There is an emerging need to develop less toxic and more effective targeted therapies for acute myeloid leukemia (AML). Natural killer (NK) cells are a distinct type of white blood cells: They are the first wave of immune defenders, can instantly and directly kill cancer cells, and their intrinsic propensity to target myeloid blasts makes NK cells particularly attractive for AML. Despite promising clinical results in blood cancer, the development of NK cell-based therapy remains challenging mostly due to NK cells' short lifespan, inadequate proliferation, and lack of specific tumor targeting. Although historically being considered as an innate immune component, recent studies from us and others indicate that NK cells can 'remember' stimuli, and the resulting memory-like (ML) NK cells persist long-term with enhanced antitumor activity. Furthermore, chimeric antigen receptors (CARs) are known to significantly enhance antitumor specificity and activity of immune effector cells; while most efforts have focused on CAR-T cells, the emerging interest in developing NK cell-based cancer immunotherapy highlights an urgent need for evaluation of CAR-NK cells.
We have developed a novel approach to arm NK cells for cellular immunotherapy by harnessing cytokine-induced memory-like (CIML) NK cells as a CAR platform using a lentivirus system better suited for transducing NK cells. Our innovative ML CAR-NK cells target mutant NPM1c, which is one of the most commonly mutated genes (30-35%) in AML. Using yeast surface display, we have isolated a unique antibody clone that specifically binds to the NPM1c epitope-HLA-A2 complex, but not HLA-A2 alone or HLA-A2 loaded with control peptides. We have incorporated scFv from this unique antibody clone into our CAR construct and utilizing a novel lentiviral vector pseudotyped with an unconventional balloon virus envelop protein instead of the traditional vesicular stomatitis virus G (VSV-G) glycoprotein, we were able to transduce ML-NK cells with very high efficiency (40%-75%). Harnessing key cytokine pathways in the CAR design substantially promoted CAR-NK cell survival (from 30% to 75%) and proliferation (60% to 95%), while the anti-NPM1c CAR significantly promoted anti-tumor function and tumor-specific killing of ML-NK cells against AML with NPM1c oncogene.
In summary, dual-armed ML-NK cells with a novel CAR and cytokine signaling exhibited optimal specificity and sustainability against AML targets in cell cultures and pre-clinical models. Our study aims to target an otherwise intracellular protein with a novel NK cell-based CAR, and we are hoping to test this treatment in an early-phase clinical trial later this year. We hope this study also helps advance the current knowledge of NK cell memory to open new opportunities in cancer therapy for patients with otherwise poor prognosis diseases.
Find more information on our program's participation at ASH 2020.