Journal Article

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

Baginska, Joanna, Dong, Han, Abdulhamid, Yasmin, Donner, Hannah, Romee, Rizwan, Glimcher, Laurie H., Xie, Guozhu, Vergara, Juliana, Ham, James Dongjoo, Hu, Guangan, Chen, Jianzhu, Soiffer, Robert J., Liang, Yong, Ali, Alaa, Tarannum, Mubin, Dinh, Khanhlinh, Ritz, Jerome

2022

Overview

Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immunebased 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.

• Publisher: National Academy of Sciences
• Subject: Acute myeloid leukemia / Anticancer properties / Antigens / Antitumor activity / Biocompatibility / Biological Sciences / Blast cells / Cell culture / Cell differentiation / Cell proliferation / Chimeric antigen receptors / Clinical trials / Cytokines / Cytometry / Differentiation (biology) / Gene sequencing / Histocompatibility antigen HLA / HLA-A2 Antigen - immunology / Humans / Immune response / Immunologic Memory / Immunological Memory Cells - immunology / Immunological Memory Cells - transplantation / Immunology and Inflammation / Immunotherapy, Adoptive - methods / Interleukin 12 / Interleukin 18 / Killer Cells, Natural - immunology / Killer Cells, Natural - transplantation / Leukemia / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - therapy / Metabolic pathways / Mutation / Natural killer cells / Nucleophosmin - genetics / Nucleophosmin - immunology / Patients / Peripheral blood / Protein folding / Proteins / Receptors, Chimeric Antigen - genetics / Receptors, Chimeric Antigen - immunology / T cell receptors / Toxicity / Xenografts / Xenotransplantation