Adoptive immunotherapy with MUC1-mRNA transfected dendritic cells and cytotoxic lymphocytes plus gemcitabine for unresectable pancreatic cancer

Journal of Translational Medicine

Masaaki Oka²  Yuji Hinoda¹  Takahiro Yamasaki¹  Yutaka Suehiro¹  Kohei Sakai¹  Shigefumi Yoshino²  Tomio Ueno²  Kiyoshi Yoshimura²  Nobuaki Suzuki²  Michihisa Iida²  Hiroto Matsui²  Yoshinari Maeda²  Shoichi Hazama²  Yoshitaro Shindo² 

[1] Department of Oncology and Laboratory Medicine, Yamaguchi University School of Medicine, 1-1- 1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan;Department of Digestive Surgery and Surgical Oncology (Department of Surgery II), Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan

关键词: Immunotherapy;    Gemcitabine;    Cytotoxic lymphocyte;    Dendritic cell;    MUC1;    Pancreatic cancer;   

Others  :  803782
DOI  :  10.1186/1479-5876-12-175

 received in 2014-02-23, accepted in 2014-06-12,  发布年份 2014

【 摘 要 】

Background

We previously reported the clinical efficacy of adoptive immunotherapy (AIT) with dendritic cells (DCs) pulsed with mucin 1 (MUC1) peptide and cytotoxic T lymphocytes (CTLs). We also reported that gemcitabine (GEM) enhances anti-tumor immunity by suppressing regulatory T cells. Therefore, in the present study, we performed combination therapy with AIT and GEM for patients with unresectable or recurrent pancreatic cancer.

Patients and methods

Forty-two patients with unresectable or recurrent pancreatic cancer were treated. DCs were generated by culture with granulocyte macrophage colony-stimulating factor and interleukin-4 and then exposed to tumor necrosis factor-α. Mature DCs were transfected with MUC1-mRNA by electroporation (MUC1-DCs). MUC1-CTLs were induced by co-culture with YPK-1, a human pancreatic cancer cell line, and then with interleukin-2. Patients were treated with GEM, while MUC1-DCs were intradermally injected, and MUC1-CTLs were intravenously administered.

Results

Median survival time (MST) was 13.9 months, and the 1-year survival rate was 51.1%. Of 42 patients, one patient had complete response (2.4%), three patients had partial response (7.1%) and 22 patients had stable disease (52.4%). The disease control ratio was 61.9%. The MST and 1-year survival rate of 35 patients who received more than 1 × 10⁷ MUC1-DCs per injection was 16.1 months and 60.3%, respectively. Liver metastasis occurred in only 5 patients among 35 patients without liver metastasis before treatment. There were no severe toxicities associated with AIT.

Conclusion

AIT with MUC1-DCs and MUC1-CTLs plus GEM may be a feasible and effective treatment for pancreatic cancer.

【 授权许可】

   
2014 Shindo et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010, 60:277-300.
• [2]Friess H, Gassmann M, Buchler MW: Adjuvant therapy of pancreatic cancer using monoclonal antibodies and immune response modifiers. Int J Pancreatol 1997, 21:43-52.
• [3]Hersh EM, Metch BS, Muggia FM, Brown TD, Whitehead RP, Budd GT, Rinehart JJ, Crawford ED, Bonnet JD, Behrens BC: Phase II studies of recombinant human tumor necrosis factor alpha in patients with malignant disease: a summary of the Southwest Oncology Group experience. J Immunother (1991) 1991, 10:426-431.
• [4]Suzuki N, Maeda Y, Tanaka S, Hida N, Mine T, Yamamoto K, Oka M, Itoh K: Detection of peptide-specific cytotoxic T-lymphocyte precursors used for specific immunotherapy of pancreatic cancer. Int J Cancer 2002, 98:45-50.
• [5]Sparano JA, Fisher RI, Weiss GR, Margolin K, Aronson FR, Hawkins MJ, Atkins MB, Dutcher JP, Gaynor ER, Boldt DH, Doroshow JH, Ernest ML, Sznol M, Mier JW: Phase II trials of high-dose interleukin-2 and lymphokine-activated killer cells in advanced breast carcinoma and carcinoma of the lung, ovary, and pancreas and other tumors. J Immunother Emphasis Tumor Immunol 1994, 16:216-223.
• [6]Petersen TR, Dickgreber N, Hermans IF: Tumor antigen presentation by dendritic cells. Crit Rev Immunol 2010, 30:345-386.
• [7]Griffioen M, Borghi M, Schrier PI, Osanto S, Schadendorf D: Analysis of T-cell responses in metastatic melanoma patients vaccinated with dendritic cells pulsed with tumor lysates. Cancer Immunol Immunother 2004, 53:715-722.
• [8]Rains N, Cannan RJ, Chen W, Stubbs RS: Development of a dendritic cell (DC)-based vaccine for patients with advanced colorectal cancer. Hepatogastroenterology 2001, 48:347-351.
• [9]Lepisto AJ, Moser AJ, Zeh H, Lee K, Bartlett D, McKolanis JR, Geller BA, Schmotzer A, Potter DP, Whiteside T, Finn OJ, Ramanathan RK: A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther 2008, 6:955-964.
• [10]Gendler SJ, Lancaster CA, Taylor-Papadimitriou J, Duhig T, Peat N, Burchell J, Pemberton L, Lalani EN, Wilson D: Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin. J Biol Chem 1990, 265:15286-15293.
• [11]Masaki Y, Oka M, Ogura Y, Ueno T, Nishihara K, Tangoku A, Takahashi M, Yamamoto M, Irimura T: Sialylated MUC1 mucin expression in normal pancreas, benign pancreatic lesions, and pancreatic ductal adenocarcinoma. Hepatogastroenterology 1999, 46:2240-2245.
• [12]Barnd DL, Lan MS, Metzgar RS, Finn OJ: Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells. Proc Natl Acad Sci U S A 1989, 86:7159-7163.
• [13]Jerome KR, Barnd DL, Bendt KM, Boyer CM, Taylor-Papadimitriou J, McKenzie IF, Bast RC Jr, Finn OJ: Cytotoxic T-lymphocytes derived from patients with breast adenocarcinoma recognize an epitope present on the protein core of a mucin molecule preferentially expressed by malignant cells. Cancer Res 1991, 51:2908-2916.
• [14]Ioannides CG, Fisk B, Jerome KR, Irimura T, Wharton JT, Finn OJ: Cytotoxic T cells from ovarian malignant tumors can recognize polymorphic epithelial mucin core peptides. J Immunol 1993, 151:3693-3703.
• [15]Kawaoka T, Oka M, Takashima M, Ueno T, Yamamoto K, Yahara N, Yoshino S, Hazama S: Adoptive immunotherapy for pancreatic cancer: cytotoxic T lymphocytes stimulated by the MUC1-expressing human pancreatic cancer cell line YPK-1. Oncol Rep 2008, 20:155-163.
• [16]Kondo H, Hazama S, Kawaoka T, Yoshino S, Yoshida S, Tokuno K, Takashima M, Ueno T, Hinoda Y, Oka M: Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes. Anticancer Res 2008, 28:379-387.
• [17]Palucka K, Banchereau J: Cancer immunotherapy via dendritic cells. Nat Rev Cancer 2012, 12:265-277.
• [18]Nonn M, Schinz M, Zumbach K, Pawlita M, Schneider A, Durst M, Kaufmann AM: Dendritic cell-based tumor vaccine for cervical cancer I: in vitro stimulation with recombinant protein-pulsed dendritic cells induces specific T cells to HPV16 E7 or HPV18 E7. J Cancer Res Clin Oncol 2003, 129:511-520.
• [19]Katano M, Morisaki T, Koga K, Nakamura M, Onishi H, Matsumoto K, Tasaki A, Nakashima H, Akiyoshi T, Nakamura M: Combination therapy with tumor cell-pulsed dendritic cells and activated lymphocytes for patients with disseminated carcinomas. Anticancer Res 2005, 25:3771-3776.
• [20]Strobel I, Berchtold S, Gotze A, Schulze U, Schuler G, Steinkasserer A: Human dendritic cells transfected with either RNA or DNA encoding influenza matrix protein M1 differ in their ability to stimulate cytotoxic T lymphocytes. Gene Ther 2000, 7:2028-2035.
• [21]Abdulhaqq SA, Weiner DB: DNA vaccines: developing new strategies to enhance immune responses. Immunol Res 2008, 42:219-232.
• [22]Ochoa-Callejero L, Berraondo P, Crettaz J, Olague C, Vales A, Ruiz J, Prieto J, Tennant BC, Menne S, Gonzalez-Aseguinolaza G: Woodchuck dendritic cells generated from peripheral blood mononuclear cells and transduced with recombinant human adenovirus serotype 5 induce antigen-specific cellular immune responses. J Med Virol 2007, 79:522-529.
• [23]Yu Z, Sun H, Zhang T, Yang T, Long H, Ma B: Specific antitumor effects of tumor vaccine produced by autologous dendritic cells transfected with allogeneic osteosarcoma total RNA through electroporation in rats. Cancer Biol Ther 2009, 8:973-980.
• [24]Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997, 15:2403-2413.
• [25]Kan S, Hazama S, Maeda K, Inoue Y, Homma S, Koido S, Okamoto M, Oka M: Suppressive effects of cyclophosphamide and gemcitabine on regulatory T-cell induction in vitro. Anticancer Res 2012, 32:5363-5369.
• [26]Dauer M, Herten J, Bauer C, Renner F, Schad K, Schnurr M, Endres S, Eigler A: Chemosensitization of pancreatic carcinoma cells to enhance T cell-mediated cytotoxicity induced by tumor lysate-pulsed dendritic cells. J Immunother 2005, 28:332-342.
• [27]Bauer C, Bauernfeind F, Sterzik A, Orban M, Schnurr M, Lehr HA, Endres S, Eigler A, Dauer M: Dendritic cell-based vaccination combined with gemcitabine increases survival in a murine pancreatic carcinoma model. Gut 2007, 56:1275-1282.
• [28]Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN, Rubin P: CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003, 13:176-181.
• [29]Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000, 92:205-216.
• [30]Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS, Fuchs JR, Eubank TD, Frankel WL, Bekaii-Saab T, Bloomston M, Lesinski GB: Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 2013, 73:3007-3018.
• [31]Foster JH, Lundy J: Liver metastases. Curr Probl Surg 1981, 18:157-202.
• [32]Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, Zaniboni A, Ducreux M, Aitini E, Taieb J, Faroux R, Lepere C, de Gramont A, Gercor G: Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005, 23:3509-3516.
• [33]Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD: Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol 2010, 28:3605-3610.
• [34]Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M: Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol 2013, 31:1640-1648.
• [35]Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W, National Cancer Institute of Canada Clinical Trials G: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007, 25:1960-1966.
• [36]Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe Tumeurs Digestives of U, Intergroup P: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011, 364:1817-1825.
• [37]Schuurhuis DH, Lesterhuis WJ, Kramer M, Looman MG, van Hout-Kuijer M, Schreibelt G, Boullart AC, Aarntzen EH, Benitez-Ribas D, Figdor CG, Punt CJ, de Vries IJ, Adema GJ: Polyinosinic polycytidylic acid prevents efficient antigen expression after mRNA electroporation of clinical grade dendritic cells. Cancer Immunol Immunother 2009, 58:1109-1115.
• [38]Rettig L, Seidenberg S, Parvanova I, Samaras P, Curioni A, Knuth A, Pascolo S: Gemcitabine depletes regulatory T-cells in human and mice and enhances triggering of vaccine-specific cytotoxic T-cells. Int J Cancer 2011, 129:832-838.
• [39]Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S: Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 2007, 179:977-983.
• [40]Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM: Gemcitabine selectively eliminates splenic Gr-1+/CD11b + myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005, 11:6713-6721.
• [41]Finn OJ: Cancer immunology. N Engl J Med 2008, 358:2704-2715.
• [42]Koga T, Duan H, Moroi Y, Urabe K, Furue M: Activated and mature CD83-positive dendritic cells and interferon-gamma-positive cells in skin eruptions of secondary syphilis. Acta Derm Venereol 2003, 83:214-217.
• [43]Morse MA, Coleman RE, Akabani G, Niehaus N, Coleman D, Lyerly HK: Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res 1999, 59:56-58.
• [44]Ridolfi R, Riccobon A, Galassi R, Giorgetti G, Petrini M, Fiammenghi L, Stefanelli M, Ridolfi L, Moretti A, Migliori G, Fiorentini G: Evaluation of in vivo labelled dendritic cell migration in cancer patients. J Transl Med 2004, 2:27.