Human ascites does not affect NK-92 cytotoxicity and intraperitoneal compared with intravenous administration of NK-92 shows superior survival in human ovarian cancer xenografted mice

Marcus, Paula; Swift, Brenna; Warrington, John M.; Munegowda, Manjunatha Ankathatti; Komparic, A.; Kosaka, Yoko; Díaz-Padilla, Iván; Wang, X.; Viswanathan, Sowmya; Oza, Amit M.; Keating, Armand

doi:10.1016/j.jcyt.2018.02.310

Cited by 1 publication

(2 citation statements)

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“…xenograft mouse model of human ovarian cancer. 27 Two preliminary studies were designed to determine the appropriate dose and interval for multiple dosing of irradiated NK111-αEpCAM-CAR. First, a single-dose escalation study revealed that 3 × 10 7 cells of NK111-αEpCAM-CAR were required to achieve noticeable tumor regression from day 7 post treatment (Figure S9).…”

Section: Resultsmentioning

confidence: 99%

“…Given the importance of multiple genetic modifications to the success of ACT therapies and the challenges associated with the manufacture and testing of multigene-modified products, NK cell line platforms are gaining increasing attentions for their unlimited engineering potential and industrial scalability along with cellular uniformity, long-term stability and batch-to-batch consistency that enable extensive characterization of final products. 27 , 28 In this study, we used a novel human NK cell line, NK101, as a backbone to integrate six transgenes through three rounds of lentiviral transduction, representing the most extensive genetic modifications described so far for any NK cell line. As a result, we have successfully derived clonal, multigene-modified cell therapeutics capable of exerting various modes of antitumor actions: (i) activation receptor-mediated innate killing; (ii) tumor-directed, antigen-specific killing; and (iii) bystander effect-mediated killing.…”

Section: Discussionmentioning

confidence: 99%

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Generation and functional characterization of a multigene-modified NK101 cell line exerting diverse mechanisms of antitumor action

Hwang¹,

Jin²,

Kang³

et al. 2022

OncoImmunology

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Clonal cell line-based, multigene-modified, off-the-shelf NK cell therapeutics are emerging as the new frontier of adoptive cellular immunotherapy. Here, we utilized a newly established NK cell line, NK101, as a backbone to derive multifaceted killer cells armored with various antitumor modalities through repeated cycles of genetic modification and clonal selection. First, NK101 cells were transduced with a tricistronic lentiviral vector expressing CD7, CD28, and cytosine deaminase (CD). The resulting cell line demonstrated enhanced cytotoxicity against B7 + tumors and exerted bystander killing effects on neighboring tumor cells upon 5-FC treatment. Second, engineered NK101 cells were again transduced with a bicistronic vector expressing membrane-bound interleukin-15 (mbIL-15) and dominant negative TGFβ type II receptor (DNTβRII). Ectopic expression of mbIL-15 resulted in further augmentation of lytic activities against all tested target cells by inducing upregulation of multiple activating receptors, while that of DNTβRII allowed the cells to maintain heightened cytotoxicity in the presence of TGFβ. Finally, dual-transduced NK101 cells were modified to express chimeric antigen receptors (CARs) targeting either a solid tumor antigen (EpCAM) or a hematologic tumor antigen (FLT3). The final engineered products not only demonstrated antigen-specific killing activities in vitro but also exerted strong tumor-inhibitory effects in preclinical models of metastatic solid tumor and hematologic malignancy. Notably, combined treatment with 5-FC further enhanced antitumor efficacy of engineered NK101 in the solid tumor model. Our results demonstrate successful generation of multigene-modified NK101 cell therapeutics exerting diverse mechanisms of antitumor action – activation receptor-mediated innate killing, antigen-specific killing, and bystander effect-mediated killing.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%