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Published in:

01-11-2018 | Original Article

Development of NKG2D-based chimeric antigen receptor-T cells for gastric cancer treatment

Authors: Kelong Tao, Meng He, Feng Tao, Guangen Xu, Minfeng Ye, Yuanyuan Zheng, Yaoqing Li

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2018

Abstract

Gastric cancer is the third leading cause of cancer-related mortalities worldwide and mostly incurable. It remains an urgent need for novel strategies in the management of patients with advanced gastric cancer. Chimeric antigen receptor (CAR) T therapy has shown unprecedented clinical success in hematological malignancies and potential utility is going on various solid tumors like gastric cancer. In this study, a broad expression of NKG2D ligands was observed in gastric cancer cell lines, making them suitable targets for gastric cancer therapy. T cells were engineered with an NKG2D-based second-generation CAR and the resulting NKG2D-CAR-T cells showed significantly increased cytolytic activity against gastric cancer compared to untransduced T cells. In vivo, these cells can significantly suppressed the growth of established gastric cancer xenografts. Besides, cisplatin was shown to upregulate NKG2D ligand expression in gastric cancer cells and enhance the susceptibility to NKG2D-CAR-T-cell-mediated cytotoxicity. In conclusion, NKG2D-based CAR-T cells have potent in vivo and in vitro anti-tumor activities against gastric cancer and could be a new paradigm for patients with gastric cancer, either used alone or combined with chemotherapy.

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Torre LA et al (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108CrossRef

Van Cutsem E et al (2016) Gastric cancer. Lancet 388(10060):2654–2664CrossRef

Ferlay J et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386CrossRef

Javle M, Smyth EC, Chau I (2014) Ramucirumab: successfully targeting angiogenesis in gastric cancer. Clin Cancer Res 20(23):5875–5881CrossRef

Fujita T (2010) Trastuzumab for gastric cancer treatment. Lancet 376(9754):1735 (author reply 1735–6) CrossRef

Kochenderfer JN, Rosenberg SA (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol 10(5):267–276CrossRef

June CH et al (2018) CAR T cell immunotherapy for human cancer. Science 359(6382):1361–1365CrossRef

Chen N et al (2018) Driving CARs on the uneven road of antigen heterogeneity in solid tumors. Curr Opin Immunol 51:103–110CrossRef

Li J et al (2018) Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward. J Hematol Oncol 11(1):22CrossRef

10.

McGilvray RW et al (2009) NKG2D ligand expression in human colorectal cancer reveals associations with prognosis and evidence for immunoediting. Clin Cancer Res 15(22):6993–7002CrossRef

11.

Pende D et al (2002) Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res 62(21):6178–6186PubMed

12.

Friese MA et al (2003) MICA/NKG2D-mediated immunogene therapy of experimental gliomas. Cancer Res 63(24):8996–9006PubMed

13.

Salih HR et al (2003) Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 102(4):1389–1396CrossRef

14.

Barber A, Meehan KR, Sentman CL (2011) Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells. Gene Ther 18(5):509–516CrossRef

15.

Barber A, Sentman CL (2009) Chimeric NKG2D T cells require both T cell- and host-derived cytokine secretion and perforin expression to increase tumor antigen presentation and systemic immunity. J Immunol 183(4):2365–2372CrossRef

16.

Zhang T, Lemoi BA, Sentman CL (2005) Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy. Blood 106(5):1544–1551CrossRef

17.

Lehner M et al (2012) Redirecting T cells to Ewing’s sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection. PLoS One 7(2):e31210CrossRef

18.

Turtle CJ et al (2016) CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Investig 126(6):2123–2138CrossRef

19.

Diefenbach A, Raulet DH (2002) The innate immune response to tumors and its role in the induction of T-cell immunity. Immunol Rev 188:9–21CrossRef

20.

Zhang T, Barber A, Sentman CL (2006) Generation of antitumor responses by genetic modification of primary human T cells with a chimeric NKG2D receptor. Cancer Res 66(11):5927–5933CrossRef

21.

Alter G, Malenfant JM, Altfeld M (2004) CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods 294(1–2):15–22CrossRef

22.

Gilham DE et al (2012) CAR-T cells and solid tumors: tuning T cells to challenge an inveterate foe. Trends Mol Med 18(7):377–384CrossRef

23.

Zhang C et al, Phase I, Escalating-Dose (2017) Trial of CAR-T therapy targeting CEA(+) metastatic colorectal cancers. Mol Ther 25(5):1248–1258CrossRef

24.

Junghans RP et al (2016) Phase I trial of anti-PSMA designer CAR-T cells in prostate cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response. Prostate 76(14):1257–1270CrossRef

25.

Mason NJ et al (2016) Immunotherapy with a HER2-targeting listeria induces HER2-specific immunity and demonstrates potential therapeutic effects in a phase I trial in canine osteosarcoma. Clin Cancer Res 22(17):4380–4390CrossRef

26.

You F et al (2016) Phase 1 clinical trial demonstrated that MUC1 positive metastatic seminal vesicle cancer can be effectively eradicated by modified anti-MUC1 chimeric antigen receptor transduced T cells. Sci China Life Sci 59(4):386–397CrossRef

27.

Spear P et al (2013) NKG2D CAR T-cell therapy inhibits the growth of NKG2D ligand heterogeneous tumors. Immunol Cell Biol 91(6):435–440CrossRef

28.

Eisenberg V et al (2017) Targeting multiple tumors using T-cells engineered to express a natural cytotoxicity receptor 2-based chimeric receptor. Front Immunol 8:1212CrossRef

29.

Beatty GL, Moon EK (2014) Chimeric antigen receptor T cells are vulnerable to immunosuppressive mechanisms present within the tumor microenvironment. Oncoimmunology 3(11):e970027CrossRef

30.

Mohammed S et al (2017) Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol Ther 25(1):249–258CrossRef

31.

Scarfo I, Maus MV (2017) Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment. J Immunother Cancer 5:28CrossRef

32.

Barber A, Rynda A, Sentman CL (2009) Chimeric NKG2D expressing T cells eliminate immunosuppression and activate immunity within the ovarian tumor microenvironment. J Immunol 183(11):6939–6947CrossRef

33.

Zhang T, Sentman CL (2013) Mouse tumor vasculature expresses NKG2D ligands and can be targeted by chimeric NKG2D-modified T cells. J Immunol 190(5):2455–2463CrossRef

34.

Dhar P, Wu JD (2018) NKG2D and its ligands in cancer. Curr Opin Immunol 51:55–61CrossRef

35.

Koch C et al (2017) Chronic NKG2D engagement in vivo differentially impacts NK cell responsiveness by activating NK receptors. Front Immunol 8:1466CrossRef

36.

Ikeda H, Old LJ, Schreiber RD (2002) The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 13(2):95–109CrossRef

37.

Schroder K et al (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75(2):163–189CrossRef

38.

Zhan Y et al (2012) The inflammatory cytokine, GM-CSF, alters the developmental outcome of murine dendritic cells. Eur J Immunol 42(11):2889–2900CrossRef

39.

Song H et al (2006) Soluble ULBP suppresses natural killer cell activity via down-regulating NKG2D expression. Cell Immunol 239(1):22–30CrossRef

40.

Kamimura H et al (2012) Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence. J Hepatol 56(2):381–388CrossRef

41.

Wu J et al (1999) An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285(5428):730–732CrossRef

42.

Garrity D et al (2005) The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure. Proc Natl Acad Sci USA 102(21):7641–7646CrossRef

Title: Development of NKG2D-based chimeric antigen receptor-T cells for gastric cancer treatment
Authors: Kelong Tao
Meng He
Feng Tao
Guangen Xu
Minfeng Ye
Yuanyuan Zheng
Yaoqing Li
Publication date: 01-11-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-018-3670-0

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