Immune checkpoint inhibitors: A new opportunity in the treatment of ovarian cancer?

International Journal of Molecular Sciences

Volumn 17, Issue 7, 2016, Pages

  Mittica, Gloria ^a,b   Genta, Sofia ^a,b   Aglietta, Massimo ^a,b   Valabrega, Giorgio ^a,b  

^a CANDIOLO CANCER INSTITUTE   (Italy)

^b UNIVERSITY OF TURIN   (Italy)

Author keywords

Cytotoxic T lymphocyte associated protein 4 (CTLA 4); Immune checkpoint inhibitor; Ipilimumab; Nivolumab; Ovarian cancer; Pembrolizumab; Programmed cell death ligand 1 (PD L1); Programmed cell death 1 (PD 1); Tumor infiltrating lymphocytes (TILs)

Indexed keywords

AVELUMAB; BMS 936559; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; IMMUNE CHECKPOINT INHIBITOR; IPILIMUMAB; NIVOLUMAB; PEMBROLIZUMAB; PEPTIDES AND PROTEINS; PROGRAMMED DEATH 1 LIGAND 1 ANTIBODY; PROGRAMMED DEATH 1 LIGAND 2 ANTIBODY; PROGRAMMED DEATH 1 RECEPTOR ANTIBODY; T LYMPHOCYTE ASSOCIATED PROTEIN 4; T LYMPHOCYTE RECEPTOR; TICILIMUMAB; TUMOR ANTIGEN; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT;

ANEMIA; ARTHRALGIA; CANCER CELL; CANCER CHEMOTHERAPY; CANCER PROGNOSIS; CANCER RECURRENCE; CANCER SURVIVAL; DECREASED APPETITE; DIARRHEA; FATIGUE; FEVER; HEADACHE; HEART ARRHYTHMIA; HUMAN; HYPERTRANSAMINASEMIA; HYPOTHYROIDISM; IMMUNE SYSTEM; INFUSION RELATED REACTION; LYMPHOCYTOPENIA; NAUSEA; OVARY CANCER; OVARY CARCINOMA; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; RASH; REVIEW; TUMOR MICROENVIRONMENT; CELL CYCLE CHECKPOINT; DRUG EFFECTS; FEMALE; IMMUNOLOGY; IMMUNOTHERAPY; OVARIAN NEOPLASMS;

ANTINEOPLASTIC AGENTS; CELL CYCLE CHECKPOINTS; FEMALE; HUMANS; IMMUNOTHERAPY; OVARIAN NEOPLASMS;

EID: 84979072500     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms17071169     Document Type: Review

References (79)

1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin. 2015, 65, 5-29
2. Mutch, D.G.; Orlando, M.; Goss, T.; Teneriello, M.G.; Gordon, A.N.; McMeekin, S.D.; Wang, Y.; Scribner, D.R.; Marciniack, M.; Naumann, R.W.; et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J. Clin. Oncol. 2007, 25, 2811-2818
3. Ferrandina, G.; Ludovisi, M.; Lorusso, D.; Pignata, S.; Breda, E.; Savarese, A.; del Medico, P.; Scaltriti, L.; Katsaros, D.; Priolo, D.; et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J. Clin. Oncol. 2008, 26, 890-896
4. Markman, M.; Blessing, J.; Rubin, S.C.; Connor, J.; Hanjani, P.; Waggoner, S.; Group, G.O. Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: A Gynecologic Oncology Group study. Gynecol. Oncol. 2006, 101, 436-440
5. Rose, P.G.; Blessing, J.A.; Mayer, A.R.; Homesley, H.D. Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: A Gynecologic Oncology Group study. J. Clin. Oncol. 1998, 16, 405-410
6. Sehouli, J.; Stengel, D.; Harter, P.; Kurzeder, C.; Belau, A.; Bogenrieder, T.; Markmann, S.; Mahner, S.; Mueller, L.; Lorenz, R.; et al. Topotecan weekly versus conventional 5-day schedule in patients with platinum-resistant ovarian cancer: A randomized multicenter phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J. Clin. Oncol. 2011, 29, 242-248
7. Gordon, A.N.; Tonda, M.; Sun, S.; Rackoff, W.; Investigators, D.S. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol. Oncol. 2004, 95, 1-8
8. Rose, P.G.; Blessing, J.A.; Ball, H.G.; Hoffman, J.; Warshal, D.; DeGeest, K.; Moore, D.H. A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: A Gynecologic Oncology Group study. Gynecol. Oncol. 2003, 88, 130-135
9. Aghajanian, C.; Blank, S.V.; Goff, B.A.; Judson, P.L.; Teneriello, M.G.; Husain, A.; Sovak, M.A.; Yi, J.; Nycum, L.R. 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, 2039-2045
10. Pujade-Lauraine, E.; Hilpert, F.; Weber, B.; Reuss, A.; Poveda, A.; Kristensen, G.; Sorio, R.; Vergote, I.; Witteveen, P.; Bamias, A.; 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, 1302-1308
11. Ledermann, J.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.L.; Meier, W.; Shapira-Frommer, R.; Safra, T.; et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a andomised phase 2 trial. Lancet Oncol. 2014, 15, 852-861
12. Koebel, C.M.; Vermi, W.; Swann, J.B.; Zerafa, N.; Rodig, S.J.; Old, L.J.; Smyth, M.J.; Schreiber, R.D. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007, 450, 903-907
13. Zhang, L.; Conejo-Garcia, J.R.; Katsaros, D.; Gimotty, P.A.; Massobrio, M.; Regnani, G.; Makrigiannakis, A.; Gray, H.; Schlienger, K.; Liebman, M.N.; et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 2003, 348, 203-213
14. Sato, E.; Olson, S.H.; Ahn, J.; Bundy, B.; Nishikawa, H.; Qian, F.; Jungbluth, A.A.; Frosina, D.; Gnjatic, S.; Ambrosone, C.; 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, 18538-18543
15. Curiel, T.J.; Coukos, G.; Zou, L.; Alvarez, X.; Cheng, P.; Mottram, P.; Evdemon-Hogan, M.; Conejo-Garcia, J.R.; Zhang, L.; Burow, M.; et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 2004, 10, 942-949
16. Dong, H.P.; Elstrand, M.B.; Holth, A.; Silins, I.; Berner, A.; Trope, C.G.; Davidson, B.; Risberg, B. NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma. Am. J. Clin. Pathol. 2006, 125, 451-458
17. Emens, L.A.; Kok, M.; Ojalvo, L.S. Targeting the programmed cell death-1 pathway in breast and ovarian cancer. Curr. Opin. Obstet. Gynecol. 2016, 28, 142-147
18. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252-264
19. Freeman, G.J.; Long, A.J.; Iwai, Y.; Bourque, K.; Chernova, T.; Nishimura, H.; Fitz, L.J.; Malenkovich, N.; Okazaki, T.; Byrne, M.C.; et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 2000, 192, 1027-1034
20. Francisco, L.M.; Salinas, V.H.; Brown, K.E.; Vanguri, V.K.; Freeman, G.J.; Kuchroo, V.K.; Sharpe, A.H. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 2009, 206, 3015-3029
21. Latchman, Y.; Wood, C.R.; Chernova, T.; Chaudhary, D.; Borde, M.; Chernova, I.; Iwai, Y.; Long, A.J.; Brown, J.A.; Nunes, R.; et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2001, 2, 261-268
22. Iwai, Y.; Ishida, M.; Tanaka, Y.; Okazaki, T.; Honjo, T.; Minato, N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci. USA 2002, 99, 12293-12297
23. Marincola, F.M.; Jaffee, E.M.; Hicklin, D.J.; Ferrone, S. Escape of human solid tumors from T-cell recognition: Molecular mechanisms and functional significance. Adv. Immunol. 2000, 74, 181-273
24. Konishi, J.; Yamazaki, K.; Azuma, M.; Kinoshita, I.; Dosaka-Akita, H.; Nishimura, M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin. Cancer Res. 2004, 10, 5094-5100
25. Mu, C.Y.; Huang, J.A.; Chen, Y.; Chen, C.; Zhang, X.G. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med. Oncol. 2011, 28, 682-688
26. Herbst, R.S.; Soria, J.C.; Kowanetz, M.; Fine, G.D.; Hamid, O.; Gordon, M.S.; Sosman, J.A.; McDermott, D.F.; Powderly, J.D.; Gettinger, S.N.; et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014, 515, 563-567
27. Thompson, R.H.; Dong, H.; Lohse, C.M.; Leibovich, B.C.; Blute, M.L.; Cheville, J.C.; Kwon, E.D. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin. Cancer Res. 2007, 13, 1757-1761
28. Thompson, R.H.; Dong, H.; Kwon, E.D. Implications of B7-H1 expression in clear cell carcinoma of the kidney for prognostication and therapy. Clin. Cancer Res. 2007, 13, 709s-715s
29. Thompson, R.H.; Gillett, M.D.; Cheville, J.C.; Lohse, C.M.; Dong, H.; Webster, W.S.; Chen, L.; Zincke, H.; Blute, M.L.; Leibovich, B.C.; et al. Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer 2005, 104, 2084-2091
30. Thompson, R.H.; Kuntz, S.M.; Leibovich, B.C.; Dong, H.; Lohse, C.M.; Webster, W.S.; Sengupta, S.; Frank, I.; Parker, A.S.; Zincke, H.; et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 2006, 66, 3381-3385
31. Thompson, R.H.; Webster, W.S.; Cheville, J.C.; Lohse, C.M.; Dong, H.; Leibovich, B.C.; Kuntz, S.M.; Sengupta, S.; Kwon, E.D.; Blute, M.L. B7-H1 glycoprotein blockade: A novel strategy to enhance immunotherapy in patients with renal cell carcinoma. Urology 2005, 66, 10-14
32. Huang, Y.; Zhang, S.D.; McCrudden, C.; Chan, K.W.; Lin, Y.; Kwok, H.F. The prognostic significance of PD-L1 in bladder cancer. Oncol. Rep. 2015, 33, 3075-3084
33. Mahoney, K.M.; Atkins, M.B. Prognostic and predictive markers for the new immunotherapies. Oncology 2014, 28, 39-48
34. Hamanishi, J.; Mandai, M.; Iwasaki, M.; Okazaki, T.; Tanaka, Y.; Yamaguchi, K.; Higuchi, T.; Yagi, H.; Takakura, K.; Minato, N.; et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci. USA 2007, 104, 3360-3365
35. Maine, C.J.; Aziz, N.H.; Chatterjee, J.; Hayford, C.; Brewig, N.; Whilding, L.; George, A.J.; Ghaem-Maghami, S. Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer. Cancer Immunol. Immunother. 2014, 63, 215-224
36. Darb-Esfahani, S.; Kunze, C.A.; Kulbe, H.; Sehouli, J.; Wienert, S.; Lindner, J.; Budczies, J.; Bockmayr, M.; Dietel, M.; Denkert, C.; et al. Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma. Oncotarget 2016, 7, 1486-1499
37. Webb, J.R.; Milne, K.; Kroeger, D.R.; Nelson, B.H. PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol. Oncol. 2016, 141, 293-302
38. Weber, J.S.; D'Angelo, S.P.; Minor, D.; Hodi, F.S.; Gutzmer, R.; Neyns, B.; Hoeller, C.; Khushalani, N.I.; Miller, W.H.; Lao, C.D.; et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015, 16, 375-384
39. Robert, C.; Ribas, A.; Wolchok, J.D.; Hodi, F.S.; Hamid, O.; Kefford, R.; Weber, J.S.; Joshua, A.M.; Hwu, W.J.; Gangadhar, T.C.; et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 2014, 384, 1109-1117
40. Ribas, A.; Puzanov, I.; Dummer, R.; Schadendorf, D.; Hamid, O.; Robert, C.; Hodi, F.S.; Schachter, J.; Pavlick, A.C.; Lewis, K.D.; et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial. Lancet Oncol. 2015, 16, 908-918
41. Robert, C.; Schachter, J.; Long, G.V.; Arance, A.; Grob, J.J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 2015, 372, 2521-2532
42. Borghaei, H.; Paz-Ares, L.; Horn, L.; Spigel, D.R.; Steins, M.; Ready, N.E.; Chow, L.Q.; Vokes, E.E.; Felip, E.; Holgado, E.; et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2015, 373, 1627-1639
43. Brahmer, J.; Reckamp, K.L.; Baas, P.; Crinò, L.; Eberhardt, W.E.; Poddubskaya, E.; Antonia, S.; Pluzanski, A.; Vokes, E.E.; Holgado, E.; et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2015, 373, 123-135
44. Herbst, R.S.; Baas, P.; Kim, D.W.; Felip, E.; Pérez-Gracia, J.L.; Han, J.Y.; Molina, J.; Kim, J.H.; Arvis, C.D.; Ahn, M.J.; et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016, 387, 1540-1550
45. Motzer, R.J.; Escudier, B.; McDermott, D.F.; George, S.; Hammers, H.J.; Srinivas, S.; Tykodi, S.S.; Sosman, J.A.; Procopio, G.; Plimack, E.R.; et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2015, 373, 1803-1813
46. Hodi, F.S.; O'Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010, 363, 711-723
47. Hodi, F.S.; Mihm, M.C.; Soiffer, R.J.; Haluska, F.G.; Butler, M.; Seiden, M.V.; Davis, T.; Henry-Spires, R.; MacRae, S.; Willman, A.; 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, 4712-4717
48. Hodi, F.S.; Butler, M.; Oble, D.A.; Seiden, M.V.; Haluska, F.G.; Kruse, A.; Macrae, S.; Nelson, M.; Canning, C.; Lowy, I.; 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, 3005-3010
49. Hamanishi, J.; Mandai, M.; Ikeda, T.; Minami, M.; Kawaguchi, A.; Murayama, T.; Kanai, M.; Mori, Y.; Matsumoto, S.; Chikuma, S.; et al. Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. J. Clin. Oncol. 2015, 33, 4015-4022
50. Crotzer, D.R.; Sun, C.C.; Coleman, R.L.; Wolf, J.K.; Levenback, C.F.; Gershenson, D.M. Lack of effective systemic therapy for recurrent clear cell carcinoma of the ovary. Gynecol. Oncol. 2007, 105, 404-408
51. Varga, A.; Piha-Paul, S.A.; Ott, P.A.; Mehnert, J.M.; Berton-Rigaud, D.; Johnson, E.A.; Cheng, J.D.; Yuan, S.; Rubin, E.H.; Matei, D.E. Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: Interim results from a phase Ib study. J. Clin. Oncol. 2015, 33, 5510
52. Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.; Hwu, W.J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K.; et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012, 366, 2455-2465
53. Disis, M.L.; Patel, M.R.; Pant, S.; Hamilton, E.P.; Lockhart, A.C.; Kelly, K.; Beck, J.T.; Gordon, M.S.; Weiss, G.J.; Taylor, M.H.; et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase Ib trial: Safety and clinical activity. J. Clin. Oncol. 2016, 34, 5533.
54. Grabosch, S.; Zeng, F.; Mad, T.; Zhang, L.; Brozick, J.G.T.; Edwards, R.P.; Vlad, A. Chemo-induced biology of pd-l1 and in vivo combination immune therapy for ovarian cancer. In Proceedings of the Poster Section of Annual Meeting on Women’s Cancer, San Diego, CA, USA, 19-22 March 2016.
55. Xu, S.; Tao, Z.; Hai, B.; Liang, H.; Shi, Y.; Wang, T.; Song, W.; Chen, Y.; OuYang, J.; Chen, J.; et al. miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint. Nat. Commun. 2016., 7, 11406
56. Peng, J.; Hamanishi, J.; Matsumura, N.; Abiko, K.; Murat, K.; Baba, T.; Yamaguchi, K.; Horikawa, N.; Hosoe, Y.; Murphy, S.K.; et al. Chemotherapy Induces Programmed Cell Death-Ligand 1 Overexpression via the Nuclear Factor-κB to Foster an Immunosuppressive Tumor Microenvironment in Ovarian Cancer. Cancer Res. 2015, 75, 5034-5045
57. Mantia-Smaldone, G.; Ronner, L.; Blair, A.; Gamerman, V.; Morse, C.; Orsulic, S.; Rubin, S.; Gimotty, P.; Adams, S. The immunomodulatory effects of pegylated liposomal doxorubicin are amplified in BRCA1-Deficient ovarian tumors and can be exploited to improve treatment response in a mouse model. Gynecol. Oncol. 2014, 133, 584-590
58. Higuchi, T.; Flies, D.B.; Marjon, N.A.; Mantia-Smaldone, G.; Ronner, L.; Gimotty, P.A.; Adams, S.F. CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer. Cancer Immunol. Res. 2015, 3, 1257-1268
59. Mesnage, S.; Genestie, C.; Auguste, A.; Pain, E.; Gouy, S.; Morice, P.; Bentivegna, E.; Lhomme, C.; Pautier, P.; Dunan, A.; et al. Tumor-infiltrating lymphocytes (TILs) and PDL1 expression in ovarian cancer (OC): Evolution with neoadjuvant chemotherapy (NCT) and prognostic value. J. Clin. Oncol. 2016, 34, 5512.
60. Ku, G.Y.; Yuan, J.; Page, D.B.; Schroeder, S.E.; Panageas, K.S.; Carvajal, R.D.; Chapman, P.B.; Schwartz, G.K.; Allison, J.P.; Wolchok, J.D. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: Lymphocyte count after 2 doses correlates with survival. Cancer 2010, 116, 1767-1775
61. Di Giacomo, A.M.; Ascierto, P.A.; Queirolo, P.; Pilla, L.; Ridolfi, R.; Santinami, M.; Testori, A.; Simeone, E.; Guidoboni, M.; Maurichi, A.; et al. Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study. Ann. Oncol. 2015, 26, 798-803
62. Llosa, N.J.; Cruise, M.; Tam, A.; Wicks, E.C.; Hechenbleikner, E.M.; Taube, J.M.; Blosser, R.L.; Fan, H.; Wang, H.; Luber, B.S.; et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015, 5, 43-51
63. Xiao, Y.; Freeman, G.J. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov. 2015, 5, 16-18
64. McAlpine, J.N.; Porter, H.; Köbel, M.; Nelson, B.H.; Prentice, L.M.; Kalloger, S.E.; Senz, J.; Milne, K.; Ding, J.; Shah, S.P.; et al. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma. Mod. Pathol. 2012, 25, 740-750
65. Strickland, K.C.; Howitt, B.E.; Shukla, S.A.; Rodig, S.; Ritterhouse, L.L.; Liu, J.F.; Garber, J.E.; Chowdhury, D.; Wu, C.J.; D'Andrea, A.D.; et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget 2016, 7, 13587-13598
66. Mabuchi, S.; Sugiyama, T.; Kimura, T. Clear cell carcinoma of the ovary: Molecular insights and future therapeutic perspectives. J. Gynecol. Oncol. 2016, 27, e31
67. Strickland, K.; Howitt, B.E.; Rodig, S.J.; Matulonis, U.A.; Konstantinopoulos, P. Immunogenicity of clear cell ovarian cancer: Association with ARID1A loss, microsatellite instability and endometriosis. J. Clin. Oncol. 2016, 34, 5514.
68. Friedlander, M.L.; Russell, K.; Millis, S.; Gatalica, Z.; Bender, R.; Voss, A. Molecular profiling of clear cell ovarian cancers: Identifying potential treatment targets for clinical trials. Int. J. Gynecol. Cancer 2016, 26, 648-654
69. Lastwika, K.J.; Wilson, W.; Li, Q.K.; Norris, J.; Xu, H.; Ghazarian, S.R.; Kitagawa, H.; Kawabata, S.; Taube, J.M.; Yao, S.; et al. Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. Cancer Res. 2016, 76, 227-238
70. Zorn, K.K.; Bonome, T.; Gangi, L.; Chandramouli, G.V.; Awtrey, C.S.; Gardner, G.J.; Barrett, J.C.; Boyd, J.; Birrer, M.J. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin. Cancer Res. 2005, 11, 6422-6430
71. Ribas, A.; Hamid, O.; Daud, A.; Hodi, F.S.; Wolchok, J.D.; Kefford, R.; Joshua, A.M.; Patnaik, A.; Hwu, W.J.; Weber, J.S.; et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA 2016, 315, 1600-1609
72. Dear, A.E. Epigenetic modulators and the new immunotherapies. N. Engl. J. Med. 2016, 374, 684-686
73. Wrangle, J.; Wang, W.; Koch, A.; Easwaran, H.; Mohammad, H.P.; Vendetti, F.; Vancriekinge, W.; Demeyer, T.; Du, Z.; Parsana, P.; et al. Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine. Oncotarget 2013, 4, 2067-2079
74. Li, H.; Chiappinelli, K.B.; Guzzetta, A.A.; Easwaran, H.; Yen, R.W.; Vatapalli, R.; Topper, M.J.; Luo, J.; Connolly, R.M.; Azad, N.S.; et al. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 2014, 5, 587-598
75. Suzuki, H.; Onishi, H.; Wada, J.; Yamasaki, A.; Tanaka, H.; Nakano, K.; Morisaki, T.; Katano, M. VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. Eur. J. Immunol. 2010, 40, 197-203
76. Coukos, G.; Benencia, F.; Buckanovich, R.J.; Conejo-Garcia, J.R. The role of dendritic cell precursors in tumour vasculogenesis. Br. J. Cancer 2005, 92, 1182-1187
77. Rossi, V.; Sarotto, I.; Maggiorotto, F.; Berchialla, P.; Kubatzki, F.; Tomasi, N.; Redana, S.; Martinello, R.; Valabrega, G.; Aglietta, M.; et al. Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer. Oncologist 2012, 17, 1418-1425
78. 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, 990-1001
79. Chen, Y.; Wang, Q.; Shi, B.; Xu, P.; Hu, Z.; Bai, L.; Zhang, X. Development of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1+ cell lines. Cytokine 2011, 56, 231-238