Glypican-3 as a Target for Immune Based Therapy in Hepatocellular Carcinoma



Glypican-3 (GPC3) is expressed on most hepatocellular carcinoma (HCC) cells and associated with liver tumorigenesis. This chapter provides a review of GPC3 as an emerging target in various investigational immunotherapies, with a focus on cancer vaccines, human or humanized antibodies, bispecific antibodies, immunotoxins, and chimeric antigen receptor (CAR) T cells. GPC3 peptide-based vaccines have been shown to prevent HCC recurrence after surgery. Interestingly, the patients with the best protection have anti-GPC3 CD4+ T cell response regardless of CD8+ T cell response. Several monoclonal antibodies including GC33, YP7, HN3 and HS20, each with a distinct epitope on GPC3, are being tested in preclinical or clinical stages. GC33 and YP7 recognize the C terminal end of GPC3. HN3 targets a cryptic Wnt binding site in the core protein of GPC3. HS20 binds a Wnt binding domain on the heparan sulfate chain. The HN3 and HS20 antibodies inhibit Wnt/Yap signaling and suppress HCC cell growth. To improve anti-tumor efficacy, anti-GPC3 immunotoxins and CAR-T cell therapies have been developed. The Wnt-blocking HN3 immunotoxin is more potent than YP7 immunotoxin. With an engineered toxin, the HN3-mPE24 immunotoxin can be given at high doses repeatedly to regress HCC xenograft tumor in mice. The CAR T-cell therapy also shows a great promise. The GC33 CAR T cells inhibit established HCC xenograft tumors in mice. Several CARs targeting different epitopes of GPC3 (including HN3) are being tested. Ongoing preclinical and clinical studies will help define the utility of GPC3 as a therapeutic target for liver cancer therapy.


Cancer vaccine Chimeric antigen receptor or CAR Hepatocellular carcinoma Immunotherapy Immunotoxin Epitope 



This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We would like to thank Alan Hoofring and Ethan Tyler, NIH Medical Arts Design Section, for making the figure and Douglas Joubert, NIH Library Editing Service, for editing the text.

Conflict of Interest Statement

The authors declare no conflict of interest.


  1. 1.
    Nakano K, Orita T, Nezu J, Yoshino T, Ohizumi I, Sugimoto M, et al. Anti-glypican 3 antibodies cause ADCC against human hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2009;378:279–84.CrossRefPubMedGoogle Scholar
  2. 2.
    Kim M-S, Saunders AM, Hamaoka BY, Beachy PA, Leahy DJ. Structure of the protein core of the glypican dally-like and localization of a region important for hedgehog signaling. Proc Natl Acad Sci. 2011;108:13112–7.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Svensson G, Awad W, Håkansson M, Mani K, Logan DT. Crystal structure of N-glycosylated human glypican-1 core protein: structure of two loops evolutionarily conserved in vertebrate glypican-1. J Biol Chem. 2012;287:14040–51.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ho M, Kim H. Glypican-3: a new target for cancer immunotherapy. Eur J Cancer. 2011;47:333–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Iglesias BV, Centeno G, Pascuccelli H, Ward F, Peters MG, Filmus J, et al. Expression pattern of glypican-3 (GPC3) during human embryonic and fetal development. Histol Histopathol. 2008;23:1333–40.PubMedGoogle Scholar
  6. 6.
    Ligato S, Mandich D, Cartun RW. Utility of glypican-3 in differentiating hepatocellular carcinoma from other primary and metastatic lesions in FNA of the liver: an immunocytochemical study. Mod Pathol. 2008;21:626–31.CrossRefPubMedGoogle Scholar
  7. 7.
    Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 2003;125:89–97.CrossRefPubMedGoogle Scholar
  8. 8.
    Toretsky JA, Zitomersky NL, Eskenazi AE, Voigt RW, Strauch ED, Sun CC, et al. Glypican-3 expression in wilms tumor and hepatoblastoma. J Pediatr Hematol Oncol. 2001;23:496–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Hav M, De Potter A, Ferdinande L, Van Bockstal M, Lem D, Eav S, et al. Glypican-3 is a marker for solid pseudopapillary neoplasm of the pancreas. Histopathology. 2011;59:1278–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Nakatsura T, Kageshita T, Ito S, Wakamatsu K, Monji M, Ikuta Y, et al. Identification of Glypican-3 as a novel tumor marker for melanoma. Clin Cancer Res. 2004;10:6612–21.CrossRefPubMedGoogle Scholar
  11. 11.
    Maeda D, Ota S, Takazawa Y, Aburatani H, Nakagawa S, Yano T, et al. Glypican-3 expression in clear cell adenocarcinoma of the ovary. Mod Pathol. 2009;22:824–32.PubMedGoogle Scholar
  12. 12.
    Zynger DL, Dimov ND, Luan C, Tean Teh B, Yang XJ. Glypican 3: a novel marker in testicular germ cell tumors. Am J Surg Pathol. 2006;30:1570–5. doi: 10.1097/01.pas.0000213322.89670.48.CrossRefPubMedGoogle Scholar
  13. 13.
    Zynger DL, McCallum JC, Luan C, Chou PM, Yang XJ. Glypican 3 has a higher sensitivity than alpha-fetoprotein for testicular and ovarian yolk sac tumour: immunohistochemical investigation with analysis of histological growth patterns. Histopathology. 2010;56:750–7.CrossRefPubMedGoogle Scholar
  14. 14.
    He H, Fang W, Liu X, Weiss LM, Chu PG. Frequent expression of glypican-3 in merkel cell carcinoma: an immunohistochemical study of 55 cases. Appl Immunohistochem Mol Morphol. 2009;17:40–6. doi: 10.1097/PAI.0b013e31817b67d1.CrossRefPubMedGoogle Scholar
  15. 15.
    Yamanaka K, Ito Y, Okuyama N, Noda K, Matsumoto H, Yoshida H, et al. Immunohistochemical study of glypican 3 in thyroid cancer. Oncology. 2007;73:389–94.CrossRefPubMedGoogle Scholar
  16. 16.
    Aviel-Ronen S, Lau SK, Pintilie M, Lau D, Liu N, Tsao MS, et al. Glypican-3 is overexpressed in lung squamous cell carcinoma, but not in adenocarcinoma. Mod Pathol. 2008;21:817–25.CrossRefPubMedGoogle Scholar
  17. 17.
    Shafizadeh N, Ferrell LD, Kakar S. Utility and limitations of glypican-3 expression for the diagnosis of hepatocellular carcinoma at both ends of the differentiation spectrum. Mod Pathol. 2008;21:1011–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Libbrecht L, Severi T, Cassiman D, Borght SV, Pirenne J, Nevens F, et al. Glypican-3 expression distinguishes small hepatocellular carcinomas from cirrhosis, dysplastic nodules, and focal nodular hyperplasia-like nodules. Am J Surg Pathol. 2006;30:1405–11. doi: 10.1097/01.pas.0000213323.97294.9a.CrossRefPubMedGoogle Scholar
  19. 19.
    Gray A, Raff AB, Chiriva-Internati M, Chen S-Y, Kast WM. A paradigm shift in therapeutic vaccination of cancer patients: the need to apply therapeutic vaccination strategies in the preventive setting. Immunol Rev. 2008;222:316–27.CrossRefPubMedGoogle Scholar
  20. 20.
    Nobuoka D, Motomura Y, Shirakawa H, Yoshikawa T, Kuronuma T, Takahashi M, et al. Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes. Int J Oncol. 2012;40:63–70.PubMedGoogle Scholar
  21. 21.
    Kawashima I, Kawashima Y, Matsuoka Y, Fujise K, Sakai H, Takahashi M, et al. Suppression of postsurgical recurrence of hepatocellular carcinoma treated with autologous formalin-fixed tumor vaccine, with special reference to glypican-3. Clin Case Rep. 2015;3:444–7.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Li S, Lin J, Qi C, Fu S, Xiao W, Peng B, et al. GPC3 DNA vaccine elicits potent cellular antitumor immunity against HCC in mice. Hepato-Gastroenterology. 2014;61:278–84.PubMedGoogle Scholar
  23. 23.
    Vreeland TJ, Hale DK, Clifton GT, Sears AK, Mittendorf EA, Peoples GE. Peptide vaccine strategies in the treatment of cancer. J Proteomics Bioinforma. 2013;6:81–4.Google Scholar
  24. 24.
    Rosalia RA, Quakkelaar ED, Redeker A, Khan S, Camps M, Drijfhout JW, et al. Dendritic cells process synthetic long peptides better than whole protein, improving antigen presentation and T-cell activation. Eur J Immunol. 2013;43:2554–65.CrossRefPubMedGoogle Scholar
  25. 25.
    Romero P, Banchereau J, Bhardwaj N, Cockett M, Disis ML, Dranoff G, et al. The human vaccines project: a roadmap for cancer vaccine development. Sci Transl Med. 2016;8:334ps9.CrossRefPubMedGoogle Scholar
  26. 26.
    Nakatsura T, Komori H, Kubo T, Yoshitake Y, Senju S, Katagiri T, et al. Mouse homologue of a novel human Oncofetal antigen, Glypican-3, evokes T-cell–mediated tumor rejection without autoimmune reactions in mice. Clin Cancer Res. 2004;10:8630–40.CrossRefPubMedGoogle Scholar
  27. 27.
    Komori H, Nakatsura T, Senju S, Yoshitake Y, Motomura Y, Ikuta Y, et al. Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for Glypican-3-specific immunotherapy of hepatocellular carcinoma. Clin Cancer Res. 2006;12:2689–97.CrossRefPubMedGoogle Scholar
  28. 28.
    Sawada Y, Yoshikawa T, Ofuji K, Yoshimura M, Tsuchiya N, Takahashi M, et al. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. OncoImmunology. 2016;5:e1129483.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sawada Y, Yoshikawa T, Fujii S, Mitsunaga S, Nobuoka D, Mizuno S, et al. Remarkable tumor lysis in a hepatocellular carcinoma patient immediately following glypican-3-derived peptide vaccination: an autopsy case. Hum Vaccin Immunother. 2013;9:1228–33.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sayem MA, Tomita Y, Yuno A, Hirayama M, Irie A, Tsukamoto H, et al. Identification of glypican-3-derived long peptides activating both CD8+ and CD4+ T cells; prolonged overall survival in cancer patients with Th cell response. OncoImmunology. 2016;5:e1062209.CrossRefPubMedGoogle Scholar
  31. 31.
    Kagamu H, Shu S. Purification of L-Selectinlow cells promotes the generation of highly potent CD4 antitumor effector T lymphocytes. J Immunol. 1998;160:3444–52.PubMedGoogle Scholar
  32. 32.
    Hu H-M, Winter H, Urba WJ, Fox BA. Divergent roles for CD4+ T cells in the priming and effector/memory phases of adoptive immunotherapy. J Immunol. 2000;165:4246–53.CrossRefPubMedGoogle Scholar
  33. 33.
    Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531:253–7.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Toes RE, Blom RJ, Offringa R, Kast WM, Melief CJ. Enhanced tumor outgrowth after peptide vaccination. Functional deletion of tumor-specific CTL induced by peptide vaccination can lead to the inability to reject tumors. J Immunol. 1996;156:3911–8.PubMedGoogle Scholar
  35. 35.
    Toes RE, Offringa R, Blom RJ, Melief CJ, Kast WM. Peptide vaccination can lead to enhanced tumor growth through specific T-cell tolerance induction. Proc Natl Acad Sci. 1996;93:7855–60.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Toes REM, van der Voort EIH, Schoenberger SP, Drijfhout JW, van Bloois L, Storm G, et al. Enhancement of tumor outgrowth through CTL Tolerization after peptide vaccination is avoided by peptide presentation on dendritic cells. J Immunol. 1998;160:4449–56.PubMedGoogle Scholar
  37. 37.
    Rahma OE, Ashtar E, Czystowska M, Szajnik ME, Wieckowski E, Bernstein S, et al. A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients. Cancer Immunol Immunother. 2012;61:373–84.CrossRefPubMedGoogle Scholar
  38. 38.
    Srinivasan M, Domanico SZ, Kaumaya PTP, Pierce SK. Peptides of 23 residues or greater are required to stimulate a high affinity class II-restricted T cell response. Eur J Immunol. 1993;23:1011–6.CrossRefPubMedGoogle Scholar
  39. 39.
    den Boer AT, Diehl L, van GJD M, van der EIH V, Fransen MF, Krimpenfort P, et al. Longevity of antigen presentation and activation status of APC are decisive factors in the balance between CTL immunity versus tolerance. J Immunol. 2001;167:2522–8.CrossRefGoogle Scholar
  40. 40.
    Iwama T, Uchida T, Sawada Y, Tsuchiya N, Sugai S, Fujinami N, et al. Vaccination with liposome-coupled glypican-3-derived epitope peptide stimulates cytotoxic T lymphocytes and inhibits GPC3-expressing tumor growth in mice. Biochem Biophys Res Commun. 2016;469:138–43.CrossRefPubMedGoogle Scholar
  41. 41.
    Phung Y, Gao W, Man Y-G, Nagata S, Ho M. High-affinity monoclonal antibodies to cell surface tumor antigen glypican-3 generated through a combination of peptide immunization and flow cytometry screening. MAbs. 2012;4:592–9.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Zhang Y-F, Ho M. Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma. Sci Rep. 2016;6:33878.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Feng M, Gao W, Wang R, Chen W, Man Y-G, Figg WD, et al. Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma. Proc Natl Acad Sci. 2013;110:E1083–E91.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Gao W, Tang Z, Zhang Y-F, Feng M, Qian M, Dimitrov DS, et al. Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis. Nat Commun. 2015;6:6536.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Gao W, Kim H, Feng M, Phung Y, Xavier CP, Rubin JS, et al. Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy. Hepatology. 2014;60:576–87.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Gao W, Xu Y, Liu J, Ho M. Epitope mapping by a Wnt-blocking antibody: evidence of the Wnt binding domain in heparan sulfate. Sci Rep. 2016;6:26245.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Golabi M, Leung A, Lopez C. Simpson-Golabi-Behmel syndrome type 1. In: Pagon RA, Adam MP, Ardinger HH, editors. Gene reviews. Seattle: University of Washington; 2006 Dec 19 [Updated 2011 Jun 23].Google Scholar
  48. 48.
    Sun CK, Chua M-S, He J, So SK. Suppression of glypican 3 inhibits growth of hepatocellular carcinoma cells through up-regulation of TGF-β2. Neoplasia. 2011;13:IN25. (New York, NY)CrossRefGoogle Scholar
  49. 49.
    Feng M, Kim H, Phung Y, Ho M. Recombinant soluble glypican 3 protein inhibits the growth of hepatocellular carcinoma in vitro. Int J Cancer. 2011;128:2246–7.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Bengochea A, de Souza MM, Lefrancois L, Le Roux E, Galy O, Chemin I, et al. Common dysregulation of Wnt/frizzled receptor elements in human hepatocellular carcinoma. Br J Cancer. 2008;99:143–50.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Capurro MI, Xiang Y-Y, Lobe C, Filmus J. Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling. Cancer Res. 2005;65:6245–54.CrossRefPubMedGoogle Scholar
  52. 52.
    Capurro M, Martin T, Shi W, Filmus J. Glypican-3 binds to frizzled and plays a direct role in the stimulation of canonical Wnt signaling. J Cell Sci. 2014;127:1565–75.CrossRefPubMedGoogle Scholar
  53. 53.
    Gao W, Kim H, Ho M. Human monoclonal antibody targeting the Heparan sulfate chains of Glypican-3 inhibits HGF-mediated migration and motility of hepatocellular carcinoma cells. PLoS One. 2015;10:e0137664.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Midorikawa Y, Ishikawa S, Iwanari H, Imamura T, Sakamoto H, Miyazono K, et al. Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling. Int J Cancer. 2003;103:455–65.CrossRefPubMedGoogle Scholar
  55. 55.
    Cheng W, Tseng C-J, Lin TTC, Cheng I, Pan H-W, Hsu H-C, et al. Glypican-3-mediated oncogenesis involves the insulin-like growth factor-signaling pathway. Carcinogenesis. 2008;29:1319–26.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Capurro MI, Xu P, Shi W, Li F, Jia A, Filmus J. Glypican-3 inhibits hedgehog signaling during development by competing with patched for hedgehog binding. Dev Cell. 2008;14:700–11.CrossRefPubMedGoogle Scholar
  57. 57.
    Cho H-S, Ahn J-M, Han H-J, Cho J-Y. Glypican 3 binds to GLUT1 and decreases glucose transport activity in hepatocellular carcinoma cells. J Cell Biochem. 2010;111:1252–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Taguchi A, Emoto M, Okuya S, Fukuda N, Nakamori Y, Miyazaki M, et al. Identification of Glypican3 as a novel GLUT4-binding protein. Biochem Biophys Res Commun. 2008;369:1204–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Capurro MI, Shi W, Filmus J. LRP1 mediates the Shh-induced endocytosis of the GPC3-Shh complex. J Cell Sci. 2012;125:3380–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Capurro M, Shi W, Izumikawa T, Kitagawa H, Filmus J. Processing by convertases is required for Glypican-3-induced inhibition of hedgehog signaling. J Biol Chem. 2015;290:7576–85.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Ishiguro T, Sugimoto M, Kinoshita Y, Miyazaki Y, Nakano K, Tsunoda H, et al. Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer. Cancer Res. 2008;68:9832–8.CrossRefPubMedGoogle Scholar
  62. 62.
    Kaymakcalan Z, Ibraghimov A, Goodearl AG, Salfeld AJG. Aspects of isotype selection. In: Kontermann R, Dubel S, editors. Antibody engineering. Berlin/Heidelberg: Springer; 2010. p. 291–306.Google Scholar
  63. 63.
    Takai H, Kato A, Kinoshita Y, Ishiguro T, Takai Y, Ohtani Y, et al. Histopathological analyses of the antitumor activity of anti-glypican-3 antibody (GC33) in human liver cancer xenograft models: the essential role of macrophages. Cancer Biol Ther. 2009;8:930–8.CrossRefPubMedGoogle Scholar
  64. 64.
    Zhu AX, Gold PJ, El-Khoueiry AB, Abrams TA, Morikawa H, Ohishi N, et al. First-in-man phase I study of GC33, a novel recombinant humanized antibody against Glypican-3, in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2013;19:920–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Ikeda M, Ohkawa S, Okusaka T, Mitsunaga S, Kobayashi S, Morizane C, et al. Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma. Cancer Sci. 2014;105:455–62.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Yen C-J, Daniele B, Kudo M, Merle P, Park J-W, Ross PJ, et al. Randomized phase II trial of intravenous RO5137382/GC33 at 1600 mg every other week and placebo in previously treated patients with unresectable advanced hepatocellular carcinoma (HCC; NCT01507168). 2014. J Clin Oncol. 32 p 4102.Google Scholar
  67. 67.
    Hanaoka H, Nakajima T, Sato K, Watanabe R, Phung Y, Gao W, et al. Photoimmunotherapy of hepatocellular carcinoma-targeting Glypican-3 combined with nanosized albumin-bound paclitaxel. Nanomedicine. 2015;10:1139–47. (London, England)CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Hanaoka H, Nagaya T, Sato K, Nakamura Y, Watanabe R, Harada T, et al. Glypican-3 targeted human heavy chain antibody as a drug carrier for hepatocellular carcinoma therapy. Mol Pharm. 2015;12:2151–7.CrossRefPubMedGoogle Scholar
  69. 69.
    FitzGerald DJ, Kreitman R, Wilson W, Squires D, Pastan I. Recombinant immunotoxins for treating cancer. Int J Med Microbiol. 2004;293:577–82.CrossRefPubMedGoogle Scholar
  70. 70.
    Kreitman RJ, Pastan I. Antibody fusion proteins: anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox. Clin Cancer Res. 2011;17:6398–405.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Hassan R, Miller AC, Sharon E, Thomas A, Reynolds JC, Ling A, et al. Major cancer regressions in mesothelioma after treatment with an anti-Mesothelin immunotoxin and immune suppression. Sci Transl Med. 2013;5:208ra147.CrossRefPubMedGoogle Scholar
  72. 72.
    Mazor R, Onda M, Pastan I. Immunogenicity of therapeutic recombinant immunotoxins. Immunol Rev. 2016;270:152–64.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Kreitman RJ. Immunoconjugates and new molecular targets in hairy cell leukemia. ASH Edu Program Book. 2012;2012:660–6.Google Scholar
  74. 74.
    Siegall CB, Haggerty HG, Warner GL, Chace D, Mixan B, Linsley PS, et al. Prevention of immunotoxin-induced immunogenicity by coadministration with CTLA4Ig enhances antitumor efficacy. J Immunol. 1997;159:5168–73.PubMedGoogle Scholar
  75. 75.
    Meister S, Schubert U, Neubert K, Herrmann K, Burger R, Gramatzki M, et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res. 2007;67:1783–92.CrossRefPubMedGoogle Scholar
  76. 76.
    Onda M, Ghoreschi K, Steward-Tharp S, Thomas C, O’Shea JJ, Pastan IH, et al. Tofacitinib suppresses antibody responses to protein therapeutics in murine hosts. J Immunol. 2014;193:48–55.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Manning ML, Mason-Osann E, Onda M, Pastan I. Bortezomib reduces pre-existing antibodies to recombinant immunotoxins in mice. J Immunol. 2015;194:1695–701.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Kreitman RJ, Stetler-Stevenson M, Jaffe ES, Conlon KC, Steinberg SM, Wilson W, et al. Complete remissions of adult T-cell leukemia with anti-CD25 recombinant immunotoxin LMB-2 and chemotherapy to block immunogenicity. Clin Cancer Res. 2016;22:310–8.CrossRefPubMedGoogle Scholar
  79. 79.
    Azemar M, Djahansouzi S, Jäger E, Solbach C, Schmidt M, Maurer AB, et al. Regression of cutaneous tumor lesions in patients Intratumorally injected with a recombinant single-chain antibody-toxin targeted to ErbB2/HER2. Breast Cancer Res Treat. 2003;82:155–64.CrossRefPubMedGoogle Scholar
  80. 80.
    Weber F, Asher A, Bucholz R, Berger M, Prados M, Chang S, et al. Safety, tolerability, and tumor response of IL4-pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. J Neuro-Oncol. 2003;64:125–37.Google Scholar
  81. 81.
    Kowalski M, Entwistle J, Cizeau J, Niforos D, Loewen S, Chapman W, et al. A phase I study of an intravesically administered immunotoxin targeting EpCAM for the treatment of nonmuscle-invasive bladder cancer in BCGrefractory and BCG-intolerant patients. Drug Des Devel Ther. 2010;4:313–20.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Llovet JM, Real MI, Montaña X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359:1734–9.CrossRefPubMedGoogle Scholar
  83. 83.
    Roscoe DM, Pai LH, Pastan I. Identification of epitopes on a mutant form of pseudomonas exotoxin using serum from humans treated with pseudomonas exotoxin containing immunotoxins. Eur J Immunol. 1997;27:1459–68.CrossRefPubMedGoogle Scholar
  84. 84.
    Onda M, Nagata S, FitzGerald DJ, Beers R, Fisher RJ, Vincent JJ, et al. Characterization of the B cell epitopes associated with a truncated form of pseudomonas exotoxin (PE38) used to make immunotoxins for the treatment of cancer patients. J Immunol. 2006;177:8822–34.CrossRefPubMedGoogle Scholar
  85. 85.
    Onda M, Beers R, Xiang L, Nagata S, Wang Q-c, Pastan I. An immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes. Proc Natl Acad Sci. 2008;105:11311–6.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Siegel DL. Translational applications of antibody phage display. Immunol Res. 2008;42:118–31.CrossRefPubMedGoogle Scholar
  87. 87.
    Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA, et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012;26:1300–5.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Mazor R, Vassall AN, Eberle JA, Beers R, Weldon JE, Venzon DJ, et al. Identification and elimination of an immunodominant T-cell epitope in recombinant immunotoxins based on pseudomonas exotoxin a. Proc Natl Acad Sci. 2012;109:E3597–E603.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Mazor R, Eberle JA, Hu X, Vassall AN, Onda M, Beers R, et al. Recombinant immunotoxin for cancer treatment with low immunogenicity by identification and silencing of human T-cell epitopes. Proc Natl Acad Sci. 2014;111:8571–6.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Mazor R, Crown D, Addissie S, Jang Y, Kaplan G, Pastan I. Elimination of murine and human T-cell epitopes in recombinant immunotoxin eliminates neutralizing and anti-drug antibodies in vivo. Cell Mol Immunol. 2015;14(5):432–42.CrossRefPubMedGoogle Scholar
  91. 91.
    Mazor R, Zhang J, Xiang L, Addissie S, Awuah P, Beers R, et al. Recombinant immunotoxin with T-cell epitope mutations that greatly reduce immunogenicity for treatment of Mesothelin-expressing tumors. Mol Cancer Ther. 2015;14:2789–96.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Wang C, Gao W, Feng M, Pastan I, Ho M. Construction of an immunotoxin, HN3-mPE24, targeting glypican-3 for liver cancer therapy. Oncotarget. 2016;5Google Scholar
  93. 93.
    Hashimoto K, Perera A, Ogita Y, Nakamura M, Ishiguro T, Sano Y, et al. A phase I dose escalation and cohort expansion study of T-cell redirecting bispecific antibody against Glypican 3 in patients with advanced solid tumors. 2016 ASCO annual meeting. J Clin Oncol. 2016; 34. p suppl; abstr TPS2592.Google Scholar
  94. 94.
    Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol. 2016;13:370–83.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    van der Stegen SJC, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov. 2015;14:499–509.CrossRefPubMedGoogle Scholar
  97. 97.
    Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci. 2009;106:3360–5.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Zhong X-S, Matsushita M, Plotkin J, Riviere I, Sadelain M. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Mol Ther. 2009;18:413–20.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Gao H, Li K, Tu H, Pan X, Jiang H, Shi B, et al. Development of T cells redirected to Glypican-3 for the treatment of hepatocellular carcinoma. Clin Cancer Res. 2014;20:6418–28.CrossRefPubMedGoogle Scholar
  100. 100.
    Giakoustidis A, Giakoustidis D, Mudan S, Sklavos A, Williams R. Molecular signalling in hepatocellular carcinoma: role of and crosstalk among WNT/ss-catenin, sonic hedgehog, notch and Dickkopf-1. Can J Gastroenterol Hepatol. 2015;29:209–17.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Li W, Guo L, Rathi P, Marinova E, Gao X, Wu M-F, et al. Redirecting T cells to Glypican-3 with 4-1BB.ζ CAR results in Th-1 polarization and potent anti-tumor activity. Hum Gene Ther. 2016;28(5):437–48.CrossRefPubMedGoogle Scholar
  102. 102.
    Li W, Guo L, Rathi P, Marinova E, Gao X, Wu MF, et al. Redirecting T cells to Glypican-3 with 4-1BB zeta chimeric antigen receptors results in Th1 polarization and potent antitumor activity. Hum Gene Ther. 2016;28(5):437–48.CrossRefPubMedGoogle Scholar
  103. 103.
    Trinh TL, Wu Q, Chang L-J, Ho M, Liu C. GPC3-specific chimeric antigen receptor T cell in combination with Sorafenib as a novel therapeutic treatment for hepatocellular carcinoma. New Orleans/Philadelphia: AACR; 2016, April 16–20. Cancer Res. p Abstract nr 2316.Google Scholar
  104. 104.
    Dargel C, Bassani-Sternberg M, Hasreiter J, Zani F, Bockmann J-H, Thiele F, et al. T cells engineered to express a T-cell receptor specific for Glypican-3 to recognize and kill hepatoma cells in vitro and in mice. Gastroenterology. 2015;149:1042–52.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Laboratory of Molecular BiologyNational Cancer InstituteBethesdaUSA

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