Abstract
Glypican-3 (GPC3) is an onco-fetal antigen expressed in the placenta and embryonic liver and over-expressed in human hepatocellular carcinoma (HCC). We found that GPC3 is useful both as a novel tumor marker and as a target antigen for immunotherapy in several mouse studies. We identified human leukocyte antigen (HLA)-A24-restricted GPC3298–306 (EYILSLEEL) and HLA-A2-restricted GPC3144–152 (FVGEFFTDV) peptides that can induce GPC3-reactive cytotoxic T lymphocytes (CTLs). Based on results obtained from preclinical mouse studies, we conducted a phase I clinical trial using a GPC3-derived peptide vaccine. Results showed that the GPC3-derived peptide vaccine was well-tolerated. Furthermore, this is the first study to show that the frequency of peptide-specific CTLs correlated with overall survival in patients with HCC receiving peptide vaccines. Next, we conducted a phase II clinical trial of the GPC3-derived peptide vaccine as an adjuvant therapy for patients with HCC after surgery or radiofrequency ablation. We are now initiating a pilot study of liver biopsies from patients with advanced HCC before and after GPC3 peptide vaccination. In addition, we investigated whether GPC3-based immunotherapy can be applied to other GPC3-expressing cancers, such as clear cell carcinoma of the ovary and pediatric cancers, and are initiating clinical trials to further these studies. We expect that the results of these trials will provide the rationale for a larger clinical trial to determine the efficacy of the GPC3-derived peptide vaccine and to advance future drug development using this approach.
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References
Amoscato AA, Prenovitz DA, Lotze MT (1998) Rapid extracellular degradation of synthetic class I peptides by human dendritic cells. J Immunol 161:4023–4032
Aviel-Ronen S, Lau SK, Pintilie M et al (2008) Glypican-3 is overexpressed in lung squamous cell carcinoma, but not in adenocarcinoma. Mod Pathol 21:817–825
Azuma K, Shichijo S, Maeda Y et al (2003) Mutated p53 gene encodes a nonmutated epitope recognized by HLA-B*4601-restricted and tumor cell-reactive CTLs at tumor site. Cancer Res 63:854–858
Chen W, Yewdell JW, Levine RL et al (1999) Modification of cysteine residues in vitro and in vivo affects the immunogenicity and antigenicity of major histocompatibility complex class I-restricted viral determinants. J Exp Med 189:1757–1764
Falk K, Rotzschke O, Stevanovic S et al (1991) Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351:290–296
Falo LD Jr, Colarusso LJ, Benacerraf B et al (1992) Serum proteases alter the antigenicity of peptides presented by class I major histocompatibility complex molecules. Proc Natl Acad Sci U S A 89:8347–8350
Filmus J, Selleck SB (2001) Glypicans: proteoglycans with a surprise. J Clin Invest 108:497–501
Hasegawa S, Furukawa Y, Li M et al (2002) Genome-wide analysis of gene expression in intestinal-type gastric cancers using a complementary DNA microarray representing 23,040 genes. Cancer Res 62:7012–7017
Jager E, Chen YT, Drijfhout JW et al (1998) Simultaneous humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J Exp Med 187:265–270
Kitahara O, Furukawa Y, Tanaka T et al (2001) Alterations of gene expression during colorectal carcinogenesis revealed by cDNA microarrays after laser-capture microdissection of tumor tissues and normal epithelia. Cancer Res 61:3544–3549
Kitahara O, Katagiri T, Tsunoda T et al (2002) Classification of sensitivity or resistance of cervical cancers to ionizing radiation according to expression profiles of 62 genes selected by cDNA microarray analysis. Neoplasia 4:295–303
Komori H, Nakatsura T, Senju S et al (2006) Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma. Clin Cancer Res 12:2689–2697
Maeda Y, Ito M, Harashima N et al (2002) Cleavage and polyadenylation specificity factor (CPSF)-derived peptides can induce HLA-A2-restricted and tumor-specific CTLs in the majority of gastrointestinal cancer patients. Int J Cancer 99:409–417
Maeda D, Ota S, Takazawa Y et al (2009) Glypican-3 expression in clear cell adenocarcinoma of the ovary. Mod Pathol 22:824–832
Maier R, Falk K, Rotzschke O et al (1994) Peptide motifs of HLA-A3, −A24, and -B7 molecules as determined by pool sequencing. Immunogenetics 40:306–308
Matsui M, Moots RJ, Warburton RJ et al (1995) Genetic evidence for difference between intracellular and extracellular peptides in influenza A matrix peptide-specific CTL recognition. J Immunol 154:1088–1096
Meadows L, Wang W, den Haan JM et al (1997) The HLA-A*0201-restricted H-Y antigen contains a posttranslationally modified cysteine that significantly affects T cell recognition. Immunity 6:273–281
Monji M, Senju S, Nakatsura T et al (2002) Head and neck cancer antigens recognized by the humoral immune system. Biochem Biophys Res Commun 294:734–741
Morgan RA, Dudley ME, Yu YY et al (2003) High efficiency TCR gene transfer into primary human lymphocytes affords avid recognition of melanoma tumor antigen glycoprotein 100 and does not alter the recognition of autologous melanoma antigens. J Immunol 171:3287–3295
Motomura Y, Ikuta Y, Kuronuma T et al (2008) HLA-A2 and -A24-restricted glypican-3-derived peptide vaccine induces specific CTLs: preclinical study using mice. Int J Oncol 32:985–990
Nakatsura T, Senju S, Yamada K et al (2001) Gene cloning of immunogenic antigens overexpressed in pancreatic cancer. Biochem Biophys Res Commun 281:936–944
Nakatsura T, Senju S, Ito M et al (2002) Cellular and humoral immune responses to a human pancreatic cancer antigen, coactosin-like protein, originally defined by the SEREX method. Eur J Immunol 32:826–836
Nakatsura T, Yoshitake Y, Senju S et al (2003) Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker. Biochem Biophys Res Commun 306:16–25
Nakatsura T, Kageshita T, Ito S et al (2004a) Identification of glypican-3 as a novel tumor marker for melanoma. Clin Cancer Res 10:6612–6621
Nakatsura T, Komori H, Kubo T et al (2004b) Mouse homologue of a novel human oncofetal antigen, glypican-3, evokes T-cell-mediated tumor rejection without autoimmune reactions in mice. Clin Cancer Res 10:8630–8640
Nobuoka D, Yoshikawa T, Takahashi M et al (2012) Intratumoral peptide injection enhances tumor cell antigenicity recognized by cytotoxic T lymphocytes: a potential option for improvement in antigen-specific cancer immunotherapy. Cancer Immunol Immunother 62:639–652
Okugawa T, Ikuta Y, Takahashi Y et al (2000) A novel human HER2-derived peptide homologous to the mouse K(d)-restricted tumor rejection antigen can induce HLA-A24-restricted cytotoxic T lymphocytes in ovarian cancer patients and healthy individuals. Eur J Immunol 30:3338–3346
Park S, Lim Y, Lee D et al (2003) Identification and characterization of a novel cancer/testis antigen gene CAGE-1. Biochim Biophys Acta 1625:173–182
Rosenberg SA (2001) Progress in human tumour immunology and immunotherapy. Nature 411:380–384
Saikali Z, Sinnett D (2000) Expression of glypican 3 (GPC3) in embryonal tumors. Int J Cancer 89:418–422
Sawada Y, Yoshikawa T, Nobuoka D et al (2012) Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival. Clin Cancer Res 18:3686–3696
Sawada Y, Yoshikawa T, Fujii S et al (2013) Remarkable tumor lysis in a hepatocellular carcinoma patient immediately following glypican-3-derived peptide vaccination: an autopsy case. Hum Vaccin Immunother 9:1228–1233
Shirakawa H, Suzuki H, Shimomura M et al (2009) Glypican-3 expression is correlated with poor prognosis in hepatocellular carcinoma. Cancer Sci 100:1403–1407
So T, Hanagiri T, Chapiro J et al (2007) Lack of tumor recognition by cytolytic T lymphocyte clones recognizing peptide 195–203 encoded by gene MAGE-A3 and presented by HLA-A24 molecules. Cancer Immunol Immunother 56:259–269
Sorensen RB, Junker N, Kirkin A et al (2009) The immunodominant HLA-A2-restricted MART-1 epitope is not presented on the surface of many melanoma cell lines. Cancer Immunol Immunother 58:665–675
Suzuki S, Yoshikawa T, Hirosawa T et al (2011) Glypican-3 could be an effective target for immunotherapy combined with chemotherapy against ovarian clear cell carcinoma. Cancer Sci 102:1622–1629
Suzuki S, Shibata K, Kikkawa F et al (2013) Significant clinical response of progressive recurrent ovarian clear cell carcinoma to glypican-3-derived peptide vaccine therapy: two case reports. Hum Vaccin Immunother 10(2):338
Toretsky JA, Zitomersky NL, Eskenazi AE et al (2001) Glypican-3 expression in Wilms tumor and hepatoblastoma. J Pediatr Hematol Oncol 23:496–499
van der Bruggen P, Traversari C, Chomez P et al (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254:1643–1647
Yamshchikov GV, Barnd DL, Eastham S et al (2001) Evaluation of peptide vaccine immunogenicity in draining lymph nodes and peripheral blood of melanoma patients. Int J Cancer 92:703–711
Yoshikawa T, Nakatsugawa M, Suzuki S et al (2011) HLA-A2-restricted glypican-3 peptide-specific CTL clones induced by peptide vaccine show high avidity and antigen-specific killing activity against tumor cells. Cancer Sci 102:918–925
Yu Y, Khan J, Khanna C et al (2004) Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med 10:175–181
Zembutsu H, Ohnishi Y, Tsunoda T et al (2002) Genome-wide cDNA microarray screening to correlate gene expression profiles with sensitivity of 85 human cancer xenografts to anticancer drugs. Cancer Res 62:518–527
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Yoshikawa, T., Sawada, Y., Yoshimura, M., Ofuji, K., Nakatsura, T. (2015). Development of Glypican-3-Targeted Cancer Immunotherapy. In: Seya, T., Matsumoto, M., Udaka, K., Sato, N. (eds) Inflammation and Immunity in Cancer. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55327-4_11
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DOI: https://doi.org/10.1007/978-4-431-55327-4_11
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