Volume 7, Issue 3, September 2019, Page: 106-116
Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies)
Satoshi Takeuchi, Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan; Division of Gynecologic Oncology, Department of Gynecology, Women’s Health Care, Kobe Tokushukai Hospital, Kobe, Hyogo, Japan
Tadahiro Shoji, Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Masahiro Kagabu, Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Tatsuya Honda Tatsuya Honda, Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Tadayuki Nagasawa, Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Yukari Nitta, Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Toru Sugiyama, Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan; Women’s Cancer Center, Gynecologic Oncology, Takagi Hospital, International, University of Health and Welfare, Ookawa City, Fukuoka, Japan
Sachiko Yoshimura, Department of Cancer, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Yusuke Nakamura, Department of Cancer, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Cancer Institute Hospital of JFCR (Japanese Foundation for Cancer Research), Tokyo, Japan
Received: Aug. 1, 2019;       Accepted: Sep. 11, 2019;       Published: Sep. 24, 2019
DOI: 10.11648/j.crj.20190703.15      View  35      Downloads  7
Despite the improvement of treatments, refractory or chemotherapy resistant ovarian and cervical cancers have been still incurable. In such tumors, the actionable salvage gene-pathways of up-regulating lung cancer 10 (URLC10), hypoxia inducible factor (HIF) and its core protein HIG2- tumor growth factor beta (TGF beta)- the Caenorhabditis elegans SMA ("small" worm phenotype) and Drosophila Mothers Against Decapentaplegic (SMAD), maternal embryonic leucine zipper kinase (MELK)- forkhead box M1 (FOXM1) which induces and stimulates stathmin concerning cell (vascular endothelial cell and tumor cell) migration and counter pathway of P53, and holliday junction recognition protein (HJURP)-histone H3-like centromeric protein A (CEMPA)-Histone, which play important roles in tumor proliferation, metastasis and cell cycling. They had been shifted from original driver gene such as Ras-MAPK or PIK3CA-mTOR. Furthermore, tumor specific micro-environmental factors such as vascular endothelial growth factor (VEGF) receptors facilitate tumor new-angiogenesis, invasion and metastasis, as well. We found human leukocyte antigen (HLA)-A*2402 and 0201 restricted epitope neo-antigens or, epitope peptides of VEGF receptor 1 and 2, using micro-cDNA assay form clinical samples. The peptides consisted in nine to eleven mer peptides, which were presented by HLA (major histocompatibility 1) on cell membrane. We administered the multiple peptides subcutaneously as vaccination and it activated intrinsic cell immune system of cytotoxic T cell (CTL). We conducted a phase 1/2 study of those peptides vaccine (PV) cocktails to elucidate their toxicity profiles and efficacy from 4 June 2010 to Jan 2013 for phase 1 studies, and subsequently continued phase 2 studies at outpatient’s clinic of our hospital. PV were administered at a dose of 1mg of each peptide with MONTANIDE*ISA51 (SEPPIC Co. Ltd, France). Enrollees were obtained written informed consent after our IRB approval on 3 June 2010. In results, no major adverse events were seen except dermatologic reactions at injection site. One patient showed complete response, two showed partial response and 10 showed stable disease out of 22 evaluable patients. Median overall survival was 5 months and 9 months in HLA-A2402 and 0201 group, respectively. In conclusion, these findings suggest the peptides cocktail vaccines were safe and applicable for advanced/recurrent OC.
Immunotherapy, Cancer Vaccination, Epitope Peptide, Ovarian Cancer, Cervical Cancer, HLA, Chemotherapy Resistance, Persistent Disease
To cite this article
Satoshi Takeuchi, Tadahiro Shoji, Masahiro Kagabu, Tatsuya Honda Tatsuya Honda, Tadayuki Nagasawa, Yukari Nitta, Toru Sugiyama, Sachiko Yoshimura, Yusuke Nakamura, Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies), Cancer Research Journal. Vol. 7, No. 3, 2019, pp. 106-116. doi: 10.11648/j.crj.20190703.15
Copyright © 2019 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010). Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 19 (363): 711-723.
Coleman R, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Calino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators (2015). Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372 (26): 2521-2532. DOI: 10.1056/NEJMoa1503093. Epub 2015 Apr 19.
Brahmer JR, Tykody SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Wigginton J (2012). Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 366 (26): 2455-2465. DOI: 10.1056/NEJMoa1200694.
Mittica G, Ghisoni E., Giannone G, Aglietta M, Genta S, Valabrega G (2017). Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity. Oncotarget. 8 (52): 90532-90544. DOI: 10.18632/oncotarget.20042.
Suda T, Tsunoda T, Daigo Y, Nakamura Y, Tahara H (2007). Identification of human leukocyte antigen-A24-restricted epitope peptides derived from gene products upregulated in lung and esophageal cancers as novel targets for immunotherapy. Cancer Sci. 98 (11): 1803-1808. DOI: 10.1111/j.1349-7006.2007.00603.x.
Yoshitake Y, Nishimura Y, Nakamura Y, Shinohara M (2015). A clinical trial of multiple peptides vaccination for advanced head and neck cancer patients induced immune responses and prolonged OS. Oncoimmunology. 1 (4): e1022307.ecollection PMID: 26405579 PMCID: PMC4570101 DOI: 10.1080/2162402X.2015.1022307
Imai K, Hirata S, Irie A, Senju S, Ikuta Y, Yokomine K, Harao M, Inoue M, Tsunoda T, Nakatsuru S, Nakagawa H, Nakamura Y, Baba H, Nishimura Y (2008). Identification of a novel tumor-associated antigen, cadherin 3/P-cadherin, as a possible target for immunotherapy of pancreatic, gastric, and colorectal cancers. Clin Cancer Res. 14 (20): 6487-6495. DOI: 10.1158/1078-0432.CCR-08-1086.
Kono K, Mizukami Y, Daigo Y, Takano A, Masuda K, Yoshida K, Tsunoda T, Kawaguchi Y, Nakamura Y, Fujii H (2009). Vaccination with multiple peptides derived from novel cancer-testis antigens can induce specific T-cell responses and clinical responses in advanced esophageal cancer. Cancer Sci. 100 (8): 1502-1509. DOI: 10.1111/j.1349-7006.2009.01200.x.
Siegel RL, Miller KD, Jemal A (2018). Cancer Statistics, 2018. CA CANCER J CLIN. 2018; 68: 7–30. DOI: 10.3322/caac.21442. https://onlinelbrary.wiley.com/doi/full/10.3322/caac.21442.
Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM, Baergen R; Gynecologic Oncology Group (2003). Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 21 (17): 3194-3200. DOI: 10.1200/JCO.2003.02.153.
Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, Tsuda H, Sugiyama T, Kodama S, Kimura E, Ochiai K, Noda K; Japanese Gynecologic Oncology Group (2009). Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomized controlled trial. Lancet. 374 (9698): 331-338. DOI: 10.1016/S0140-6736 (09)61157-0.
Burger RA, Brady MF, Rhee J, Sovak MA, Kong G, Nguyen HP, Bookman MA (2013). Independent radiologic review of the Gynecologic Oncology Group Study 0218, a phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. Gynecol Oncol. 131 (1): 21-26. DOI: 10.1016/j.ygyno.2013.07.100.
Tewari KS, Sill MW, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, DiSaia PJ, Copeland LJ, Creasman WT, Stehman FB, Brady MF, Burger RA, Thigpen JT, Birrer MJ, Waggoner SE, Moore DH, Look KY, Koh WJ, Monk BJ (2017). Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomized, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 390 (10103): 1654-1663.
Pujade-Lauraine E, Lederman JE, Selle F, Gebski V, Penson RT, Oza AM, Korach J, Huzarski T, Poveda A, Pignata S, Friedlander M, Colombo N, Harter P, Fujiwara K, Ray-Coquard I, Banerjee S, Liu J, Lowe ES, Bloomfield R, Pautier P; SOLO2/ENGOT-Ov21 investigators (2017). Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomized, placebo-controlled, phase 3 trial. Lancet Oncol. (9): 1274-1284. DOI: 10.1016/S1470-2045 (17)30469-2.
Isobe A, Sawada K, Kinose Y, Ohyagi-Hara C, Nakatsuka E, Makino H, Ogura T, Mizuno T, Suzuki N, Morii E, Nakamura K, Sawada I, Toda A, Hashimoto K, Mabuchi S, Ohta T, Morishige K, Kurachi H, Kimura T (2015). Interleukin 6 receptor is an independent prognostic factor and a potential therapeutic target of ovarian cancer. PLoS One. 10 (2): e0118080. DOI: 10.1371/journal.pone.0118080. eCollection 2015.
Togashi A, Katagiri T, Ashida S, Fujioka T, Maruyama O, Wakumoto Y, Sakamoto Y, Fujime M, Kawachi Y, Shuin T, Nakamura Y (2005). Hypoxia-inducible protein 2 (HIG2), a novel diagnostic marker for renal cell carcinoma and potential target for molecular therapy. Cancer Res, 2005; 65: 4817-4826. DOI: 10.1158/0008-5472.CAN-05-0120.
Ishizaki H, Tsunoda T, Wada S, Yamauchi M, Shibuya M, Tahara H (2006). Inhibition of tumor growth with antiangiogenic cancer vaccine using epitope peptides derived from human vascular endothelial growth factor receptor 1. Clin Cancer Res. 12 (19): 5841-5849. DOI: 10.1158/1078-0432.CCR-06-0750.
Wada S, Tsunoda T., Baba T, Primus FJ, Kuwano H, Shibuya M, Tahara, H (2005). Rationale for antiangiogenic cancer therapy with vaccination using epitope peptides derived from human vascular endothelial growth factor receptor 2. Cancer Res. 65: 4939-4946. DOI: 10.1158/0008-5472.can-04-3759.
Yokomine K, Senju S, Nakatsura T, Irie A, Hayashida Y, Ikuta Y, Harao M, Imai K, Baba H, Iwase H, Nomori H, Takahashi K, Daigo Y, Tsunoda T, Nakamura Y, Sasaki Y, Nishimura Y (2010). The forkhead box M1 transcription factor as a candidate of target for anti-cancer immunotherapy. Int J Cancer. 2010; 123 (9): 2153-2163. DOI: 10.1002/ijc.24836.
Gu C, Banasavadi-Siddegowda YK, Joshi K, Nakamura Y, Kurt H, Gupta S, Nakano I (2013). Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner. Stem Cells. 31 (5): 870-881. DOI: 10.1002/stem.1322.
Seo T, Konda R, Sugimura J, Iwasaki K, Nakamura Y, Fujioka T (2010). Expression of hypoxia-inducible protein 2 in renal cell carcinoma: A promising candidate for molecular targeting therapy. Oncol Lett. 1 (4): 697-701. DOI: 10.3892/ol_00000122.
Kanehira M, Katagiri T, Shimo A, Takata R, Shuin T, Miki T, Fujioka T, Nakamura Y (2007). Oncogenic role of MPHOSPH1, a cancer-testis antigen specific to human bladder cancer. Cancer Res. 67 (7): 3276-3285. DOI: 10.1158/0008-5472.CAN-06-3748.
Mizukami Y, Kono K, Daigo Y, Takano A, Tsunoda T, Kawaguchi Y, Nakamura Y, Fujii H (2008). Detection of novel cancer-testis antigen-specific T-cell responses in TIL, regional lymph nodes, and PBL in patients with esophageal squamous cell carcinoma. Cancer Sci. 99: 1448-1454. DOI: 10.1111/j.1349-7006.2008.00844.x.
Fujiwara Y, Sugimura K., Miyata H, Omori T, Nakano H, Mochizuki C, Shimizu K, Saito H, Ashida K, Honjyo S, Nakamura Y, Yano M (2017) A Pilot Study of Post-Operative Adjuvant Vaccine for Advanced Gastric Cancer. Yonago Acta Med. 60 (2): 101-105. PMCID: PMC5502221.
Obara W, Karashima T, Takeda K, Kato R, Kato Y, Kanehira M, Takata R, Inoue K, Katagiri T, Shuin T, Nakamura Y, Fujioka T (2017) Effective induction of cytotoxic T cells recognizing an epitope peptide derived from hypoxia-inducible protein 2 (HIG2) in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother. 66 (1): 17-24. DOI: 10.1007/s00262-016-1915-5.
Nishimura S, Tsuda H., Ito K, Takano M, Terai Y, Jobo T, Kigawa J, Sugiyama T, Yaegashi N, Aoki D (2010). Differential expression of hypoxia-inducible protein 2 among different histological types of epithelial ovarian cancer and in clear cell adenocarcinomas. Int J Gynecol Cancer. 20: 220-226. DOI: 10.1111/IGC.0b013e3181ca1e16.
Down CF, Millour J, Lam EW, Watson RJ (2012). Binding of FoxM1 to G2/M gene promoters is dependent upon B-Myb. Biochim Biophys Acta. 1819 (8): 855-862. DOI: 10.1016/j.bbagrm.2012.03.008.
Millour J, de Olano N, Horimoto Y, Monteiro LJ, Langer JK, Aligue R, Hajji N, Lam EW (2011). ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Mol Cancer Ther. 10 (6): 1046-1058. DOI: 10.1158/1535-7163.MCT-11-0024.
Xu XS, Miao RC, Wan Y, Zhang LQ, Qu K, Liu C (2015). FoxM1 as a novel therapeutic target for cancer drug therapy. Asian Pac J Cancer Prev. 2015; 16 (1): 23-29. 10.7314/apjcp. 16.1.23.
Roh YG, Mun MH, Jeong MS, Kim WT, Lee SR, Chung JW, Kim SI, Kim TN, Nam JK, Leem SH (2018). Drug resistance of bladder cancer cells through activation of ABCG2 by FOXM1. BMB Rep., 51 (2): 98-103. DOI: 10.5483/bmbrep.2018.51.2.222.
Chen H, Zou Y, Yang H, Wang J, Pan H (2014). Downregulation of FoxM1 inhibits proliferation, invasion and angiogenesis of HeLa cells in vitro and in vivo. Int J Oncol. 45 (6): 2355-64. DOI: 10.3892/ol.2016.4932.
Barger CJ, Zhang W, Hillman J, Stablewski AB, Higgins MJ, Vanderhyden BC, Odunsi K, Karpf AR (2015). Genetic determinants of FOXM1 overexpression in epithelial ovarian cancer and functional contribution to cell cycle progression. Oncotargets. 6 (29): 27613-27627. DOI: 10.1016/j.ygyno.2013.07.100.
Wang Y, Lee YM, Baitsch L, Huang A, Xiang Y, Tong H, Lako A, Von T, Choi C, Lim E, Min J, Li L, Stegmeier F, Schlegel R, Eck MJ, Gray NS, Mitchison TJ, Zhao JJ (2014) MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. Elife, 3: e01763. DOI: 10.7554/eLife.01763.
Janostiak R, Rauniyar N, Lam TT, Ou J, Zhu LJ, Green MR, Wajapeyee N (2017). MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway. Cell Rep. 2017; 21 (10): 2829-2841. DOI: 10.1016/j.celrep.2017.11.033.
Cheng J, Qin B, Liu B, Huang T, Li Y, Ma L (2017). Maternal embryonic leucine zipper kinase inhibits epithelial-mesenchymal transition by regulating transforming growth factor-β signaling. Oncol Lett. 13 (6): 4794-4798. DOI: 10.3892/ol.2017.6081.
Kohler RS, Kettlehack H, Knipprath-Mészaros AM, Fedier A, Schoetzau A, Jacob F, Heinzelmann-Schwarz V (2017). MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells. 145 (1): 159-166. DOI: 10.1016/j.ygyno.2017.02.016.
Hasegawa K, Ikeda Y, Kunugi Y, Kurosaki A, Imai Y, Kohyama S, Nagao S, Kozawa E, Yoshida K, Tsunoda T, Nakamura Y, Fujiwara K (2018). Phase I Study of Multiple Epitope Peptide Vaccination in Patients with Recurrent or Persistent Cervical Cancer. J Immunother., 41 (4): 201-207. DOI: 10.1097/CJI.0000000000000214.
Campbell AM, Decker RH. (2017) Mini-review of conventional and hypofractionated radiation therapy combined with immunotherapy for non-small cell lung cancer. Transl Lung Cancer Res. 6 (2): 220-229. DOI: 10.21037/tlcr.2017.03.02.
Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, von Moos R, Viéitez JM, Bouché O, Borg C, Steffens CC, Alonso-Orduña V, Schlichting C, Reyes-Rivera I, Bendahmane B, André T, Kubicka S; ML18147 Study Investigators (2013). Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomized phase 3 trial. Lancet Oncol. 14 (1): 29-37. DOI: 10.1016/S1470-2045(12)70477-1.
Browse journals by subject