Abstract
Natural killer (NK) cells are part of the first line of defense that rapidly respond to malignant transformed cells. Chimeric antigen receptor- (CAR-) engineered NK cells, although are still at the preliminary stage, have been shown to be alternative to CAR-T cells, mainly due to the absence of graft-versus-host disease and safer clinical profile. Allogeneic human NK cell line NK-92 cells, equipped by CAR, are being developed for clinical applications. Herein, we designed third-generation CARs, optimized the production protocol, and generated CAR-NK-92 cells, targeting CD19 and/or CD138 antigens that employ CD28, 4-1BB, and CD3ζ signaling, with >80% CAR expression, designated as CD19-NK-92, CD138-NK-92, and dual-NK-92 cells. The generated CAR-NK-92 cells displayed high and selective cytotoxicity toward various corresponding leukemia, lymphoma, and multiple myeloma cell lines in vitro. Multitargeting approach using a mixture of CD19-NK-92 and CD138-NK-92 cells was also evaluated at various ratios to test the idea of personalized formulation to match the patients' antigen expression profile. Our data indicate that increasing the ratio of CD19-NK-92 to CD138-NK-92 could improve NK cytotoxicity in leukemia cells with a relatively higher expression of CD19 over CD138, supporting the personalized proof of concept. This information represents the basis for further in vivo studies and future progress to clinical trials.
Highlights
Chimeric antigen receptor- (CAR-) engineered T cell therapy represents a major advancement in personalized cancer therapy, providing hope to patients with relapsed and refractory diseases [1, 2]
There are three CAR-T cell platforms targeting CD19 approved by the US Food and Drug Administration (FDA) for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in pediatric and young adults (Kymriah®), for the treatment of relapsed or refractory diffused large B-cell lymphoma (DLBCL) in adults (Kymriah® and Yescarta®), and for the treatment of relapsed or refractory mantle cell lymphoma (MCL) in adults (TecartusTM)
Human embryonic kidney (HEK) 293T cells, human Natural killer (NK)-92 cells, and hematologic cancer cell lines, including human chronic myeloid leukemia- (CML-) derived K562 cells [9], human ALL-derived REH cells [10], human Burkitt’s lymphoma- (BL-) derived Raji cells [11], and human MM-derived H929 and RPMI-8226 [12] were obtained from American Type Culture Collection (ATCC, Manassas, VA)
Summary
Chimeric antigen receptor- (CAR-) engineered T cell therapy represents a major advancement in personalized cancer therapy, providing hope to patients with relapsed and refractory diseases [1, 2]. One of the limitations of CAR-T cell therapy is the manufacturing of autologous CAR-T cells from patients, which is laborious, increasing the risk of production failure in clinical settings, especially from those with limited number of healthy T cells, and rendering these CAR-T cells unsuitable for patients with rapidly progressing disease. Natural killer (NK) cells are part of the first line of defense that are rapidly activated to protect body against foreign materials and abnormal cells, including malignant transformed cells, without prior sensitization, representing an important effector cell type for cellular immunotherapy.
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