abnormality in AML, detectable in blast cells from about one third of adults with AML. AML NPM1mut is recognized as a separate entity in the World Health Organization (WHO) classification of AML. Clinical and survival data suggest that patients with this form of AML often have a more favorable prognosis, which may be due to the immunogenicity created by the mutations in the NPM1 protein. Consequently, AML with NPM1mut can be considered an immunogenic subtype of AML. However, the underlying mechanisms of this immunogenicity and associated favorable survival outcomes need to be further investigated. Immune checkpoint molecules, such as the programmed cell death-1 (PD-1) protein and its ligand, PD-L1, play important roles in leukemogenesis through their maintenance of an immunosuppressive tumor microenvironment. Preclinical trials have shown that the use of PD-1/PD-L1 (PDx) checkpoint inhibitors in solid tumors and lymphoma work best in novel therapy combinations. Patients with NPM1mut AML may be better suited to immunogenic strategies that are based on the inhibition of the immune checkpoint pathway of PDx than patients without this mutation, suggesting the genetic landscape of patients may also inform best practice for the use of PDx inhibitors.

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Section: The Immune Checkpoint Inhibitors -αPd-1 and αPd-l1mentioning

confidence: 99%

Immunotherapeutic Potential of Mutated NPM1 for the Treatment of AML

Greiner,

Mohamed,

Fletcher

et al. 2024

Preprint

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Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody

Stefańczyk,

Hagelstein,

Lutz

et al. 2024

Blood Cancer J.

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Acute myeloid leukemia (AML) remains a therapeutic challenge despite recent therapeutic advances. Although monoclonal antibodies (mAbs) engaging natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC) hold promise in cancer therapy, almost none have received clinical approval for AML, so far. Recently, CD276 (B7-H3) has emerged as a promising target for AML immunotherapy, due to its high expression on leukemic blasts of AML patients. Here, we present the preclinical development of the Fc-optimized CD276 mAb 8H8_SDIE with enhanced CD16 affinity. We demonstrate that 8H8_SDIE specifically binds to CD276 on AML cell lines and primary AML cells and induces pronounced NK cell activation and degranulation as measured by CD69, CD25, and CD107a. Secretion of IFNγ, TNF, granzyme B, granulysin, and perforin, which mediate NK cell effector functions, was induced by 8H8_SDIE. A pronounced target cell-restricted lysis of AML cell lines and primary AML cells was observed in cytotoxicity assays using 8H8_SDIE. Finally, xenograft models with 8H8_SDIE did not cause off-target immune activation and effectively inhibited leukemia growth in vivo. We here present a novel attractive immunotherapeutic compound that potently induces anti-leukemic NK cell reactivity in vitro and in vivo as treatment option for AML.

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Identification of single-cell blasts in pediatric acute myeloid leukemia using an autoencoder

Driessen,

Unger,

Nguyen

et al. 2024

Life Sci. Alliance

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Pediatric acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis and high relapse rate. Current challenges in the identification of immunotherapy targets arise from patient-specific blast immunophenotypes and their change during disease progression. To overcome this, we present a new computational research tool to rapidly identify malignant cells. We generated single-cell flow cytometry profiles of 21 pediatric AML patients with matched samples at diagnosis, remission, and relapse. We coupled a classifier to an autoencoder for anomaly detection and classified malignant blasts with 90% accuracy. Moreover, our method assigns a developmental stage to blasts at the single-cell level, improving current classification approaches based on differentiation of the dominant phenotype. We observed major immunophenotype and developmental stage alterations between diagnosis and relapse. Patients with KMT2A rearrangement had more profound changes in their blast immunophenotypes at relapse compared to patients with other molecular features. Our method provides new insights into the immunophenotypic composition of AML blasts in an unbiased fashion and can help to define immunotherapy targets that might improve personalized AML treatment.

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A perspective of immunotherapy for acute myeloid leukemia: Current advances and challenges

Cited by 3 publications

References 194 publications

Immunotherapeutic Potential of Mutated NPM1 for the Treatment of AML

Immunotherapeutic Potential of Mutated NPM1 for the Treatment of AML

Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody

Identification of single-cell blasts in pediatric acute myeloid leukemia using an autoencoder

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