Abstract
For over a century, research has sought ways to boost the immune system of cancer patients in order to eradicate tumors that arose after escaping presumptive immunosurveillance. With increasing knowledge of the immune system, immunotherapeutic strategies to break tolerance to the tumor evolved from largely nonspecific to more specific and increasingly potent forms of cancer vaccination. Overall however, immunotherapeutic strategies for the treatment of cancer have had limited clinical success and an urgent need exists, therefore, to introduce more effective, knowledge-based therapeutic approaches. Invariant natural killer T (iNKT) cells constitute an evolutionary conserved T lymphocyte lineage with dominant immunoregulatory and antitumor effector cell properties. iNKT specifically recognize the glycolipid α-galactosylceramide (α-GalCer/KRN7000) in the context of the CD1d antigen-presenting molecule resulting in their activation. Activated iNKT have been shown to promote the development of a long-lasting Th1-biased proinflammatory antitumor immune response in a variety of murine tumor-metastasis models of liver, lung and lymph nodes, including colon and lung carcinoma, lymphoma, sarcoma, and melanoma, suggesting broad clinical applicability. Here, we will provide an overview of the preclinical data of α-GalCer that formed the basis for subsequent clinical trials in advanced cancer patients, review these clinical trials, focusing on our own experience with α-GalCer, and discuss future perspectives.
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References
Bontkes HJ, Moreno M, Hangalapura B, et al (2010) Attenuation of invariant natural killer T-cell anergy induction through intradermal delivery of α-galactosylceramide. Clin Immunol 136:364–374
Brandes M, et al (2005) Professional antigen-presentation function by human γδ-T cells. Science 309:264–268
Chang DH, Osman K, Connolly J, et al (2005) Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J Exp Med 201:1503–1517
Crowe NY, Smyth MJ, Godfrey DI (2002) A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas. J Exp Med 196:119–127
Dellabona P, Padovan E, Casorati G, et al (1994) An invariant Vα24-JαQ/Vβ11 T cell receptor is expressed in all individuals by clonally expanded CD4-CD8- T cells. J Exp Med 180:1171–1176
Exley M, Garcia J, Balk SP, Porcelli S. (1997) Requirements for CD1d recognition by human invariant Vα24+ CD4- CD8- T cells. J Exp Med 186:109–120
Fowlkes BJ, Kruisbeek AM, Ton-That H, et al (1987) A novel population of T-cell receptor αβ-bearing thymocytes which predominantly expresses a single Vb gene family. Nature 329:251–254
Giaccone G, Punt CJ, Ando Y, et al (2002) A phase 1 study of the natural killer T-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 8:3702–3709
Gumperz JE, Miyake S, Yamamura T, Brenner MB (2002) Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J Exp Med 195:625–636
Hayakawa Y, Takeda K, Yagita H, et al (2001) Critical contribution of IFN-γ and NK cells, but not perforin-mediated cytotoxicity, to anti-metastatic effect of α-galactosylceramide. Eur J Immunol 31:1720–1727
Ishikawa A, Motohashi S, Ishikawa E, et al (2005) A phase 1 study of α-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res 11:1910–1917
Kawano T, Cui J, Koezuka Y, et al (1997) CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278:1626–1629
Kobayashi E, Motoki K, Uchida T, et al (1995) KRN7000, a novel immunomodulator, and its antitumor activities. Oncol Res 7:529–534
Koseki H, Asano H, Inaba T, et al (1991) Dominant expression of a distinctive V14+ T-cell antigen receptor α chain in mice. Proc Natl Acad Sci USA 88:7518–7522
La Cava A, Van Kaer L, Fu-Dong-Shi (2006) CD4+CD25+ Tregs and NKT cells: regulators regulating regulators. Trends Immunol 27:322–327
Lee PT, Benlagha K, Teyton L, Bendelac A (2002) Distinct functional lineages of human Vα24 natural killer T cells. J Exp Med 195:637–641
Metelitsa LS, Wu HW, Wang H, et al (2004) Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2. J Exp Med 199:1213–1221
Molling JW, Kolgen W, van der Vliet HJ, et al (2005) Peripheral blood IFN-γ-secreting Vα24 + Vβ11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load. Int J Cancer 116:87–93
Molling JW, Langius JA, Langendijk JA, et al (2007) Low levels of circulating invariant natural killer T cells predict poor clinical outcome in patients with head and neck squamous cell carcinoma. J Clin Oncol 25:862–868
Moser B, Brandes M (2006) γδ-T cells: an alternative type of professional APC. Trends Immunol 27:112–118
Motohashi S, Ishikawa A, Ishikawa E, et al (2006) A phase 1 study of in vitro expanded natural killer T cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res 12:6079–6086
Nakagawa R, Motoki K, Ueno H, et al (1998) Treatment of hepatic metastasis of the colon26 adenocarcinoma with an α-galactosylceramide, KRN7000. Cancer Res 58:1202–1207
Nakagawa R, Motoki K, Nakamura H, et al (1998) Antitumor activity of α-galactosylceramide, KRN7000, in mice with EL-4 hepatic metastasis and its cytokine production. Oncol Res 10:561–568
Nakagawa R, Nagafune I, Tazunoki Y, et al (2001) Mechanisms of the antimetastatic effect in the liver and of the hepatocyte injury induced by α-galactosylceramide in mice. J Immunol 166:6578–6584
Nieda M, Okai M, Tazbirkova A, et al (2004) Therapeutic activation of Vα24 + Vβ11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood 103:383–389
Osman Y, Kawamura T, Naito T, et al (2000) Activation of hepatic NKT cells and subsequent liver injury following administration of α-galactosylceramide. Eur J Immunol 30:1919–1928
Ridge JP, DiRosa F, Matzinger P. (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393:474–478
Silk JD, Salio M, Gopal Reddy B, et al (2008) Cutting edge: nonglycosidic CD1d lipid ligands activate human and murine invariant NKT cells. J Immunol 180:6452–6456
Song W, van der Vliet HJ, Tai YT, et al (2008) Generation of antitumor invariant natural killer T cell lines in multiple myeloma and promotion of their functions via lenalidomide: a strategy for immunotherapy. Clin Cancer Res 14:6955–6962
Spada FM, Koezuka Y, Porcelli SA. (1998) CD1d-restricted recognition of synthetic glycolipid antigens by human natural killer T cells. J Exp Med 188:1529–1534
Stirnemann K, Romero JF, Baldi L, et al (2008) Sustained activation and tumor targeting of NKT cells using a CD1d-anti-HER2-scFv fusion protein induce antitumor effects in mice. J Clin Invest 118:994–1005
Sullivan BA, Kronenberg M (2005) Activation or anergy: NKT cells are stunned by α-galactosylceramide. J Clin Invest 115:2328–2329
Tachibana T, Onodera H, Tsuruyama T, et al (2005) Increased intratumor Vα24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas. Clin Cancer Res 11:7322–7327
Toura I, Kawano T, Akutsu Y, et al (1999) Cutting edge: inhibition of experimental tumor metastasis by dendritic cells pulsed with α-galactosylceramide. J Immunol 163:2387–2391
Uchida T, Horiguchi S, Tanaka Y, et al (2008) Phase 1 study of α-galactosylceramide-pulsed antigen presenting cells administration to the nasal submucosa in unresectable or recurrent head and neck cancer. Cancer Immunol Immunother 57:337–345
van der Vliet HJ, Molling JW, Nishi N, et al (2003) Polarization of Vα24 + Vβ11+ natural killer T cells of healthy volunteers and cancer patients using α-galactosylceramide-loaded and environmentally instructed dendritic cells. Cancer Res 63:4101–4106
van der Vliet HJ, Molling JW, von Blomberg BM, et al (2004) The immunoregulatory role of CD1d-restricted natural killer T cells in disease. Clin Immunol 112:8–23
van der Vliet HJ, Balk SP, Koon HB, et al (2007) Exploiting regulatory T cell populations for the immunotherapy of cancer. J Immunother 30:591–595
Veldt BJ, van der Vliet HJ, von Blomberg BM, et al (2007) Randomized placebo controlled phase I/II trial of α-galactosylceramide for the treatment of chronic hepatitis C. J Hepatol 47:356–365
Wilson MT, Johansson C, Olivares-Villagomez D, et al (2003) The response of natural killer T cells to glycolipid antigens is characterized by surface receptor down-modulation and expansion. Proc Natl Acad Sci USA 100:10913–10918
Zeng Z, Castano AR, Segelke BW, et al (1997) Crystal structure of mouse CD1: an MHC-like fold with a large hydrophobic binding groove. Science 277:339–345
Acknowledgments
Our work is supported by grant no. 90700309 from The Netherlands Organization for Health Research and Development (ZonMw) and grant VU2010-4728 from the Dutch Cancer Society (KWF)
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Schneiders, F.L. et al. (2012). Clinical Trials with α-Galactosylceramide (KRN7000) in Advanced Cancer. In: Terabe, M., Berzofsky, J. (eds) Natural Killer T cells. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0613-6_10
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DOI: https://doi.org/10.1007/978-1-4614-0613-6_10
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