Manufacturing of primary CAR-NK cells in an automated system for the treatment of acute myeloid leukemia

Albinger, Nawid; Müller, Sabine; Kostyra, Julia; Kuska, Jan; Mertlitz, Sarah; Penack, Olaf; Zhang, Congcong; Möker, Nina; Ullrich, Evelyn

doi:10.1038/s41409-023-02180-4

Cited by 2 publications

References 30 publications

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Automated and closed clinical-grade manufacturing protocol produces potent NK cells against neuroblastoma cells and AML blasts

Jahan,

Penna,

Luostarinen

et al. 2024

Preprint

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Natural killer (NK) cells have great potential as allogeneic immune cell therapy due to their natural ability to recognize and kill tumor cells, and due to their apparent safety. This study describes the development of an immunotherapy option tailored for high-risk acute myeloid leukemia (AML) in adults and neuroblastoma in children. A GMP-compliant manufacturing protocol for the local production of functionally potent NK cells is detailed in the study, including a comprehensive description of the quality control strategy and considerations for product batch specifications in early clinical development. The protocol is based on the closed, automated CliniMACS Prodigy® platform (Miltenyi Biotec) and a modified Natural Killer Cell Transduction (NKCT) process without transduction and expansion. NK cells are isolated from leukapheresis through CD3 depletion and CD56 enrichment, followed by a 12-hour activation with cytokines (500 IU/ml IL-2, 140 IU/ml IL-15). Three CliniMACS Prodigy® NKCT processes were executed, demonstrating the feasibility and consistency of the modified NKCT process. A three-step process without expansion, however, compromised the NK cell yield. T cells were depleted effectively, indicating excellent safety of the product for allogeneic use. Phenotypic and functional characterization of the NK cells before and after cytokine activation revealed a notable increase in the expression of activation markers, particularly CD69, consistent with enhanced functionality. Intriguingly, even following a brief 12-hour activation period, the NK cells exhibited increased killing efficacy against CD33+ AML blasts isolated from patients and against SH-SY5Y neuroblastoma (NBL) target cells in vitro, suggesting a potential therapeutic benefit for AML and NBL patients.

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Automated and closed clinical-grade manufacturing protocol produces potent NK cells against neuroblastoma cells and AML blasts

Jahan,

Penna,

Luostarinen

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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Impact of p53-associated acute myeloid leukemia hallmarks on metabolism and the immune environment

Chomczyk,

Gazzola,

Dash

et al. 2024

Front. Pharmacol.

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Acute myeloid leukemia (AML), an aggressive malignancy of hematopoietic stem cells, is characterized by the blockade of cell differentiation, uncontrolled proliferation, and cell expansion that impairs healthy hematopoiesis and results in pancytopenia and susceptibility to infections. Several genetic and chromosomal aberrations play a role in AML and influence patient outcomes. TP53 is a key tumor suppressor gene involved in a variety of cell features, such as cell-cycle regulation, genome stability, proliferation, differentiation, stem-cell homeostasis, apoptosis, metabolism, senescence, and the repair of DNA damage in response to cellular stress. In AML, TP53 alterations occur in 5%–12% of de novo AML cases. These mutations form an important molecular subgroup, and patients with these mutations have the worst prognosis and shortest overall survival among patients with AML, even when treated with aggressive chemotherapy and allogeneic stem cell transplant. The frequency of TP53-mutations increases in relapsed and recurrent AML and is associated with chemoresistance. Progress in AML genetics and biology has brought the novel therapies, however, the clinical benefit of these agents for patients whose disease is driven by TP53 mutations remains largely unexplored. This review focuses on the molecular characteristics of TP53-mutated disease; the impact of TP53 on selected hallmarks of leukemia, particularly metabolic rewiring and immune evasion, the clinical importance of TP53 mutations; and the current progress in the development of preclinical and clinical therapeutic strategies to treat TP53-mutated disease.

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Manufacturing of primary CAR-NK cells in an automated system for the treatment of acute myeloid leukemia

Cited by 2 publications

References 30 publications

Automated and closed clinical-grade manufacturing protocol produces potent NK cells against neuroblastoma cells and AML blasts

Automated and closed clinical-grade manufacturing protocol produces potent NK cells against neuroblastoma cells and AML blasts

Impact of p53-associated acute myeloid leukemia hallmarks on metabolism and the immune environment

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