Advertisement

Developmental Therapeutics for Gynecologic Cancers: An Overview

  • Jennifer L. BrownEmail author
  • Christina S. Chu
Chapter
Part of the Current Clinical Oncology book series (CCO)

Abstract

Traditionally, gynecologic cancers are approached in a multimodal fashion, employing surgery, chemotherapy, and radiation. These important therapies, while often very effective at treating malignancy, often result in difficult multisystem toxicities for patients. Identification of genomic and molecular differences between normal and cancer cells has allowed development of targeted therapies that focus on inhibition of pathways involved in cancer proliferation and metastasis. These therapies ideally provide a more directed approach by selectively acting on targets that are expressed on or in close proximity to tumor cells, thereby limiting toxicity and allowing administration at minimum effective dose rather than maximum tolerated dose, as is standard for traditional cytotoxics. Pathways involving DNA damage repair, angiogenesis, signal transduction, cell proliferation, survival, and metabolism are under active investigation in gynecologic malignancies. Immune therapies involving vaccination and adoptive T-cell infusion are also under evaluation to augment innate tumor-specific immunity.

Keywords

Immunotherapy Targeted therapy Ovarian cancer Endometrial cancer Cervical cancer Angiogenesis mTOR EGFR Tumor vaccination Adoptive immunotherapy 

References

  1. 1.
    Umene K, Banno K, Kisu I, Yanokura M, Nogami Y, Tsuji K, et al. Aurora kinase inhibitors: potential molecular-targeted drugs for gynecologic malignant tumors (Review). Biomed Rep. 2013;1(3):335–40.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, Delbono O. Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Phyiol Cell Physiol. 2014;307(1):C25–38.CrossRefGoogle Scholar
  3. 3.
    Ide AG, Baker NH, Warren SL. Vascularization of the Brown Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am J Roentgenol. 1939;42:891–9.Google Scholar
  4. 4.
    Folkman J, Merler E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med. 1971;133:275–88.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Achen MG, Stacker SA. The vascular endothelial growth factor family; proteins which guide the development of the vasculature. Int J Exp Pathol. 1998;79(5):255–65.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82(1):4–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Cao Y. Antiangiogenic cancer therapy. Semin Cancer Biol. 2004;14(2):139–45.PubMedCrossRefGoogle Scholar
  8. 8.
    Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989;161:851–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Ferrara N, Carver Moore K, Chen H, Dowd M, Lu L, O'Shea KS, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380(6573):439–42.PubMedCrossRefGoogle Scholar
  10. 10.
    Moreira IS, Fernandes PA, Ramos MJ. Vascular endothelial growth factor (VEGF) inhibition--a critical review. Anticancer Agents Med Chem. 2007;7(2):223–45.PubMedCrossRefGoogle Scholar
  11. 11.
    Ce ́be-Suarez S, Zehnder-Fja ̈llman A, Ballmer-Hofer K. The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci. 2006;63(5):601–15.CrossRefGoogle Scholar
  12. 12.
    Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res. 2006;312(5):549–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8(8):579–91.PubMedCrossRefGoogle Scholar
  14. 14.
    Zeng H, Dvorak HF, Mukhopadhyay D. Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) peceptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem. 2001;276(29):26969–79.PubMedCrossRefGoogle Scholar
  15. 15.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.PubMedCrossRefGoogle Scholar
  16. 16.
    Merritt WM, Sood AK. Markers of angiogenesis in ovarian cancer. Dis Markers. 2007;23(5-6):419–31.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999;13(1):9–22.PubMedGoogle Scholar
  18. 18.
    Garzetti GG, Ciavattini A, Lucarini G, Pugnaloni A, De Nictolis M, Amati S, et al. Vascular endothelial growth factor expression as a prognostic index in serous ovarian cystoadenocarcinomas: relationship with MIB1 immunostaining. Gynecol Oncol. 1999;73(3):396–401.PubMedCrossRefGoogle Scholar
  19. 19.
    Giatromanolaki A, Sivridis E, Brekken R, Thorpe PE, Anastasiadis P, Gatter KC, et al. The angiogenic "vascular endothelial growth factor/flk-1(KDR) receptor" pathway in patients with endometrial carcinoma: prognostic and therapeutic implications. Cancer. 2001;92(10):2569–77.PubMedCrossRefGoogle Scholar
  20. 20.
    Guidi AJ, Abu-Jawdeh G, Berse B, Jackman RW, Tognazzi K, Dvorak HF, et al. Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Inst. 1995;87(16):1237–45.PubMedCrossRefGoogle Scholar
  21. 21.
    Obermair A, Kohlberger P, Bancher-Todesca D, Tempfer C, Sliutz G, Leodolter S, et al. Influence of microvessel density and vascular permeability factor/vascular endothelial growth factor expression on prognosis in vulvar cancer. Gynecol Oncol. 1996;63(2):204–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Shen GH, Ghazizadeh M, Kawanami O, Shimizu H, Jin E, Araki T, et al. Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma. Br J Cancer. 2000;83(2):196–203.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Alvarez AA, Krigman HR, Whitaker RS, Dodge RK, Rodriguez GC. The prognostic significance of angiogenesis in epithelial ovarian carcinoma. Clin Cancer Res. 1999;5(3):587–91.PubMedGoogle Scholar
  24. 24.
    Genentech BioOncology™. Avastin® (bevacizumab), product insert. Code revision date: June 2006. ©2006 Genentech, Inc. http://www.gene.com/gene/products/information/oncology/avastin/insert.jspGoogle Scholar
  25. 25.
    Ferrara N, Hillian K, Gerber H, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3:391–400.PubMedCrossRefGoogle Scholar
  26. 26.
    Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JL. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a gynecologic oncology group study. J Clin Oncol. 2007;25(33):5165–71.PubMedCrossRefGoogle Scholar
  27. 27.
    Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473–83.PubMedCrossRefGoogle Scholar
  28. 28.
    Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484–96.PubMedCrossRefGoogle Scholar
  29. 29.
    Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039–45.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Aghajanian C, Sill MW, Darcy KM, Greer B, McMeekin DS, Rose PG, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a gynecologic oncology group study. J Clin Oncol. 2011;29(16):2259–65.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Tewari KS, Sill MW, Long HJ, Penson RT, Huang H, Ramondetta LM, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370:734–43.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Tew WP, Gordon M, Murren J, Dupont J, Pezzulli S, Aghajanian C, et al. Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors. Clin Cancer Res. 2010;16(1):358–66.PubMedCrossRefGoogle Scholar
  34. 34.
    Grothey A, Galanis E. Targeting angiogenesis: progress with anti-VegF treatment with large molecules. Nat Rev Clin Oncol. 2009;6:507–18.PubMedCrossRefGoogle Scholar
  35. 35.
    Rudge JS, Holash J, Hylton D, Russell M, Jiang S, Leidich R. VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci U S A. 2007;104(47):18363–70.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Byrne AT, Ross L, Holash J, Nakanishi M, Hu L, Hofmann JI. Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res. 2003;9(15):5721–8.PubMedGoogle Scholar
  37. 37.
    Hu L, Hofmann J, Holash J, Yancopoulos GD, Sood AK, Jaffe RB. Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model. Clin Cancer Res. 2005;11:6966–71.PubMedCrossRefGoogle Scholar
  38. 38.
    Coleman RL, Duska LR, Ramirez PT, et al. Phase II multi-institutional study of docetaxel plus aflibercept in recurrent ovarian, primary peritoneal and fallopian tube cancer. J Clin Oncol. 2011;29:5017.Google Scholar
  39. 39.
    Coleman RL, Sill MW, Lankes HA, Fader AN, Finkler NJ, Hoffman JS, et al. A phase II evaluation of aflibercept in the treatment of recurrent or persistent endometrial cancer: a Gynecologic oncology group study. Gynecol Oncol. 2013;130(1):252–3.CrossRefGoogle Scholar
  40. 40.
    Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65(10):4389–400.PubMedCrossRefGoogle Scholar
  41. 41.
    Liu JF, Tolaney SM, Birrer M, Fleming GF, Buss MK, Dahlberg SE, et al. A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer. 2013;49(14):2972–8.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomized phase 2 study. Lancet Oncol. 2014;15(11):1207–14.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Friedlander M, Hancock KC, Rischin D, Messing MJ, Stringer CA, Matthys GM, et al. A phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol. 2010;119(1):32–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.PubMedCrossRefGoogle Scholar
  45. 45.
    Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet. 1999;21(1):99–102.PubMedCrossRefGoogle Scholar
  46. 46.
    Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, Boyd J. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res. 2005;11(8):2875–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Rudd ML, Price JC, Fogoros S, Godwin AK, Sgroi DC, Merino MJ, Bell DW. A unique spectrum of somatic PIK3CA mutations within primary endometrial cancinomas. Clin Cancer Res. 2011;17(6):1331–40.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Cheung LW, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011;1(2):170–85.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Sudo T. Molecular-targeted therapies for ovarian cancer: prospects for the future. Int J Clin Oncol. 2012;17(5):424–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4(12):988–1004.PubMedCrossRefGoogle Scholar
  51. 51.
    Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27(13):2278–87.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F. Regulation of hypoxia-inducible factor 1 expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2000;22(20):7004–14.CrossRefGoogle Scholar
  53. 53.
    Mundt A, Yashar C, Mell L. Biological agents and immune therapy. Gynecologic cancer: radiation medicine rounds. New York, NY: Demos Medical Publishing; 2012. p. 401–25.Google Scholar
  54. 54.
    Husseinzadeh N, Husseinzadeh H. mTOR inhibitors and their clinic application in cervical endometrial and ovarian cancers: a critical review. Gynecol Oncol. 2014;133(2):375–81.PubMedCrossRefGoogle Scholar
  55. 55.
    Wullschleger R, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471–84.PubMedCrossRefGoogle Scholar
  56. 56.
    Slomovitz BM, Wu W, Broaddus RR, Soliman PT, Wolf J, Sun CC. mTOR inhibition is a rational target for the treatment of endometrial cancer. Proc Am Soc Clin Oncol. 2004;22:5076.Google Scholar
  57. 57.
    Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011;29(24):3278–85.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Fleming GF, Filliaci VL, Hanjani P, Burks JJ, Davidson SA, Leslie KK, et al. Hormone therapy plus temsirolimus for endometrial cancer (EC): Gynecologic Oncology Group trial #248. J Clin Oncol. 2011;29:335.Google Scholar
  59. 59.
    Alvarez EA, Brady WE, Walker JL, Rotmensch J, Zhou XC, Kendrick JE, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129(1):22–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Behbakht K, Sill MW, Darcy KM, Rubin SC, Mannel RS, Waggoner S, et al. Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: a Gynecologic Oncology Group study. Gynecol Oncol. 2011;123(1):19–26.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Temkin SM, Yamada SD, Fleming GF. A phase I study of weekly temsirolimus and topotecan in the treatment of advanced and/or recurrent gynecologic malignancies. Gynecol Oncol. 2010;11(3):473–6.CrossRefGoogle Scholar
  62. 62.
    Tinker AV, Ellard S, Welch S, Moens F, Allo G, Tsao MS, et al. Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199). Gynecol Oncol. 2013;130(2):269–74.PubMedCrossRefGoogle Scholar
  63. 63.
    Slomovitz BM, Lu KH, Johnston T, Coleman RL, Munsell M, Broaddus RR, et al. A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer. 2010;23:5415–9.CrossRefGoogle Scholar
  64. 64.
    Milani A, Geuna E, Mittica G, Valabrega G. Overcoming endocrine resistance in metastatic breast cancer: current evidence and future directions. World J Clin Oncol. 2014;5(5):990–1001.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Coussy F, Teixeira L, Giacchetti S, Cuvier C, Hocini H, Espié M. New targeted therapies in breast cancer. Gynecol Obstet Fertil. 2014;42(11):787–94.PubMedCrossRefGoogle Scholar
  66. 66.
    Bansal N, Yendluri V, Wenham RM. The molecular biology of endometrial cancers and the implications for pathogenesis, classification, and targeted therapies. Cancer Control. 2009;16(1):8–13.PubMedGoogle Scholar
  67. 67.
    Growdon WB, Boisvert SL, Akhavanfard S, Oliva E, Dias-Santagata DC, et al. Decreased survival in EGFR gene amplified vulvar carcinoma. Gynecol Oncol. 2008;111(2):289–97.PubMedCrossRefGoogle Scholar
  68. 68.
    Kersemaekers AM, Fleuren GJ, Kenter GG, Van den Broek LJ, Uljee SM, Hermans J, et al. Oncogene alterations in carcinomas of the uterine cervix: overexpression of the epidermal growth factor receptor is associated with poor prognosis. Clin Cancer Res. 1999;5(3):577–86.PubMedGoogle Scholar
  69. 69.
    Kim JW, Kim YT, Kim DK, Song CH, Lee JW. Expression of epidermal growth factor receptor in carcinoma of the cervix. Gynecol Oncol. 1996;60(2):283–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Oonk MH, de Bock GH, van der Veen DJ, Ten Hoor KA, de Hullu JA, Hollema H, et al. EGFR expression is associated with groin node metastases in vulvar cancer, but does not improve their prediction. Gynecol Oncol. 2007;104(1):109–13.PubMedCrossRefGoogle Scholar
  71. 71.
    Zagouri F, Bozas G, Kafantari E, Tsiatas M, Nikitas N, Dimopoulos MA, Papadimitriou CA. Endometrial cancer: what is new in adjuvant and molecularly targeted therapy? Obstet Gynecol Int. 2010;2010:749579.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Moscatello DK, Holgado-Madruga M, Godwin AK, Ramirez G, Gunn G, Zoltick PW, Gunn G, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res. 1995;55(23):5536–9.PubMedGoogle Scholar
  73. 73.
    Bartlett JM, Langdon SP, Simpson BJ, Stewart M, Katsaros D, Sismondi P, et al. The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer. Br J Cancer. 1996;73(3):301–6.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Fischer-Colbrie J, Witt A, Heinzl H, Speiser P, Czerwenka K, Sevelda P, et al. EGFR and steroid receptors in ovarian carcinoma: comparison with prognostic parameters and outcome of patients. Anticancer Res. 1997;17(18):613–9.PubMedGoogle Scholar
  75. 75.
    Colombo N, McMeekin S, Schwartz P, Kostka J, Sessa C, Gehrig P, et al. A phase II trial of the mTOR inhibitor AP23573 as a single agent in advanced endometrial cancer. J Clin Oncol. 2007;25:5516.Google Scholar
  76. 76.
    Mackay H, Welch S, Tsao MS, Biagi JJ, Elit L, Ghatage P, et al. Phase II study of oral ridaforolimus in patients with metastatic and/or locally advanced recurrent endometrial cancer: NCIC CTG IND 192. J Clin Oncol. 2011;29:5013.Google Scholar
  77. 77.
    Oza AM, Poveda A, Clamp AR, Pignata S, Scambia G, Del Campo JM, et al. A randomized phase II (RP2) trial of ridaforolimus (R) compared with progestin (P) or chemotherapy (C) in female adult patients with advanced endometrial carcinoma. J Clin Oncol. 2011;29:509.CrossRefGoogle Scholar
  78. 78.
    Fleming GF, Sill MW, Darcy KM, McMeekin DS, Thigpen JT, Alder LM, et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116:15–20.PubMedCrossRefGoogle Scholar
  79. 79.
    Oza AM, Eisenhauer EA, Elit L, Cutz JC, Sakurada A, Tsao MSA, et al. A phase II study of erlotinib in recurrent or metastatic endometrial cancer, NCIC IND-148. J Clin Oncol. 2008;26(26):4319–25.PubMedCrossRefGoogle Scholar
  80. 80.
    Leslie KK, Sill MW, Darcy KM, Baron AT, Wilken JA, Godwin AK, et al. Efficacy and safety of gefitinib and potential prognostic value of soluble EGFR, EGFR mutations, and tumor markers in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer. J Clin Oncol. 2009;27:e16542.Google Scholar
  81. 81.
    McMeekin DS, Sill MW, Benbrook D, Darcy KM, Stearns-Kurosawa DJ, Eaton L, et al. A phase II trial of thalidomide in patients with refractory endometrial cancer and correlation with angiogenesis biomarkers: a Gynecologic Oncology Group study. Gynecol Oncol. 2007;105(2):508–16.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Welch S, Mackay HJ, Hirte H, Fleming GF, Morgan R, Wang L, et al. A phase II study of sunitinib in recurrent or metastatic endometrial carcinoma: a trial of the PMH Phase II Consortium. J Clin Oncol. 2009;28:15s.Google Scholar
  83. 83.
    Correa R, Mackay H, Hirte HW, Morgan R, Welch S, Fleming GF, et al. A phase II study of sunitinib in recurrent or metastatic endometrial carcinoma: a trial of the Princess Margaret Hospital, the University of Chicago, and California Cancer Phase II Consortia. J Clin Oncol. 2010;28.Google Scholar
  84. 84.
    Nimeiri HS, Oza AM, Morgan RJ, Huo D, Elit L, Knost J. Sorafenib (SOR) in patients (pts) with advanced/recurrent uterine carcinoma (UCA) or carcinosarcoma (CS): a phase II trial of the University of Chicago, PMH, and California Phase II Consortia. J Clin Oncol. 2008;26:15S.Google Scholar
  85. 85.
    Schilder RJ, Pathak HB, Lokshin AE, Holloway RW, Alvarez RD, Aghajanian C, et al. Phase II trial of single agent cetuximab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with the potential for dose escalation to rash. Gynecol Oncol. 2009;113(1):21–7.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Secord AA, Blessing JA, Armstrong DK, Rodgers WH, Miner Z, Barnes MN, et al. Phase II trial of cetuximab and carboplatin in relapsed platinum-sensitive ovarian cancer and evaluation of epidermal growth factor receptor expression: a Gynecologic Oncology Group study. Gynecol Oncol. 2008;108(3):493–9.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Gordon AN, Finkler N, Edwards RP, Garcia AA, Crozier M, Irwin DH, et al. Efficacy and safety of erlotinib HCL, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicenter study. Int J Gynecol Cancer. 2005;15(5):785–92.PubMedCrossRefGoogle Scholar
  88. 88.
    Blank SV, Christos P, Curtin JP, Runowicz CD, Goldman N, Sparano JA, et al. Erlotinib added to carboplatin and paclitaxel as first-line treatment of ovarian cancer, phase II study based on surgical reassessment. Gynecol Oncol. 2010;119(3):451–6.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Vasey PA, Gore M, Wilson R, Rustin G, Gabra H, Guastalla JP, et al. A phase Ib trial of docetaxel, carboplatin and erlotinib in ovarian, fallopian tube and primary peritoneal cancers. Br J Cancer. 2008;98(11):1774–80.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Hirte H, Oza A, Swenerton K, Ellard SL, Grimshaw R, Fisher B, Seymour L. A phase II study of erlotinib (OSI-774) given in combination with carboplatin in patients with recurrent epithelial ovarian cancer (NCIC CTG IND.149). Gynecol Oncol. 2010;118(3):308–12.PubMedCrossRefGoogle Scholar
  91. 91.
    Schilder RJ, Sill MW, Chen X, Darcy KM, Decesara SL, Lewandowski G, et al. Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study. Clin Cancer Res. 2005;11(15):5539–48.PubMedCrossRefGoogle Scholar
  92. 92.
    Posadas EM, Liel MS, Kwitkowski V, Minasian L, Godwin AK, Hussain MM, et al. A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer. Cancer. 2007;109(7):1323–30.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Wagner U, du Bois A, Pfisterer J, Huober J, Loibl S, Luck HJ, et al. Gefitinib in combination with tamoxifen in patients with ovarian cancer refractory or resistant to platinum-taxane based therapy – a phase II trial of the AGO Ovarian Cancer Study Group (AGO-OVAR 2.6). Gynecol Oncol. 2007;105(1):132–7.PubMedCrossRefGoogle Scholar
  94. 94.
    Pautier P, Joly F, Kerbrat P, Bougnoux P, Fumoleau P, Petit T, et al. Phase II study of gefitinib in combination with paclitaxel (P) and carboplatin (C) as secondline therapy for ovarian, tubal or peritoneal adenocarcinoma (1839IL/0074). Gynecol Oncol. 2010;116(2):157–62.PubMedCrossRefGoogle Scholar
  95. 95.
    Tewari KS, Sill M, Long HJ, Ramondetta LM, Landrum LM, Oaknin A, et al. Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: a phase III randomized trial of the Gynecologic Oncology Group. J Clin Oncol. 2013;31(18):3.Google Scholar
  96. 96.
    Schefter TE, Winter K, Kwon JS, Stuhr K, Balaraj K, Yaremko BP, et al. A phase II study of bevacizumab in combination with definitive radiotherapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma: preliminary results of RTOG 0417. Int J Radiat Oncol Biol Phys. 2012;83(4):1179–84.PubMedCrossRefGoogle Scholar
  97. 97.
    Zighelboim I, Wright JD, Gao F, Case AS, Massad LS, Mutch DG, et al. Multicenter phase II trial of topotecan, cisplatin and bevacizumab for recurrent or persistent cervical cancer. Gynecol Oncol. 2013;130(1):64–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Mackay HJ, Tinker A, Winquist E, Thomas G, Swenerton K, Oza A, et al. A phase II study of sunitinib in patients with locally advanced or metastatic cervical carcinoma, NCIC CTG Trial IND.184. Gynecol Oncol. 2010;116(2):163–7.PubMedCrossRefGoogle Scholar
  99. 99.
    Goncalves A, Fabbro M, Lhommé C, Gladieff L, Extra JM, Floquet A, et al. A phase II trial to evaluate gefitinib as second- or third-line treatment in patients with recurring locoregionally advanced or metastatic cervical cancer. Gynecol Oncol. 2008;108(1):42–6.PubMedCrossRefGoogle Scholar
  100. 100.
    Schilder RJ, Sill MW, Lee YC, Mannel R. A phase II trial of erlotinib in recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. Int J Gynecol Cancer. 2009;19(5):929–33.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Santin AD, Sill MW, McMeekin DS, Leitao Jr MM, Brown J, Sutton GP, et al. Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2011;122(3):495–500.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Tinker AV, Ellard S, Welch S, Tinker AV, Ellard S, Welch S, et al. Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199). Gynecol Oncol. 2013;130(2):269–74.PubMedCrossRefGoogle Scholar
  103. 103.
    Coronel J, Cetina L, Pacheco I, Trejo-Becerril C, González-Fierro A, de la Cruz-Hernandez E, et al. A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results. Med Oncol. 2011;28 Suppl 1:S540–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Zhou J, Liu F, Xiao J. Recombinant adenovirus-p53 combined with chemo- therapy in treatment of locally advanced cervical cancer (a phase II study). J Clin Oncol. 2013;31.Google Scholar
  105. 105.
    Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, et al. Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer. A trial of the Chicago, PMH, and California phase II consortia. Gynecol Oncol. 2008;110(1):49–55.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78.PubMedCrossRefGoogle Scholar
  107. 107.
    Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Konner J, Schilder RJ, DeRosa FA, Gerst SR, Tew WP, Sabbatini PJ, et al. A phase II study of cetuximab/paclitaxel/carboplatin for the initial treatment of advanced-stage ovarian, primary peritoneal, or fallopian tube cancer. Gynecol Oncol. 2008;110(2):140–5.PubMedCrossRefGoogle Scholar
  109. 109.
    Kurtz JE, Hardy-Bessard AC, Deslandres M, Lavau-Denes S, Largillier R, et al. Cetuximab, topotecan and cisplatin for the treatment of advanced cervical cancer: a phase II GINECO trial. Gynecol Oncol. 2009;113(1):16–20.PubMedCrossRefGoogle Scholar
  110. 110.
    Beck C, Robert I, Reina-San-Martin B, Schreiber V, Dantzer F. Poly(ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3. Exp Cell Res. 2014;329(1):18–25.PubMedCrossRefGoogle Scholar
  111. 111.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.PubMedCrossRefGoogle Scholar
  112. 112.
    Boulton S, Kyle S, Durkacz BW. Interactive effects of inhibitors of poly(ADP-ribose) polymerase and DNA-dependent protein kinase on cellular responses to DNA damage. Carcinogenesis. 1999;20(2):199–203.PubMedCrossRefGoogle Scholar
  113. 113.
    Saffhill R, Ockey CH. Strand breaks arising from the repair of the 5-bromodeoxyuridine-substituted template and methyl methanesulphonate-induced lesions can explain the formation of sister chromatid exchanges. Chromosoma. 1985;92(3):218–24.PubMedCrossRefGoogle Scholar
  114. 114.
    Duan W, Gao L, Zhao W, Leon M, Sadee W, Webb A, et al. Assessment of FANCD2 nuclear foci formation in paraffin-embedded tumors: a potential patient-enrichment strategy for treatment with DNA inter-strand crosslinking agents. Transl Res. 2013;161(3):156–64.PubMedCrossRefGoogle Scholar
  115. 115.
    McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109–15.PubMedCrossRefGoogle Scholar
  116. 116.
    Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer. 2004;4(10):814–9.PubMedCrossRefGoogle Scholar
  117. 117.
    Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13(9):2728–37.PubMedCrossRefGoogle Scholar
  118. 118.
    Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34.PubMedCrossRefGoogle Scholar
  119. 119.
    Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376(9737):245–51.PubMedCrossRefGoogle Scholar
  120. 120.
    Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;8:852–61.CrossRefGoogle Scholar
  121. 121.
    Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852–61.PubMedCrossRefGoogle Scholar
  122. 122.
    Reinbolt RE, Hays JL. The role of PARP inhibitors in the treatment of gynecologic malignancies. Front Oncol. 2013;3:237.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    FDA News Release “FDA approved Lynparza to treat advanced ovarian cancer” for immediate release December 19, 2014. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm427554.htm
  124. 124.
    Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7(10):3129–40.PubMedCrossRefGoogle Scholar
  125. 125.
    Matei D, Sill MW, Lankes HA, DeGeest K, Bristow RE, Mutch D, et al. Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: a gynecologic oncology group trial. J Clin Oncol. 2011;29(1):69–75.PubMedCrossRefGoogle Scholar
  126. 126.
    Azad NS, Posadas EM, Kwitkowski VE, Steinberg SM, Jain L, Annunziata CM, et al. Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol. 2008;26(22):3709–14.PubMedCrossRefGoogle Scholar
  127. 127.
    Herzog TJ, Scambia G, Kim BG, Lhommé C, Markowska J, Ray-Coquard I, et al. A randomized phase II trial of maintenance therapy with Sorafenib in front-line ovarian carcinoma. Gynecol Oncol. 2013;130(1):25–30.PubMedCrossRefGoogle Scholar
  128. 128.
    Schwandt A, von Gruenigen VE, Wenham RM, Frasure H, Eaton S, Fusco N, et al. Randomized phase II trial of sorafenib alone or in combination with carboplatin/paclitaxel in women with recurrent platinum sensitive epithelial ovarian, peritoneal, or fallopian tube cancer. Invest New Drugs. 2014;32(4):729–38.PubMedCrossRefGoogle Scholar
  129. 129.
    Zsiros E, Tanyi J, Balint K, Kandalaft LE. Immunotherapy for ovarian cancer: recent advances and perspectives. Curr Opin Oncol. 2014;26(5):492–500.PubMedCrossRefGoogle Scholar
  130. 130.
    Schlienger K, Chu CS, Woo EY, Rivers PM, Toll AJ, Hudson B, et al. TRANCE- and CD40 ligand-matured dendritic cells reveal MHC class I-restricted T cells specific for autologous tumor in late-stage ovarian cancer patients. Clin Cancer Res. 2003;9(4):1517–27.PubMedGoogle Scholar
  131. 131.
    Shiao S, Ganesan A, Rugo H, Coussen L. Immune microenvironments in solid tumors: new targets for therapy. Genes Dev. 2011;25(24):2559–72.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Bright RK. Book review: peptide based cancer vaccines. Leukemia. 2002;16:970–1.CrossRefGoogle Scholar
  133. 133.
    Mantia-Smaldone GM, Corr B, Chu CS. Immunotherapy in ovarian cancer. Hum Vaccin Immunother. 2012;8(9):1179–91.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Disis ML, Goodell V, Schiffman K, Knutson KL. Humoral epitope-spreading following immunization with a HER-2/neu peptide based vaccine in cancer patients. J Clin Immunol. 2004;24(5):571–8.PubMedCrossRefGoogle Scholar
  135. 135.
    Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA, et al. Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol. 2002;20(11):2624–32.PubMedCrossRefGoogle Scholar
  136. 136.
    Odunsi K, Qian F, Matsuzaki J, Mhawech-Fauceglia P, Andrews C, Hoffman EW, et al. Vaccination with an NY-ESO-1 peptide of HLA class I/II specifici- ties induces integrated humoral and T cell responses in ovarian cancer. Proc Natl Acad Sci U S A. 2007;104(3):12837–42.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    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(3):373–84.PubMedCrossRefGoogle Scholar
  138. 138.
    Stockert E, Jäger E, Chen YT, Scanlan MJ, Gout I, Karbach J, et al. A survey of the humoral immune response of cancer patients to a panel of human tumor antigens. J Exp Med. 1998;187(8):1349–54.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Richards ER, Devine PL, Quin RJ, Fontenot JD, Ward BG, McGuckin MA. Antibodies reactive with the protein core of MUC1 mucin are present in ovarian cancer patients and healthy women. Cancer Immunol Immunother. 1998;46(5):245–52.PubMedCrossRefGoogle Scholar
  140. 140.
    Chinni SR, Falchetto R, Gercel-Taylor C, Shabanowitz J, Hunt DF, Taylor DD. Humoral immune responses to cathepsin D and glucose-regulated protein 78 in ovarian cancer patients. Clin Cancer Res. 1997;3(9):1557–64.PubMedGoogle Scholar
  141. 141.
    Kim JH, Herlyn D, Wong KK, Park DC, Schorge JO, Lu KH, et al. Identification of epithelial cell adhesion molecule autoantibody in patients with ovarian cancer. Clin Cancer Res. 2003;9(13):4782–91.PubMedGoogle Scholar
  142. 142.
    Ho M, Hassan R, Zhang J, Wang QC, Onda M, Bera T, et al. Humoral immune response to mesothelin in mesothelioma and ovarian cancer patients. Clin Cancer Res. 2005;11(10):3814–20.PubMedCrossRefGoogle Scholar
  143. 143.
    Chapman C, Murray A, Chakrabarti J, Thorpe A, Woolston C, Sahin U, et al. Autoantibodies in breast cancer: their use as an aid to early diagnosis. Ann Oncol. 2007;18(5):868–73.PubMedCrossRefGoogle Scholar
  144. 144.
    Luo LY, Herrera I, Soosaipillai A, Diamandis EP. Identification of heat shock protein 90 and other proteins as tumour antigens by serological screening of an ovarian carcinoma expression library. Br J Cancer. 2002;87(3):339–43.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Naora H, Yang YQ, Montz FJ, Seidman JD, Kurman RJ, Roden RB. A serologically identified tumor antigen encoded by a homeobox gene promotes growth of ovarian epithelial cells. Proc Natl Acad Sci U S A. 2001;98:4060–5.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Kalli KR, Oberg AL, Keeney GL, Christianson TJ, Low PS, Knutson KL, Hartmann LC. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008;108(3):619–26.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Kobayashi H, Terao T, Kawashima Y. Serum sialyl Tn as an independent predictor of poor prognosis in patients with epithelial ovarian cancer. J Clin Oncol. 1992;10(1):95–101.PubMedGoogle Scholar
  148. 148.
    Coosemans A, Vergote I, Van Gool SW. Wilms' tumor gene 1 immunotherapy in pelvic gynecological malignancies. Expert Rev Clin Immunol. 2014;10(6):705–11.PubMedCrossRefGoogle Scholar
  149. 149.
    Scanlan MJ, Chen YT, Williamson B, Gure AO, Stockert E, Gordan JD, et al. Characterization of human colon cancer antigens recognized by autologous antibodies. Int J Cancer. 1998;76(5):652–8.PubMedCrossRefGoogle Scholar
  150. 150.
    Bleul C, Muller M, Frank R, Gausepohl H, Koldovsky U, Mgaya HN, et al. Human papillomavirus type 18 E6 and E7 antibodies in human sera: increased anti- E7 prevalence in cervical cancer patients. J Clin Microbiol. 1991;29(8):1579–88.PubMedPubMedCentralGoogle Scholar
  151. 151.
    Muller M, Viscidi RP, Sun Y, Guerrero E, Hill PM, Shah F, et al. Antibodies to HPV-16 E6 and E7 proteins as markers for HPV-16-associated invasive cervical cancer. Virology. 1992;187(2):508–14.PubMedCrossRefGoogle Scholar
  152. 152.
    Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348:203–13.PubMedCrossRefGoogle Scholar
  153. 153.
    Hwang WT, Adams SF, Tahirovic E, et al. Progrostic significance of tumor infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol. 2012;124(2):192–8.PubMedCrossRefGoogle Scholar
  154. 154.
    Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaquchi T. Regulatory T cells: how do they suppress immune responses? Int Immunol. 2009;21(10):1105–11.PubMedCrossRefGoogle Scholar
  155. 155.
    Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–9.PubMedCrossRefGoogle Scholar
  156. 156.
    Wang DP, Konishi I, Koshiyama M, Nanbu Y, Iwai T, Nonogaki H, et al. Immunohistochemical localization of c-erbB-2 protein and epidermal growth factor receptor in normal surface epithelium, surface inclusion cysts, and common epithelial tumours of the ovary. Virchows Arch A Pathol Anat Histopathol. 1992;421(5):393–400.PubMedCrossRefGoogle Scholar
  157. 157.
    McCaughan H, Um I, Langdon SP, Harrison DJ, Faratian D. HER2 expression in ovarian carcinoma: caution and complexity in biomarker analysis. J Clin Pathol. 2012;65(7):670–1.PubMedCrossRefGoogle Scholar
  158. 158.
    Lassus H, Leminen A, Vayrynen A, Cheng G, Gustafsson JA, Isola J, et al. ERBB2 amplification is superior to protein expression status in predicting patient outcome in serous ovarian carcinoma. Gynecol Oncol. 2004;92(1):31–9.PubMedCrossRefGoogle Scholar
  159. 159.
    Felip E, Del Campo JM, Rubio D, Vidal MT, Colomer R, Bermejo B. Overexpression of c-erbB-2 in epithelial ovarian cancer. Prognostic value and relationship with response to chemotherapy. Cancer. 1995;75(8):2147–52.PubMedCrossRefGoogle Scholar
  160. 160.
    Disis ML, Goodell V, Schiffman K, Knutson KL. Humoral epitope-spreading following immunization with a HER-2/neu peptide based vaccine in cancer patients. J Clin Immunol. 2004;24(5):571–8.PubMedCrossRefGoogle Scholar
  161. 161.
    Disis ML, Dang Y, Coveler AL, Marzbani E, Kou ZC, Childs JS, et al. HER-2/neu vaccine-primed autologous T-cell infusions for the treatment of advanced stage HER-2/neu expressing cancers. Cancer Immunol Immunother. 2014;63(2):101–9.PubMedCrossRefGoogle Scholar
  162. 162.
    Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR. Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol. 2003;21(2):283–90.PubMedCrossRefGoogle Scholar
  163. 163.
    Odunsi K, Matsuzaki J, Karbach J, Neumann A, Mhawech-Fauceglia P, Miller A, et al. Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients. Proc Natl Acad Sci U S A. 2012;109(15):5797–802.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Odunsi K, Matsuzaki J, James SR, Mhawech-Fauceglia P, Tsuji T, Miller A, et al. Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol Res. 2014;2(1):37–49.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Vierboom MPM, Nijman HW, Offringa R, van der Voort EL, van Hall T, van den Broek L, et al. Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes. J Exp Med. 1997;186(5):695–704.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Zwaveling S, Vierboom MPM, Ferreira Mota SC, Hendriks JA, Ooms ME, Sutmuller RP, et al. Antitumor efficacy of wild-type p53-specific CD4+ T-helper cells. Cancer Res. 2002;62(21):6187–93.PubMedGoogle Scholar
  167. 167.
    Vermeij R, Leffers N, Hoogeboom BN, Hamming IL, Wolf R, Reyners AK, et al. Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer: a single-arm phase II study. Int J Cancer. 2012;131(5):E670–80.PubMedCrossRefGoogle Scholar
  168. 168.
    Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8(4):299–308.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 2006;12(20):6106–15.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Geller MA, Cooley S, Judson PL, Ghebre R, Carson LF, Argenta PA, et al. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy. 2011;13(1):98–107.PubMedCrossRefGoogle Scholar
  171. 171.
    Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature. 2007;449(7161):419–26.PubMedCrossRefGoogle Scholar
  172. 172.
    Chu CS, Boyer J, Schullery DS, Gimotty PA, Gamerman V, Bender J, et al. Phase I/II randomized trial of dendritic cell vaccination with or with- out cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission. Cancer Immunol Immunother. 2012;61(5):629–41.PubMedCrossRefGoogle Scholar
  173. 173.
    Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L, Brugger W. Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood. 2000;96(9):3102–8.PubMedGoogle Scholar
  174. 174.
    Oregovomab: anti-CA-125 monoclonal antibody B43.13—AltaRex, B43.13, MAb B43.13, monoclonal antibody B43.13. Drugs R D 2006;7(6):379–83.Google Scholar
  175. 175.
    Liu B, Nash J, Runowicz C, Swede H, Stevens R, Li Z. Ovarian cancer immunotherapy: opportunities, progresses and challenges. J Hematol Oncol. 2010;3:7.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Mobus VJ, Baum RP, Bolle M, Kreienberg R, Noujaim AA, Schultes BC, et al. Immune responses to murine monoclonal antibody-B43.13 correlate with prolonged survival of women with recurrent ovarian cancer. Am J Obstet Gynecol. 2003;189(1):28–36.PubMedCrossRefGoogle Scholar
  177. 177.
    Tse C, Collins A, Oehler M, Zippelius A, Heinzelmann-Schwarz V. Antibody-based immunotherapy for ovarian cancer: where are we at? Ann Oncol. 2014;25(2):322–31.PubMedCrossRefGoogle Scholar
  178. 178.
    Schultes BC, Baum RP, Niesen A, Noujaim AA, Madiyalakan R. Anti-idiotype induction therapy, anti-CA125 antibodies (Ab3) mediated tumor killing in patients treated with Ovarex mAb B43.13 (Ab1). Cancer Immunol Immunother. 1998;46(4):201–12.PubMedCrossRefGoogle Scholar
  179. 179.
    Gordon AN, Schultes BC, Gallion H, Edwards R, Whiteside TL, Cermak JM, et al. CA125- and tumor-specific T-cell responses correlate with prolonged survival in oregovomab-treated recurrent ovarian cancer patients. Gynecol Oncol. 2004;94(2):340–51.PubMedCrossRefGoogle Scholar
  180. 180.
    Berek J, Taylor P, McGuire W, Smith LM, Schultes B, Nicodemus CF. Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer. J Clin Oncol. 2009;27(3):418–25.PubMedCrossRefGoogle Scholar
  181. 181.
    Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008;105(8):3005–10.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Hurteau JA, Blessing JA, DeCesare SL, Creasman WT. Evaluation of recombinant human interleukin-12 in patients with recurrent or refractory ovarian cancer: a gynecologic oncology group study. Gynecol Oncol. 2001;82(1):7–10.PubMedCrossRefGoogle Scholar
  183. 183.
    Vlad AM, Budiu RA, Lenzner DE, Wang Y, Thaller JA, Colonello K. A phase II trial of intraperitoneal interleukin-2 in patients with platinum-resistant or platinum-refractory ovarian cancer. Cancer Immunol Immunother. 2010;59(2):293–301.PubMedCrossRefGoogle Scholar
  184. 184.
    Pardoll D. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol. 2011;29(36):4828–48.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100(14):8372–7.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Ribas A, Camacho LH, Lopez-Berestein G, Pavlov D, Bulanhaqui CA, Millham R, et al. Antitumor activity in melanoma and anti-self-responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol. 2005;23(35):8968–77.PubMedCrossRefGoogle Scholar
  188. 188.
    Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23(25):6043–53.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Bulter M, Seiden MV, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100(8):4712–7.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008;105(8):3005–10.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Wallecha A, French C, Petit R, Singh R, Amin A, Rothman J. Lm-LLO-based immunotherapies and HPV-associated disease. J Oncol. 2012;2012:542851.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Santin A, Bellone S, Palmieri M, Ravaggi A, Romani C, Tassi R, et al. HPV16/18 E7-pulsed dendritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities. Gynecol Oncol. 2006;100(3):469–78.PubMedCrossRefGoogle Scholar
  193. 193.
    Kim SH, Castro F, Gonzalez D, Maciag PC, Paterson Y, Gravekamp C. Mage-b vaccine delivered by recombinant Listeria monocytogenes is highly effective against breast cancer metastases. Br J Cancer. 2008;99(5):741–9.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Maciag PC, Radulovic S, Rothman J. The first clinical use of a live-attenuated Listeria monocytogenes vaccine: a Phase I safety study of Lm-LLO-E7 in patients with advanced carcinoma of the cervix. Vaccine. 2009;27(30):3975–83.PubMedCrossRefGoogle Scholar
  195. 195.
    Petit R, Mehta A, Jain M, Gupta S, Nagarkar R, Kumar V, et al. ADXS11-001 immunotherapy targeting HPV-E7: final results from a Phase II study in Indian women with recurrent cervical cancer. J Immunother Cancer. 2014;2 Suppl 3:92.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of Gynecologic OncologyFox Chase Cancer CenterPhiladelphiaUSA

Personalised recommendations