Generation of Antitumor Responses by Genetic Modification of Primary Human T Cells with a Chimeric NKG2D Receptor

Zhang, Tong; Barber, Amorette; Sentman, Charles L.

doi:10.1158/0008-5472.can-06-0130

Cited by 116 publications

(142 citation statements)

References 38 publications

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“…This strategy can en hance tumor recognition by primary T cells (11)(12)(13)(14) and generate specific killing of tumor target cells by NK cell lines (15)(16)(17)(18) or primary human NK cells (19)(20)(21). The aim of the present study was to investigate the potential role of genetically modified NK-92 cells in the therapeutic treatment of cancer cells expressing erbB2 (HER2/neu).…”

Section: Introductionmentioning

confidence: 99%

Specific growth inhibition of ErbB2‑expressing human breast cancer cells by genetically modified NK‑92 cells

Liu

Yang

Sun³

et al. 2014

Oncol Rep

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Abstract. The natural killer cell line NK-92 shows great cytotoxicity against various types of cancer. Several types of solid tumor cells, however, can effectively resist NK-mediated lysis by interaction of major histocompatibility complex (MHC) molecules with NK cell inhibitory receptors. To generate a eukaryotic expression vector encoding chimeric antigen receptor scFv anti-erbB2-CD28-ζ and to investigate the expression and action of this chimeric antigen receptor in cancer cells both in vitro and in vivo, NK-92 cells were genetically modified with an scFv anti-erbB2-CD28-ζ chimeric recep tor by optimized electro poration using the Amaxa Nucleofector system. The expression of the chimeric receptor was evaluated by RT-PCR and immunofluorescence. The ability of the genetically modified NK-92 cells to induce cell death in tumor targets was assessed in vitro and in vivo. The transduced NK-92-anti-erbB2 scFv-CD28-ζ cells expressing high levels of the fusion protein on the cell surface were analyzed by fluorescence-activated cell-sorting (FACS) analysis. These cells specifically enhanced the cell death of the erbB2-expressing human breast cancer cell lines MDA-MB-453 and SKBr3. Furthermore, adoptive transfer of genetically modified NK-92 cells specifically reduced tumor size and lung metastasis of nude mice bearing established MDA-MB-453 cells, and significantly enhanced the survival period of these mice. The genetically modified NK-92 cells significantly enhanced the killing of erbB2-expressing cancer and may be a novel therapeutic strategy for erbB2-expressing cancer cells.

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Section: Introductionmentioning

confidence: 99%

Specific growth inhibition of ErbB2‑expressing human breast cancer cells by genetically modified NK‑92 cells

Liu

Yang

Sun³

et al. 2014

Oncol Rep

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“…47–49 However, the effect of DAP10 incorporation had not been tested in CAR-T cells containing CD28 or 4-1BB co-stimulatory domains and targeting diverse types of TAAs. In the present study, we hypothesized that the activation of DAP10 signaling in CAR-T cells will improve anti-tumor activity.…”

Section: Discussionmentioning

confidence: 99%

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

et al. 2018

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Chimeric antigen receptor (CAR) T cell immunotherapies have shown remarkable efficacy in treating multiple types of hematological malignancies but are not sufficiently effective at treating solid tumors. NKG2D is a strong activating receptor for NK cells and a co-stimulatory receptor for T cells. NKG2D signal transduction depends on DNAX-activating protein 10 (DAP10). Here, we introduced the cytoplasmic domain of DAP10 into the second-generation CARs M28z and G28z to generate M28z10 and G28z10, which target mesothelin (MSLN) and glypican 3 (GPC3), respectively. T cells expressing M28z10 or G28z10 showed enhanced and prolonged effector function against MSLN+ lung cancer or GPC3+ hepatocellular carcinoma cell lines in culture and secreted elevated levels of cytokines, including IL-2, IFN-γ, granzyme B, and GM-CSF. In addition, M28z10 CAR-T cells showed greater anti-tumor activity than those expressing M28z in both A549 cell line xenografts and human lung cancer patient-derived xenografts (PDX). Similarly, G28z10 exhibited higher efficacy in causing tumor regression than did G28z in hepatocellular carcinoma PDX. Therefore, our results show that DAP10 signaling contributes to the function of CAR-T cells in both lung cancer and hepatocellular carcinoma and can enhance the efficacy of CAR-T cells.

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“…For example, linking human NKG2D to the CD3z chain generated a chimeric NKG2D receptor that allowed activation of primary human T cells on engagement with NKG2D ligand-positive tumor cells. 45 These approaches may offer novel opportunities to develop immunocompetent effector cellular reagents and improve the efficacy of adoptive immunotherapy of cancer.…”

Section: Discussionmentioning

confidence: 99%

Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression

Yang

Urban

et al. 2008

Cancer Gene Ther

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In this report, we developed a chimeric receptor (N29g chR) involving the single chain Fv (scFv) derived from N29 monoclonal antibody (mAb) specific for p185HER2 and characterized the therapeutic efficacy of primary T cells engineered to express N29g chR in two histologically distinct murine tumor models. Murine breast (MT901) and fibrosarcoma (MCA207) cancer cell lines were engineered to express human HER2 as targets. Administration of N29g chR-expressing T cells eliminated 3-day pulmonary micrometastases of MT901/HER2 and MCA207/HER2 but not parental tumor cells. A 5 to 8-fold increased dose of N29g T cells was required to mediate regression of advanced 8-day macrometastases. Exogenous administration of interleukin-2 (IL-2) after N29g T-cell transfer was dispensable for treatment of 3-day micrometastases, but was required for mediating regression of wellestablished 8-day macrometastases. Moreover, fractionated CD8 T cells expressing N29g chR suppressed HER2-positive tumor cell growth after adoptive transfer independent of CD4 þ cells. These data indicate that genetically modified T cells expressing a HER2-targeting chimeric receptor can mediate antigen-specific regression of preestablished metastatic cancers in a cell dose-dependent fashion. Systemic administration of IL-2 augments the therapeutic efficacy of these genetically engineered T cells in advanced diseases. These results are relevant to the implication of genetically redirected T cells in clinical cancer immunotherapy.

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Generation of Antitumor Responses by Genetic Modification of Primary Human T Cells with a Chimeric NKG2D Receptor

Cited by 116 publications

References 38 publications

Specific growth inhibition of ErbB2‑expressing human breast cancer cells by genetically modified NK‑92 cells

Specific growth inhibition of ErbB2‑expressing human breast cancer cells by genetically modified NK‑92 cells

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression

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