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Published in: Experimental Hematology & Oncology 1/2015

Open Access 01-12-2015 | Research

The combination of dendritic cells-cytotoxic T lymphocytes/cytokine-induced killer (DC-CTL/CIK) therapy exerts immune and clinical responses in patients with malignant tumors

Authors: Ying Wang, Zenghui Xu, Fuping Zhou, Yan Sun, Jingbo Chen, Linfang Li, Huajun Jin, Qijun Qian

Published in: Experimental Hematology & Oncology | Issue 1/2015

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Abstract

Background

The clinical trials using immunotherapy have been performed for the treatment of variety of malignant tumors. However, large-scale meta-analysis of combined DC-CTL/CIK therapy on immune and clinical response in patients has not been well studied yet. The purpose of this study is to investigate the role of DC-CTL/CIK therapy and evaluate the changes of immune indicators and tumor serological markers both at an individual level and at a system level, which is an important basis for immunotherapy as well as prognosis estimation.

Methods

Three cohorts were designed to estimate therapeutic effects on patients with malignant tumors. Tumor serological markers were detected pre- and post-treatment by immunoradiometric methods using commercially available diagnostic kits. Lymphocyte subsets were identified by flow cytometry. The quality of life was assessed by EORTC QLQ-C30 questionnaire.

Results

In this study, we found out that Tregs was significantly reduced after transfusion of DC-CTL/CIK cells companied by decreasing serological tumor markers including AFP, CA199 and CA242 in primary liver cancer and CA724 in gastric cancer. A system-level analysis showed that lower percentages of Tregs were detected in patients with long-lasting courses of immunotherapy. Strikingly, a tumor progression indicator, myeloid-derived suppressor cells (MDSC), was dramatically decreased in patients after DC-CTL/CIK treatment. These results suggested that DC-CTL/CIK therapy improves immune functions and the quality of life post-treatment versus pre-therapy, indicating that DC-CTL/CIK therapy might block the deterioration of invasive cancers in these patients.

Conclusions

This study demonstrated that DC-CTL/CIK therapy could reduce Tregs, MDSCs, and several crucial serological tumor markers in particular tumors, and improve the function of T cells immune systems and the quality of life in patients with malignant tumor.
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Literature
1.
go back to reference Chen R, Deng X, Wu H, Peng P, Wen B, Li F, Li F. Combined immunotherapy with dendritic cells and cytokine-induced killer cells for malignant tumors: a systematic review and meta-analysis. Int Immunopharmacol. 2014;22:451–64.CrossRefPubMed Chen R, Deng X, Wu H, Peng P, Wen B, Li F, Li F. Combined immunotherapy with dendritic cells and cytokine-induced killer cells for malignant tumors: a systematic review and meta-analysis. Int Immunopharmacol. 2014;22:451–64.CrossRefPubMed
2.
go back to reference El Ansary M, Mogawer S, Elhamid SA, Alwakil S, Aboelkasem F, Sabaawy HE, Abdelhalim O. Immunotherapy by autologous dendritic cell vaccine in patients with advanced HCC. J Cancer Res Clin Oncol. 2013;139:39–48.CrossRefPubMed El Ansary M, Mogawer S, Elhamid SA, Alwakil S, Aboelkasem F, Sabaawy HE, Abdelhalim O. Immunotherapy by autologous dendritic cell vaccine in patients with advanced HCC. J Cancer Res Clin Oncol. 2013;139:39–48.CrossRefPubMed
3.
go back to reference Hontscha C, Borck Y, Zhou H, Messmer D, Schmidt-Wolf IG. Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol. 2011;137:305–10.CrossRefPubMed Hontscha C, Borck Y, Zhou H, Messmer D, Schmidt-Wolf IG. Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol. 2011;137:305–10.CrossRefPubMed
4.
go back to reference Shi M, Zhang B, Tang ZR, Lei ZY, Wang HF, Feng YY, Fan ZP, Xu DP, Wang FS. Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma. World J Gastroenterol. 2004;10:1146–51.PubMed Shi M, Zhang B, Tang ZR, Lei ZY, Wang HF, Feng YY, Fan ZP, Xu DP, Wang FS. Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma. World J Gastroenterol. 2004;10:1146–51.PubMed
5.
go back to reference Jakel CE, Vogt A, Gonzalez-Carmona MA, Schmidt-Wolf IG. Clinical studies applying cytokine-induced killer cells for the treatment of gastrointestinal tumors. J Immunol Res. 2014;2014:897214.PubMedCentralCrossRefPubMed Jakel CE, Vogt A, Gonzalez-Carmona MA, Schmidt-Wolf IG. Clinical studies applying cytokine-induced killer cells for the treatment of gastrointestinal tumors. J Immunol Res. 2014;2014:897214.PubMedCentralCrossRefPubMed
6.
go back to reference Zhu H, Yang X, Li J, Ren Y, Zhang T, Zhang C, Zhang J, Li J, Pang Y. Immune response, safety, and survival and quality of life outcomes for advanced colorectal cancer patients treated with dendritic cell vaccine and cytokine-induced killer cell therapy. Biomed Res Int. 2014;2014:603871.PubMedCentralPubMed Zhu H, Yang X, Li J, Ren Y, Zhang T, Zhang C, Zhang J, Li J, Pang Y. Immune response, safety, and survival and quality of life outcomes for advanced colorectal cancer patients treated with dendritic cell vaccine and cytokine-induced killer cell therapy. Biomed Res Int. 2014;2014:603871.PubMedCentralPubMed
7.
go back to reference Cui Y, Yang X, Zhu W, Li J, Wu X, Pang Y. Immune response, clinical outcome and safety of dendritic cell vaccine in combination with cytokine-induced killer cell therapy in cancer patients. Oncol Lett. 2013;6:537–41.PubMedCentralPubMed Cui Y, Yang X, Zhu W, Li J, Wu X, Pang Y. Immune response, clinical outcome and safety of dendritic cell vaccine in combination with cytokine-induced killer cell therapy in cancer patients. Oncol Lett. 2013;6:537–41.PubMedCentralPubMed
8.
go back to reference Ma Y, Xu YC, Tang L, Zhang Z, Wang J, Wang HX. Cytokine-induced killer (CIK) cell therapy for patients with hepatocellular carcinoma: efficacy and safety. Exp Hematol Oncol. 2012;1:11.PubMedCentralCrossRefPubMed Ma Y, Xu YC, Tang L, Zhang Z, Wang J, Wang HX. Cytokine-induced killer (CIK) cell therapy for patients with hepatocellular carcinoma: efficacy and safety. Exp Hematol Oncol. 2012;1:11.PubMedCentralCrossRefPubMed
9.
go back to reference Li XD, Xu B, Wu J, Ji M, Xu BH, Jiang JT, Wu CP. Review of Chinese clinical trials on CIK cell treatment for malignancies. Clin Transl Oncol. 2012;14(2):102–8.CrossRefPubMed Li XD, Xu B, Wu J, Ji M, Xu BH, Jiang JT, Wu CP. Review of Chinese clinical trials on CIK cell treatment for malignancies. Clin Transl Oncol. 2012;14(2):102–8.CrossRefPubMed
10.
go back to reference Shi L, Chen S, Yang L, Li Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol. 2013;6:74.PubMedCentralCrossRefPubMed Shi L, Chen S, Yang L, Li Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol. 2013;6:74.PubMedCentralCrossRefPubMed
11.
go back to reference Wang XP, Xu M, Gao HF, Zhao JF, Xu KC. Intraperitoneal perfusion of cytokine-induced killer cells with local hyperthermia for advanced hepatocellular carcinoma. World J Gastroenterol. 2013;19(19):2956–62.PubMedCentralPubMed Wang XP, Xu M, Gao HF, Zhao JF, Xu KC. Intraperitoneal perfusion of cytokine-induced killer cells with local hyperthermia for advanced hepatocellular carcinoma. World J Gastroenterol. 2013;19(19):2956–62.PubMedCentralPubMed
12.
go back to reference Jiang J, Xu N, Wu C, Deng H, Lu M, Li M, Xu B, Wu J, Wang R, Xu J, Nilsson-Ehle P. Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells. Anticancer Res. 2006;26:2237–42.PubMed Jiang J, Xu N, Wu C, Deng H, Lu M, Li M, Xu B, Wu J, Wang R, Xu J, Nilsson-Ehle P. Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells. Anticancer Res. 2006;26:2237–42.PubMed
13.
go back to reference Zhao M, Li H, Li L, Zhang Y. Effects of a gemcitabine plus platinum regimen combined with a dendritic cell-cytokine induced killer immunotherapy on recurrence and survival rate of non-small cell lung cancer patients. Exp Ther Med. 2014;7(5):1403–7.PubMedCentralPubMed Zhao M, Li H, Li L, Zhang Y. Effects of a gemcitabine plus platinum regimen combined with a dendritic cell-cytokine induced killer immunotherapy on recurrence and survival rate of non-small cell lung cancer patients. Exp Ther Med. 2014;7(5):1403–7.PubMedCentralPubMed
14.
go back to reference Pan Y, Tao Q, Wang H, Xiong S, Zhang R, Chen T, Tao L, Zhai Z. Dendritic cells decreased the concomitant expanded Tregs and Tregs related IL-35 in cytokine-induced killer cells and increased their cytotoxicity against leukemia cells. PLoS One. 2014;9:e93591.PubMedCentralCrossRefPubMed Pan Y, Tao Q, Wang H, Xiong S, Zhang R, Chen T, Tao L, Zhai Z. Dendritic cells decreased the concomitant expanded Tregs and Tregs related IL-35 in cytokine-induced killer cells and increased their cytotoxicity against leukemia cells. PLoS One. 2014;9:e93591.PubMedCentralCrossRefPubMed
15.
go back to reference Qu HQ, Zhou XS, Zhou XL, Wang J. Effect of DC-CIK cell on the proliferation, apoptosis and differentiation of leukemia cells. Asian Pac J Trop Med. 2014;7:659–62.CrossRefPubMed Qu HQ, Zhou XS, Zhou XL, Wang J. Effect of DC-CIK cell on the proliferation, apoptosis and differentiation of leukemia cells. Asian Pac J Trop Med. 2014;7:659–62.CrossRefPubMed
16.
go back to reference Tao Q, Wang H, Zhai Z. Targeting regulatory T cells in cytokine-induced killer cell cultures (Review). Biomed Rep. 2014;2(3) :317–20.PubMedCentralPubMed Tao Q, Wang H, Zhai Z. Targeting regulatory T cells in cytokine-induced killer cell cultures (Review). Biomed Rep. 2014;2(3) :317–20.PubMedCentralPubMed
17.
go back to reference Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci. 2014;1319:47–65.CrossRefPubMed Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci. 2014;1319:47–65.CrossRefPubMed
18.
go back to reference Greimel ER, Kuljanic Vlasic K, Waldenstrom AC, Duric VM, Jensen PT, Singer S, Chie W, Nordin A, Bjelic Radisic V, Wydra D. The European Organization for Research and Treatment of Cancer (EORTC) quality-of-Life questionnaire cervical cancer module: EORTC QLQ-CX24. Cancer. 2006; 107:1812–22. Greimel ER, Kuljanic Vlasic K, Waldenstrom AC, Duric VM, Jensen PT, Singer S, Chie W, Nordin A, Bjelic Radisic V, Wydra D. The European Organization for Research and Treatment of Cancer (EORTC) quality-of-Life questionnaire cervical cancer module: EORTC QLQ-CX24. Cancer. 2006; 107:1812–22.
19.
go back to reference Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–76.CrossRefPubMed Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–76.CrossRefPubMed
20.
go back to reference Li H, Yu JP, Cao S, Wei F, Zhang P, An XM, Huang ZT, Ren XB. CD4 +CD25 + regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J Clin Immunol. 2007;27:317–26.CrossRefPubMed Li H, Yu JP, Cao S, Wei F, Zhang P, An XM, Huang ZT, Ren XB. CD4 +CD25 + regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J Clin Immunol. 2007;27:317–26.CrossRefPubMed
21.
go back to reference Heeren AM, Koster BD, Samuels S, Ferns DM, Chondronasiou D, Kenter GG, Jordanova ES, de Gruijl TD. High and interrelated rates of PD-L1+ CD14+ antigen-presenting cells and regulatory T cells mark the microenvironment of metastatic lymph nodes from patients with cervical cancer. Cancer Immunol Res. 2015;3(1):48–58.CrossRefPubMed Heeren AM, Koster BD, Samuels S, Ferns DM, Chondronasiou D, Kenter GG, Jordanova ES, de Gruijl TD. High and interrelated rates of PD-L1+ CD14+ antigen-presenting cells and regulatory T cells mark the microenvironment of metastatic lymph nodes from patients with cervical cancer. Cancer Immunol Res. 2015;3(1):48–58.CrossRefPubMed
22.
go back to reference Weiss JM, Subleski JJ, Back T, Chen X, Watkins SK, Yagita H, Sayers TJ, Murphy WJ, Wiltrout RH. Regulatory T Cells and myeloid-derived suppressor cells in the tumor microenvironment undergo fas-dependent cell death during IL-2/alphaCD40 therapy. J Immunol. 2014;192(12):5821–9.PubMedCentralCrossRefPubMed Weiss JM, Subleski JJ, Back T, Chen X, Watkins SK, Yagita H, Sayers TJ, Murphy WJ, Wiltrout RH. Regulatory T Cells and myeloid-derived suppressor cells in the tumor microenvironment undergo fas-dependent cell death during IL-2/alphaCD40 therapy. J Immunol. 2014;192(12):5821–9.PubMedCentralCrossRefPubMed
23.
go back to reference Lin G, Wang J, Lao X, Li L, Li S, Zhang J, Dong Y, Chang AE, Li Q. Interleukin-6 inhibits regulatory T cells and improves the proliferation and cytotoxic activity of cytokine-induced killer cells. J Immunother. 2012;35:337–43.CrossRefPubMed Lin G, Wang J, Lao X, Li L, Li S, Zhang J, Dong Y, Chang AE, Li Q. Interleukin-6 inhibits regulatory T cells and improves the proliferation and cytotoxic activity of cytokine-induced killer cells. J Immunother. 2012;35:337–43.CrossRefPubMed
25.
go back to reference Sawabu N, Watanabe H, Yamaguchi Y, Ohtsubo K, Motoo Y. Serum tumor markers and molecular biological diagnosis in pancreatic cancer. Pancreas. 2004;28:263–7.CrossRefPubMed Sawabu N, Watanabe H, Yamaguchi Y, Ohtsubo K, Motoo Y. Serum tumor markers and molecular biological diagnosis in pancreatic cancer. Pancreas. 2004;28:263–7.CrossRefPubMed
26.
go back to reference Kurebayashi J, Nishimura R, Tanaka K, Kohno N, Kurosumi M, Moriya T, Ogawa Y, Taguchi T. Significance of serum tumor markers in monitoring advanced breast cancer patients treated with systemic therapy: a prospective study. Breast Cancer. 2004;11:389–95.CrossRefPubMed Kurebayashi J, Nishimura R, Tanaka K, Kohno N, Kurosumi M, Moriya T, Ogawa Y, Taguchi T. Significance of serum tumor markers in monitoring advanced breast cancer patients treated with systemic therapy: a prospective study. Breast Cancer. 2004;11:389–95.CrossRefPubMed
27.
go back to reference Sigari N, Mohsenpour B, Nikkhoo B, Ghaderi B, Afkhamzadeh A, Azadi NA, Fathi F, Abdi M. Determination of the best prognostic value of serum tumor markers in patients with suspected lung cancer in an Iranian population. Clin Lab. 2014;60(1):23–7.PubMed Sigari N, Mohsenpour B, Nikkhoo B, Ghaderi B, Afkhamzadeh A, Azadi NA, Fathi F, Abdi M. Determination of the best prognostic value of serum tumor markers in patients with suspected lung cancer in an Iranian population. Clin Lab. 2014;60(1):23–7.PubMed
28.
go back to reference Angell H, Galon J. From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol. 2013;25:261–7.CrossRefPubMed Angell H, Galon J. From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol. 2013;25:261–7.CrossRefPubMed
29.
go back to reference Weide B, Martens A, Zelba H, Stutz C, Derhovanessian E, Di Giacomo AM, Maio M, Sucker A, Schilling B, Schadendorf D, et al. Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or melan-A-specific T cells. Clin Cancer Res. 2014;20(6):1601–9.CrossRefPubMed Weide B, Martens A, Zelba H, Stutz C, Derhovanessian E, Di Giacomo AM, Maio M, Sucker A, Schilling B, Schadendorf D, et al. Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or melan-A-specific T cells. Clin Cancer Res. 2014;20(6):1601–9.CrossRefPubMed
30.
go back to reference Jitschin R, Braun M, Buttner M, Dettmer-Wilde K, Bricks J, Berger J, Eckart MJ, Krause SW, Oefner PJ, Le Blanc K, et al. CLL-cells induce IDOhi CD14+ HLA-DRlo myeloid derived suppressor cells that inhibit T-cell responses and promote TRegs. Blood. 2014;124(5):750–60.CrossRefPubMed Jitschin R, Braun M, Buttner M, Dettmer-Wilde K, Bricks J, Berger J, Eckart MJ, Krause SW, Oefner PJ, Le Blanc K, et al. CLL-cells induce IDOhi CD14+ HLA-DRlo myeloid derived suppressor cells that inhibit T-cell responses and promote TRegs. Blood. 2014;124(5):750–60.CrossRefPubMed
32.
go back to reference Ostrand-Rosenberg S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother. 2010;59(10):1593–1600.PubMedCentralCrossRefPubMed Ostrand-Rosenberg S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother. 2010;59(10):1593–1600.PubMedCentralCrossRefPubMed
33.
go back to reference Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009;58:49–59.PubMedCentralCrossRefPubMed Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009;58:49–59.PubMedCentralCrossRefPubMed
34.
35.
36.
go back to reference Han EQ, Li XL, Wang CR, Li TF, Han SY. Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges. J Hematol Oncol. 2013;6:47.PubMedCentralCrossRefPubMed Han EQ, Li XL, Wang CR, Li TF, Han SY. Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges. J Hematol Oncol. 2013;6:47.PubMedCentralCrossRefPubMed
Metadata
Title
The combination of dendritic cells-cytotoxic T lymphocytes/cytokine-induced killer (DC-CTL/CIK) therapy exerts immune and clinical responses in patients with malignant tumors
Authors
Ying Wang
Zenghui Xu
Fuping Zhou
Yan Sun
Jingbo Chen
Linfang Li
Huajun Jin
Qijun Qian
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Experimental Hematology & Oncology / Issue 1/2015
Electronic ISSN: 2162-3619
DOI
https://doi.org/10.1186/s40164-015-0027-9

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