Background
Ovarian cancer is one of the most fatal gynaecological malignancies, being responsible for at least 5% of female deaths caused by malignant tumours [1]. Due to scarce symptomatology during early development and aggressive growth of the tumour, most women worldwide are diagnosed in advanced clinical FIGO stage III/IV. Despite improved surgical treatment and modern chemotherapy the prognosis in advanced ovarian cancer is poor, and the overall survival rate is still unsatisfactory. Moreover, observed tumour chemoresistance against protocols based on cisplatin and taxanes necessitates the investigation of the possible benefits of alternative management which could augment or
replace the classical chemotherapy. There are many forms of alternative therapies, including immunotherapy and therapy with inhibitors/modifiers of intracellular signalling pathways.
Immunotherapy
Monoclonal antibodies
Monoclonal antibodies (mAb) are directed against different molecules produced by the tumour, which are involved in its growth and spread. The most intensively studied candidates for mAb targets are: mucin (cancer antigen-CA-125, MUC16), vascular-endothelial growth factor (VEGF), epidermal growth factor receptor-2 (HER-2),
epidermal growth factor receptor-1 (EGFR-1), insulin-like growth factor-I (IGF-I) and folate receptor [2-4].
Oregovomab
Mucins function as lubricants of the epithelial surface and regulators of adhesion and signalling between epithelium and other cells. A mucin classically associated with serous ovarian cancer and used commonly for treatment monitoring is CA-125, which was shown to inhibit the host (natural killer) NK cell cytotoxic activity against the tumour [5, 6]. Murine mAb oregovomab (B43.13, OvaRex™) forms strong complexes with CA-125,
and being foreign for the host provokes effector cells to attack ovarian tumour [7]. Patients treated with oregovomab who showed proliferation and activation of T cells and occurrence of anti-CA-125 antibodies were characterized by significantly longer survival [7, 8]. Management was found to be safe, and side effects were usually mild and transient [8]. However, prospective phase II trial indicated that despite effector response observed in 58% of patients with recurrent ovarian cancer, in only 23% was it accompanied by stabilization of the disease [9]. To overcome that problem, oregovomab was combined with carboplatin-paclitaxel chemotherapy in a phase II randomized trial in advanced ovarian cancer, showing moderate clinical improvement [10]. An alternative form of treatment tested in a phase II clinical trial was combination of 131I(iodine)-labelled OC125 mAb for intraperitoneal treatment of disseminated recurrent ovarian cancer [11]. During therapy with anti-CA 125 mAb the serum levels of that mucin are not representative for the real tumour spread; thus anti-CA-125 mAb hampers monitoring of the disease progression/regression [12]. The murine mAb HMFG1 (human milk fat globule 1) against another mucin antigen CA-15.3 produced by mucinous ovarian tumours was tested in a phase I clinical trial, but despite an immunological response seen in a minority of treated patients (38%), it did not show satisfactory clinical efficacy [13].
Bevacizumab
Vascular-endothelial growth factor (VEGF) is engaged in tumour neo-vascularisation and interactions with tumour-associated macrophages (TAMs) and dendritic cells (DCs). Therefore, anti-VEGF mAb is suspected to prevent these mechanisms [14]. Bevacizumab (Avastin®) is a murine-human chimeric IgG1 mAb directed exclusively against VEGF-A [15]. Although preclinical studies on mice inoculated with human ovarian cancer showed regression of the tumour [16, 17] randomized controlled trials with bevacizumab monotherapy were not able to show significant improvement of survival in ovarian cancer patients [18]. Treatment improved the clinical status and decreased ascites in only 20% of patients [19]. Moreover, in patients subjected previously to chemotherapy treatment with bevacizumab was associated with serious toxicity including intestine perforation (11%) [20]. Phase II randomized trials [21] of combined anti-VEGF/chemotherapy protocols showed a low response rate of 16-24% of patients with advanced cancer [22, 23]. However, when given as a first line treatment, they showed a response rate of up to 80% of patients [24]. Several trials (about 25) are underway in order to evaluate the role of bevacizumab in both mono- and combined therapy for ovarian cancer [reviewed in 4, 25]. Bevacizumab monotherapy in cancer recurrence after previous therapy and as a maintenance therapy is assessed in the NCT00866723 phase II trial. One of the most important trials assesses combined therapy with chemotherapeutics. The ICON7 phase III trial compares carboplatin/paclitaxel therapy with or without addition of bevacizumab followed by 12 cycles of bevacizumab monotherapy in newly diagnosed patients. The GOG 218 phase III trial in previously untreated FIGO III/IV patients compares three arms: carboplatin/paclitaxel versus carboplatin/paclitaxel + bevacizumab versus carboplatin/paclitaxel + bevacizumab + main-
tenance bevacizumab monotherapy. The GOG 213 phase III trial investigates patients with platinum-
sensitive recurrence treated with carboplatin/paclitaxel versus carboplatin/paclitaxel + bevacizumab prior to secondary debulking surgery. The similar OCEANS
phase III trial is devoted to study of carboplatin/gemcitabine versus carboplatin/gemcitabine + bevacizumab in patients with platinum-sensitive recurrence. The
TEACO phase II trial on newly diagnosed FIGO IB-IV patients assesses the protocol of oxaliplatin/docetaxel + bevacizumab. The interesting NCT00491855 phase I trial in advanced peritoneal carcinomatosis studies the effects of intraperitoneal oxaliplatin/paclitaxel with intravenous paclitaxel/bevacizumab [25].
Another anti-VEGF agent is aflibercept (VEGF Trap), which consists of VEGF receptor binding regions combined with human IgG1. Preliminary results of a randomized phase II trial in patients with platinum-resistant ovarian cancer indicated a 11% partial response rate [26].
Trastuzumab and pertuzumab
Human epidermal growth factor receptor-2 (HER-2) controls expression of pro-angiogenic factors, including VEGF, and is present in up to 16% of epithelial ovarian cancers [27, 28]. Trastuzumab (Herceptin®) is a chimeric murine-human IgG1 mAb that binds to an extracellular domain of HER-2 and increases tumour apoptosis [29, 30]. Similarly as in the case of bevacizumab, preclinical studies on murine models showed reduction of growth of HER-2-positive ovarian tumours [30, 31], but when implemented in humans during phase II clinical trials they failed to show satisfactory results (overall response rate 7%) [32]. Low efficacy is connected with resistance to trastuzumab, which depends on some molecules overexpressed on the tumour surface, such as MUC4, CD44 or insulin-like growth factor-I receptor (IGF-I R) [33]. Pertuzumab (Omnitarg™) is another anti-HER-2 mAb, having a different binding site than trastuzumab, but exerting similar effects. The clinical efficacy of pertuzumab therapy was evaluated in a phase II clinical study performed on patients with advanced ovarian cancer refractory to chemotherapy. Both the response rate and stabilization of disease were low and reached about 5%, while patients reported some serious side effects [8]. Another phase II randomized study evaluated the use of gemcitabine with or without pertuzumab in a group of platinum-refractory patients. The results suggested a moderate advantage of the combined protocol over gemcitabine monotherapy [34]. In contrast to trastuzumab, pertuzumab does not require HER-2 over-
expression to exert cytotoxic effects and has limited efficacy in cases of trastuzumab resistance [35, 36].
Cetuximab
Epidermal growth factor receptor-1 (EGFR-1) belongs to HER-2-related receptors activating cellular proliferation and angiogenesis [37]. Its presence in up to 70% of epithelial ovarian tumours was confirmed [38-41]. Cetuximab (Erbitux™) is a murine-human chimeric mAb that binds to the EGFR extracellular domain [42]. Although preclinical in vitro studies confirmed cetuximab efficacy, especially in combination with docetaxel and pertuzumab [43], clinical studies in humans on use of platinum and cetuximab in platinum-sensitive patients showed unsatisfactory efficacy with a relatively high rate of toxicity [41].
Anti-IGF-I-R therapy
Insulin-like growth factor-I (IGF-I) is involved not only in regulation of metabolism by insulin hormone, but also in induction of cell invasion and proliferation. It indirectly regulates angiogenesis by stimulating cyclooxygenase-2 (COX-2) and VEGF, and positively influences migration of tumour cells [44, 45]. Therefore, immunotherapy using different mechanisms of IGF-I neutralization was introduced to management of ovarian cancer. One of them was the use of a soluble form of IGF-I receptor (IGF-I-R) designated 486/STOP. Its efficacy was demonstrated in preclinical in vitro and animal studies [46], similarly to another drug composed of mAb against IGF-I-R called EM164 [47]. Both immunotherapeutics reduced ovarian tumour proliferation and survival. There are two clinical trials ongoing to estimate efficacy of anti-IGF-I-R mAb AMG-479: as an additional drug to classical carboplatin/paclitaxel chemotherapy in optimally debulked FIGO grade III/IV ovarian cancer patients, and as therapy for platinum-sensitive patients with recurrent cancer [48, 49].
Farletuzumab
Alpha-folate receptor (-FR) is a tumour-associated antigen that induces immune responses in about 70% of breast and ovarian cancer patients [50]. Farletuzumab (MORAb-003) is an example of mAb against -FR that increases both cell-mediated and complement-
dependent anti-tumour cytotoxicity [51]. A phase II clinical trial on combined treatment in platinum-sensitive patients with ovarian cancer recurrence showed significant prolongation of remission time compared to patients treated with chemotherapy only [52]. Ongoing clinical trials include: a phase II trial on efficacy of farletuzumab combined with carboplatin/taxane therapy in platinum-resistant primary and recurrent tumours, and a phase III trial on safety of the same combined therapy in platinum-sensitive relapsed tumours [4].
Cytokines
Interferons indicate in vitro cytotoxic activity against ovarian cancer cells [53-55]. Although phase I clinical trials in patients with persistent ovarian cancer revealed that intraperitoneal administration of interferon- (IFN-) after platinum-based chemotherapy resulted in a 36-53% response rate [56, 57], a phase II multicentre study indicated that intraperitoneal IFN- had no better effectiveness than platinum given alone as second-line chemotherapy [58, 59]. Synergistic effects of intraperitoneal IFN- combined with platinum failed to show any advantage over monotherapy [60, 61]. Phase III studies of IFN2a given subcutaneously after completion of first-
line chemotherapy or intraperitoneally together with platinum also failed to show satisfactory results [62, 63]. With a high rate of side effects, IFN- seems to be a doubtful solution for ovarian cancer patients. Subcutaneous IFN- was initially found to be effective in a combined regimen with cisplatin and cyclophosphamide for less advanced ovarian cancer (Ic-IIIc FIGO), as well as for advanced (III/IV FIGO) ovarian cancer in first-line combined therapy with paclitaxel and carboplatin [64, 65]. However, recent randomized trials either in optimally/sub-optimally debulked patients, or in patients qualified for neoadjuvant therapy were unable to confirm previous results [66].
Because administration of higher doses of IL-2 was connected with serious toxicity, only low doses of IL-2 were found useful for clinical testing [67]. A pilot study on low-dose recombinant IL-2 (rIL-2) given intraperitoneally together with tumour-infiltrating lymphocytes expanded in vitro in rIL-2-enriched medium gave unsatisfactory results [68]. Another phase II study of intraperitoneal administration of rIL-2 in taxane/platinum refractory ovarian cancer showed complete/partial response or disease stabilization in about 40% of patients [69]. Due to the scarcity of studies on this form of immunotherapy in ovarian cancer, a definite conclusion regarding its efficacy cannot be drawn [70].
Immunological cells
Recognition of cancer cells by host effector lymphocytes depends on the proper function of antigen-presenting dendritic cells (DCs). The main goal of DC-based immunotherapy is to deliver previously extracted and prepared host own DCs back to the patient in order to restore anti-tumour cytotoxic activity (so-called DC vaccines) [71]. The preparation of DCs means that they are pulsed in vitro with tumour-derived antigen(s) or whole cancer cell lysate in order to potentiate and direct their antigen-presenting capacity [72]. An alternative source of functional DCs could be tumour-associated macrophages (TAMs) isolated either from ascites or from the tumour itself [73]. Although the effectiveness of DC vaccines for induction of tumour-specific CD8+ cytotoxic Th1-biased T lymphocytes was proved in in vitro studies [74, 75], clinical trials performed on patients with advanced ovarian cancer, using HER-2/MUC-1 pulsed DCs, induced immunological responses but no satisfactory clinical response [76-78]. The exception was the study on a vaccination regimen created with autologous dendritic cells engineered with mRNA-encoded -FR [79], which indicated 50% regression of para-aortic lymph node metastases and decrease of CA-125 serum levels 16 months after DC vaccination. However, the study was based on a single case.
Besides DCs, also T lymphocytes were tested for their usefulness in adoptive immunotherapy of ovarian cancer. Autologous T cells subjected to in vitro sensitization against cancer folate receptor were tested in a phase I trial, which however did not show reduction in tumour size [80]. In most studies an increased number of CD4+CD25+Foxp3+ T regulatory cells (Tregs) in peripheral blood, lymph nodes and ascites was noted, correlating with worse prognosis for patient survival [81-83]. Elimination of tumour-tolerogenic Tregs function could be based on use of anti-CTLA-4 mAbs, which block CTLA-4-dependent Tregs suppressive properties. Clinical trials performed on ovarian cancer patients showed that anti-CTLA-4 mAb was able to reduce
CA-125 levels and produce tumour necrosis, but with no satisfactory tumour regression [84, 85]. Moreover, effective anti-tumour responses obtained by Tregs manipulation were accompanied by serious side effects, such as uveitis, hepatitis, nephritis and colitis [86]. What is even more important, too strong Tregs “switch off”
could adversely interfere with anti-tumour defence [87].
Other forms of immunotherapy
The possible future techniques that may be considered for immunotherapy of ovarian cancer include: targeting human leukocyte antigen-G (HLA-G) [88], indoleamine 2,3-dioxygenase (IDO) [89], or CD200 molecule on cancer cells [90]; adoptive immunotherapy
using T cells [91] or natural killer T (NKT) cells [92]; or modulation of TAMs [93]. As some tumour-associated antigens are over-expressed on both the placenta and tumour surface, there is a possibility of immunoplacental therapy that could enhance host defence against multiple tumour targets [94, 95].
Summary
Immunotherapy of ovarian cancer has not demon-
strated satisfactory efficacy in most studied cases, despite promising results of preliminary preclinical studies. Also disappointing is the fact that the immunological response in the host induced by immunotherapy is not equivalent to a clinical response and prolonged survival. The plethora of mechanisms employed by the tumour to avoid host immunosurveillance necessitates the use of combined protocols based on immunotherapy with classical chemotherapy. However, this increases treatment toxicity. And last, but not least, immunotherapy was assessed mostly in advanced cancer, when reversal of unwanted immunological events is very difficult, if possible at all. Moreover, not every type of ovarian cancer is a good candidate for every form of immunological treatment, as only some of the tumours are characterized by expression of sufficient amounts of a particular antigen. All these problems await a solution, and further clinical trials are needed to draw nearer to victory over ovarian cancer.
References
1. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer
J Clin 2003; 53: 5-26.
2. Frederick PJ, Straughn JM Jr, Alvarez RD, Buchsbaum DJ. Preclinical
studies and clinical utilization of monoclonal antibodies in epithelial ovarian cancer. Gynecol Oncol 2009; 113: 384-90.
3. Beauchamp MC, Yasmeen A, Knafo A, Gotlieb WH. Targeting insulin and insulin-like growth factor pathways in epithelial ovarian cancer. J Oncol 2010; 2010: 257058.
4. Campos SM, Ghosh S. A current review of targeted therapeutics for
ovarian cancer. J Oncol 2010; 2010: 149362.
5. Belisle JA, Gubbels JA, Raphael CA, et al. Peritoneal natural killer cells from epithelial ovarian cancer patients show an altered phenotype and bind to the tumour marker MUC16 (CA125). Immunology 2007; 122:
418-29.
6. Patankar MS, Jing Y, Morrison JC, et al. Potent suppression of natural
killer cell response mediated by the ovarian tumor marker CA125. Gynecol Oncol 2005; 99: 704-13.
7. Noujaim AA, Schultes BC, Baum RP, Madiyalakan R. Induction of CA125-specific B and T cell responses in patients injected with MAb-B43.13-
-evidence for antibody-mediated antigen-processing and presentation of CA125 in vivo. Cancer Biother Radiopharm 2001; 16: 187-203.
8. Gordon MS, Matei D, Aghajanian C, et al. Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J Clin Oncol 2006; 24: 4324-32.
9. Ehlen TG, Hoskins PJ, Miller D, et al. A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic agent for recurrent ovarian cancer. Int J Gynecol Cancer 2005; 15: 1023-34.
10. Braly P, Nicodemus CF, Chu C, et al. The Immune adjuvant properties of front-line carboplatin-paclitaxel: a randomized phase 2 study of alternative schedules of intravenous oregovomab chemoimmunotherapy in advanced ovarian cancer. J Immunother 2009; 32: 54-65.
11. Haisma HJ, Moseley KR, Battaile A, et al. Distribution and pharmacokinetics of radiolabeled monoclonal antibody OC 125 after intravenous and intraperitoneal administration in gynecologic tumors. Am J Obstet Gynecol 1988; 159: 843-8.
12. Marth C, Egle D, Auer D, et al. Modulation of CA-125 tumor marker shedding in ovarian cancer cells by erlotinib or cetuximab. Gynecol Oncol 2007; 105: 716-21.
13. Nicholson S, Bomphray CC, Thomas H, et al. A phase I trial of idiotypic vaccination with HMFG1 in ovarian cancer. Cancer Immunol Immunother 2004; 53: 809-16.
14. Kerbel RS. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 2006; 312: 1171-5.
15. Ferrara N, Hillan K, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3: 391-400.
16. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362: 841-4.
17. Hu L, Hofmann J, Zaloudek C, et al. Vascular endothelial growth factor immunoneutralization plus Paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol 2002; 161: 1917-24.
18. Jain RK, Duda DG, Clark JW, Loeffer JS. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 2006; 3: 24-40.
19. Numnum TM, Rocconi RP, Whitworth J, Barnes MN. The use of bevacizumab to palliate symptomatic ascites in patients with refractory ovarian carcinoma. Gynecol Oncol 2006; 102: 425-8.
20. Wright JD, Secord AA, Numnum TM, et al. A multi-institutional evaluation of factors predictive of toxicity and efficacy of bevacizumab for recurrent ovarian cancer. Int J Gynecol Cancer 2008; 18: 400-6.
21. Eskens FA, Sleijfer S. The use of bevacizumab in colorectal, lung, breast, renal and ovarian cancer: where does it fit? Eur J Cancer 2008; 44: 2350-6.
22. Burger R, Sill M, Monk B, et al. 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: 5165-71.
23. Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 2008; 26: 76-82.
24. Micha J, Goldstein B, Rettenmaier M, et al. A phase II study of outpatient first-line paclitaxel, carboplatin, and bevacizumab for advanced-stage epithelial ovarian, peritoneal, and fallopian tube cancer. Int J Gynecol Cancer 2007; 17: 771-6.
25. Duhoux FP, Machiels JP. Antivascular therapy for epithelial ovarian cancer. J Oncol 2010; 2010: 372547.
26. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996; 335: 1950-5.
27. Ménard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene 2003; 22: 6570-8.
28. Tuefferd M, Couturier J, Penault-Llorca F, et al. HER2 status in ovarian carcinomas: a multicenter GINECO study of 320 patients. PLoS ONE 2007; 2: e1138.
29. Carter P, Presta L, Gorman CM, et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 1992; 89: 4285-9.
30. Delord JP, Allal C, Canal M, et al. Selective inhibition of HER2 inhibits AKT signal transduction and prolongs disease-free survival in a micrometastasis model of ovarian carcinoma. Ann Oncol 2005; 16: 1889-97.
31. Fendly BM, Winget M, Hudziak RM, et al. Characterization of murine
monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product. Cancer Res 1990; 50: 1550-8.
32. Bookman MA, Darcy KM, Clarke-Pearson D, et al. 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: 283-90.
33. Nahtaa R, Esteva FJ. Herceptin: mechanisms of action and resistance. Cancer Lett 2006; 232: 123-38.
34. Amler L, Makhija S, Januario T, et al. HER pathway gene expression analysis in a phase II study of pertuzumab + gemcitabine vs. gemcitabine + placebo in patients with platinum-resistant epithelial ovarian cancer.
J Clin Oncol 2008; 26 (suppl): abstract 5552.
35. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2
signaling inhibits breast and prostate tumor growth. Cancer Cell 2002; 2: 127-37.
36. Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 2004; 5: 317-28.
37. Ciardiello F, Tortora G. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 2001; 7: 2958-70.
38. Berchuck A, Rodriguez GC, Kamel A, et al. Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer.
I. Correlation of receptor expression with prognostic factors in patients with ovarian cancer. Am J Obstet Gynecol 1991; 164: 669-74.
39. Scambia G, Benedetti Panici P, Battaglia F, et al. Significance of epidermal growth factor receptor in advanced ovarian cancer. J Clin Oncol 1992; 10: 529-35.
40. Bartlett JM, Langdon SP, Simpson BJ, et al. The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer. Br J Cancer 1996; 73: 301-6.
41. Secord AA, Blessing JA, Armstrong DK, et al.; Gynecologic Oncology Group. 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: 493-9.
42. Zandi R, Larsen AB, Andersen P, et al. Mechanisms for oncogenic activation of the epidermal growth factor receptor. Cell Signal 2007; 19: 2013-23.
43. Bijman MN, van Berkel MP, Kok M, et al. Inhibition of functional HER family members increases the sensitivity to docetaxel in human ovarian cancer cell lines. Anticancer Drugs 2009; 20: 450-60.
44. Cao Z, Liu LZ, Dixon DA, et al. Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells. Cell Signal 2007; 19: 1542-53.
45. Whitley BR, Beaulieu LM, Carter JC, Church FC. Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells. Gynecol Oncol 2007; 104: 470-9.
46. Hongo A, Kuramoto H, Nakamura Y, et al. Antitumor effects of a soluble insulin-like growth factor I receptor in human ovarian cancer cells: advantage of recombinant protein administration in vivo. Cancer Res 2003; 63: 7834-9.
47. Maloney EK, McLaughlin JL, Dagdigian NE, et al. An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation. Cancer Res 2003; 63: 5073-83.
48. Hewish M, Chau I, Cunningham D. Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. Recent Pat Anti-Cancer Drug Discov 2009; 4: 54-72.
49. Beltran PJ, Mitchell P, Chung YA, et al. AMG 479, a fully human anti-insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells. Mol Cancer Ther 2009; 8: 1095-105.
50. Knutson KL, Krco CJ, Erskine CL, et al. T-cell immunity to the folate receptor alpha is prevalent in women with breast or ovarian cancer. J Clin Oncol 2006; 24: 4254-61.
51. Ebel W, Routhier EL, Foley B, et al. Preclinical evaluation of MORAb-003, a humanized monoclonal antibody antagonizing folate receptor-alpha. Cancer Immunity 2007; 7: 6.
52. Armstrong DK, Bicher A, Coleman RL, et al. Exploratory phase II efficacy study of MORAb-003, a monoclonal antibody against folate receptor alpha, in platinum sensitive ovarian cancer in first relapse. J Clin Oncol 2008; 26: abstract 5500.
53. Epstein LB, Shen JT, Abele JS, Reese CC. Sensitivity of human ovarian carcinoma cells to interferon and other antitumor agents as assessed by an in vitro semi-solid agar technique. Ann N Y Acad Sci 1980; 350: 228-35.
54. Einhorn N, Cantell K, Einhorn S, Stander H. Human leukocyte interferon therapy for advanced ovarian carcinoma. Am J Clin Oncol 1982; 5: 167-72.
55. Freedman RS, Gutterman JU, Wharton JT, Rutledge FN. Leukocyte interferon (IFN alpha) in patients with epithelial ovarian carcinoma. J Biol Response Modif 1983; 2: 133-8.
56. Berek JS, Hacker NF, Lichtenstein A, et al. Intraperitoneal recombinant alpha-interferon for “salvage” immunotherapy in stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. Cancer Res 1985; 45: 4447-53.
57. Willemse PH, de Vries EG, Mulder NH, et al. Intraperitoneal human recombinant interferon alpha-2b in minimal residual ovarian cancer. Eur
J Cancer 1990; 26: 353-8.
58. Howell S, Pfeifle C, Wung W, et al. Intraperitoneal cisplatin with systemic thiosulfate protection. Ann Intern Med 1982; 97: 845-51.
59. Pretorius RG, Hacker NF, Berek JS, et al. Pharmacokinetics of Ip cisplatin in refractory ovarian carcinoma. Cancer Treat Rep 1983; 67: 1085-92.
60. Berek JS, Welander C, Schink JC, et al. A phase I-II trial of intraperitoneal cisplatin and alpha-interferon in patients with persistent epithelial ovarian cancer. Gynecol Oncol 1991; 40: 237-43.
61. Berek JS, Markman M, Blessing JA, et al. Intraperitoneal alpha-interferon alternating with cisplatin in residual ovarian carcinoma: a phase II Gynecologic Oncology Group study. Gynecol Oncol 1999; 74: 48-52.
62. Hall GD, Brown JM, Coleman RE, et al. Maintenance treatment with interferon for advanced ovarian cancer: results of the Northern and Yorkshire gynaecology group randomised phase III study. Br J Cancer 2004; 91: 621-6.
63. Bruzzone M, Rubagotti A, Gadducci A, et al. Intraperitoneal carboplatin with or without interferon-alpha in advanced ovarian cancer patients with minimal residual disease at second look: a prospective randomized trial of 111 patients. G.O.N.O. Gruppo Oncologic Nord Ovest. Gynecol Oncol 1997; 65: 499-505.
64. Windbichler GH, Hausmaninger H, Stummvoll W, et al. Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial.
Br J Cancer 2000; 82: 1138-44.
65. Marth C, Windbichler GH, Hausmaninger H, et al. Interferon-gamma in combination with carboplatin and paclitaxel as a safe and effective first-
line treatment option for advanced ovarian cancer: results of a phase I/II
study. Int J Gynecol Cancer 2006; 16: 1522-8.
66. Alberts DS, Hannigan EV, Liu PY, et al. Randomized trial of adjuvant intraperitoneal alpha-interferon in stage III ovarian cancer patients who have no evidence of disease after primary surgery and chemotherapy: An intergroup study. Gynecol Oncol 2006; 100: 133-8.
67. Yee C, Wallen H, Hunder N, et al. Recent advances in the use of antigen-specific T cells for the treatment of cancer. Update Cancer Therap 2006; 1: 333-42.
68. Freedman RS, Edwards CL, Kavanagh JJ, et al. Intraperitoneal adoptive immunotherapy of ovarian carcinoma with tumor-infiltrating lymphocytes and low-dose recombinant interleukin-2: a pilot trial. J Immunother Emphasis Tumor Immunol 1994; 16: 198-210.
69. Edwards RP, Gooding W, D’Angelo G, et al. A phase II trial of intraperitoneal interleukin-2 demonstrates extended survival in taxane platinum refractory ovarian cancer. Proc Am Soc Clin Oncol 2003; 22: 171-6.
70. Grande C, Firvida JL, Navas V, Casal J. Interleukin-2 for the treatment of solid tumors other than melanoma and renal cell carcinoma. Anticancer Drugs 2006; 17: 1-12.
71. Nencioni A, Grünebach F, Schmidt SM, et al. The use of dendritic cells in cancer immunotherapy. Crit Rev Oncol Hematol 2008; 65: 191-9.
72. Neller MA, López JA, Schmidt CW. Antigens for cancer immunotherapy. Semin Immunol 2008; 20: 286-95.
73. Chu CS, Woo EY, Toll AJ, et al. Tumor-associated macrophages as
a source of functional dendritic cells in ovarian cancer patients. Clin Immunol 2002; 102: 291-301.
74. Yang T, Wall EM, Milne K, et al. CD8+ T cells induce complete regression of advanced ovarian cancers by an interleukin (IL)-2/IL-15 dependent mechanism. Clin Cancer Res 2007; 13: 7172-80.
75. Santin AD, Hermonat PL, Ravaggi A, et al. In vitro induction of tumor-specific human lymphocyte antigen class I-restricted CD8 cytotoxic T lymphocytes by ovarian tumor antigen-pulsed autologous dendritic cells from patients with advanced ovarian cancer. Am J Obstet Gynecol 2000; 183: 601-9.
76. Brossart P, Wirths S, Stuhler G, et al. Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood 2000; 96: 3102-8.
77. Loveland BE, Zhao A, White S, et al. Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma. Clin Cancer Res 2006; 12: 869-77.
78. Hernando JJ, Park TW, Kübler K, et al. Vaccination with autologous
tumour antigen-pulsed dendritic cells in advanced gynaecological
malignancies: clinical and immunological evaluation of a phase I trial. Cancer Immunol Immunother 2002; 51: 45-52.
79. Hernando JJ, Park TW, Fischer HP, et al. Vaccination with dendritic cells transfected with mRNA-encoded folate-receptor-alpha for relapsed
metastatic ovarian cancer. Lancet Oncol 2007; 8: 451-4.
80. Kershaw MH, Westwood JA, Parker LL, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 2006; 12: 6106-15.
81. Betts GJ, Clarke SL, Richards HE, et al. Regulating the immune response to tumours. Adv Drug Deliv Rev 2006; 58: 948-61.
82. Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 2005; 102: 18538-43.
83. Leffers N, Gooden MJ, de Jong RA, et al. Prognostic significance of
tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 2009; 58: 449-59.
84. Hodi FS, Mihm MC, Soiffer RJ, 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 USA 2003; 100: 4712-7.
85. Hodi FS, Butler M, Oble DA, 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 USA 2008; 105: 3005-10.
86. Phan G, Yang J, Sherry R, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003; 100: 8372-7.
87. Shah CA, Allison KH, Garcia RL, et al. Intratumoral T cells, tumor-
associated macrophages, and regulatory T cells: association with p53 mutations, circulating tumor DNA and survival in women with ovarian cancer. Gynecol Oncol 2008; 109: 215-9.
88. Sheu JJ, Shih IeM. Clinical and biological significance of HLA-G expression in ovarian cancer. Semin Cancer Biol 2007; 17: 436-43.
89. Van den Eynde BJ, Théate I, Uyttenhove C, et al. Tumoral immune resistance based on tryptophan degradation by indoleamine 2,3-dioxygenase. Int Congress Series 2007; 1304: 274-7.
90. Kawasaki BT, Farrar WL. Cancer stem cells, CD200 and immunoevasion. Trends Immunol 2008; 29: 464-8.
91. Martinet L, Poupot R, Fournié JJ. Pitfalls on the roadmap to gammadelta T cell-based cancer immunotherapies. Immunol Lett 2009; 124: 1-8.
92. Molling JW, Moreno M, van der Vliet HJ, et al. Invariant natural killer
T cells and immunotherapy of cancer. Clin Immunol 2008; 129: 182-94.
93. Mantovani A, Porta C, Rubino L, et al. Tumor-associated macrophages (TAMs) as new target in anticancer therapy. Drug Discov Today Ther Strateg 2006; 3: 361-6.
94. Harandi A. Immunoplacental therapy, a potential multi-epitope cancer vaccine. Med Hypoth 2006; 66: 1182-7.
95. Brewer BG, Mitchell RA, Harandi A, Eaton JW. Embryonic vaccines
against cancer: an early history. Exp Mol Pathol 2009; 86: 192-7.
