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Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia.

ABSTRACT: Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2⁺ AML patients with NPM1c mutations.

SUBMITTER: Dong H

PROVIDER: S-EPMC9231490 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia.

Dong Han H Ham James Dongjoo JD Hu Guangan G Xie Guozhu G Vergara Juliana J Liang Yong Y Ali Alaa A Tarannum Mubin M Donner Hannah H Baginska Joanna J Abdulhamid Yasmin Y Dinh Khanhlinh K Soiffer Robert J RJ Ritz Jerome J Glimcher Laurie H LH Chen Jianzhu J Romee Rizwan R

Proceedings of the National Academy of Sciences of the United States of America 20220613 25

Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical t ...[more]

PMID: 35696582

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Project description:BackgroundCytokine-induced memory-like natural killer (CIML NK) cells have been found to possess potent antitumor responses and induce complete remissions in patients with leukemia. However, the poor infiltration of transferred NK cells is a major obstacle in developing adoptive cell immunotherapy for solid tumors. In our study, we explored the potential of using the tumor-penetrating peptide iRGD to deliver activated CIML NK cells deep into tumor tissues.MethodsAfter being briefly stimulated with interleukin-12 (IL-12), IL-15, and IL-18, CIML NK cells were assessed for their phenotype and function with flow cytometry. The penetrating and killing capability of iRGD-modified CIML NK cells in tumor spheroids was revealed by confocal microscopy. The anti-tumor efficacy of these modified CIML NK cells was tested in hepatocellular carcinoma (HCC) xenograft mouse models.ResultsTreating NK cells with cytokines led to a substantial activation, which was evidenced by the upregulation of CD25 and CD137. After a resting period of six days, CIML NK cells were still able to display strong activation when targeting HepG2 and SK-Hep-1 HCC cell lines. Additionally, CIML NK cells produced increased amounts of cytokines (interferon-gamma and tumor necrosis factor alpha) and exhibited heightened cytotoxicity towards HCC cell lines. The iRGD modification enabled CIML NK cells to infiltrate multicellular spheroids (MCSs) and, consequently, to induce cytotoxicity against the target cancer cells. Moreover, the CIML NK cells modified with iRGD significantly decreased tumor growth in a HCC xenograft mouse model.ConclusionOur findings demonstrate that CIML NK cells possess augmented potency and durability against HCC cell lines in vitro. Additionally, we have seen that the incorporation of iRGD to CIML NK cells facilitates enhanced infiltration and targeted destruction of MCSs. Moreover, the application of iRGD-modified CIML NK cells reveal remarkable anti-tumor efficacy against HCC in vivo.

Dataset Information

Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia.

Publications

Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia.

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