Tumors of the gastrointestinal system represent a significant share of solid tumors worldwide. Despite the advances in diagnosis and treatment, the prognosis of gastrointestinal tumors is still very poor and improved therapies are indispensable. Cytokine-induced killer (CIK) cells are feasible for an immunotherapeutic approach as they are easily available and have an advantageous biologic profile; they are rapidly proliferating and their high cytotoxicity is non-MHC-restricted. We summarize and discuss twenty recent clinical studies applying CIK cells for the treatment of gastric, pancreatic, hepatocellular, and colorectal cancer. Autologous CIK cells were transfused intravenously, intraperitoneally, or via the common hepatic artery. In all studies side effects and toxicity of CIK cell therapy were mild and easily controllable. The combination of CIK cell therapy with conventional adjuvant or palliative therapies was superior to the standard therapy alone, indicating the benefit of CIK cell therapy for cancer patients. Thus, CIK cells represent a promising immunotherapy for the treatment of gastrointestinal tumors. The optimal treatment schedule and ideal combination with conventional therapies should be evaluated in further clinical studies. 1. Introduction Tumors of the gastrointestinal (GI) system constitute a major part of the cancer incidence and mortality statistics. Worldwide, colorectal cancer is the most frequent type of GI cancer: it is the third most common cancer in men and the second most common in women. Moreover, colorectal cancer accounts for the largest share of GI cancer-related deaths in women, while liver cancer is the most common cause of death among GI tumors of men [1]. Despite the recent advances in diagnosis and therapy, outcomes for patients with GI tumors remain very poor. Often, GI tumors are diagnosed only at advanced stages due to the lack of specific symptoms and screening methods. As a result, 5-year survival rates are low [2–5]. Adoptive cell immunotherapy might be used in combination with standard therapies—as adjuvant postsurgical treatment and as palliative treatment—to improve survival and quality of life of GI cancer patients. Cytokine-induced killer (CIK) cells have the best credentials to be effective in this therapeutic approach. Compared to lymphokine-activated killer (LAK) cells, CIK cells can be obtained more easily and reveal a higher tumor-specific cytotoxic activity [6–10]. Similarly, there are several factors hampering the adoptive cell therapy with tumor-infiltrating lymphocytes (TILs), for example, the
References
[1]
American Cancer Society, Global Cancer Facts & Figures, American Cancer Society, Atlanta, Ga, USA, 2nd edition, 2011.
[2]
P. G. Toomey, N. A. Vohra, T. Ghansah, A. A. Sarnaik, and S. A. Pilon-Thomas, “Immunotherapy for gastrointestinal malignancies,” Cancer Control, vol. 20, no. 1, pp. 32–42, 2013.
[3]
A. Amedei, M. Benagiano, C. Della Bella, E. Niccolai, and M. M. D'Elios, “Novel immunotherapeutic strategies of gastric cancer treatment,” Journal of Biomedicine and Biotechnology, vol. 2011, Article ID 437348, 17 pages, 2011.
[4]
D. G. Power, D. P. Kelsen, and M. A. Shah, “Advanced gastric cancer—slow but steady progress,” Cancer Treatment Reviews, vol. 36, no. 5, pp. 384–392, 2010.
[5]
K. S. Gunturu, G. R. Rossi, and M. W. Saif, “Immunotherapy updates in pancreatic cancer: are we there yet?” Therapeutic Advances in Medical Oncology, vol. 5, no. 1, pp. 81–89, 2013.
[6]
I. G. H. Schmidt-Wolf, R. S. Negrin, H.-P. Kiem, K. G. Blume, and I. L. Weissman, “Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity,” The Journal of Experimental Medicine, vol. 174, no. 1, pp. 139–149, 1991.
[7]
C. Scheffold, K. Brandt, V. Johnston et al., “Potential of autologous immunologic effector cells for bone marrow purging in patients with chronic myeloid leukemia,” Bone Marrow Transplantation, vol. 15, no. 1, pp. 33–39, 1995.
[8]
I. G. H. Schmidt-Wolf, P. Lefterova, V. Johnston et al., “Sensitivity of multidrug-resistant tumor cell lines to immunologic effector cells,” Cellular Immunology, vol. 169, no. 1, pp. 85–90, 1996.
[9]
X. Ren, J. Yu, H. Liu et al., “Th1 bias in PBMC induced by multicycles of auto-CIKs infusion in malignant solid tumor patients,” Cancer Biotherapy & Radiopharmaceuticals, vol. 21, no. 1, pp. 22–33, 2006.
[10]
P.-H. Lu and R. S. Negrin, “A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency,” The Journal of Immunology, vol. 153, no. 4, pp. 1687–1696, 1994.
[11]
C. Yee, S. R. Riddell, and P. D. Greenberg, “Prospects for adoptive T cell therapy,” Current Opinion in Immunology, vol. 9, no. 5, pp. 702–708, 1997.
[12]
P. Frost, R. Caliliw, A. Belldegrun, and B. Bonavida, “Immunosensitization of resistant human tumor cells to cytotoxicity by tumor infiltrating lymphocytes,” International Journal of Oncology, vol. 22, no. 2, pp. 431–437, 2003.
[13]
I. G. H. Schmidt-Wolf, P. Lefterova, B. A. Mehta et al., “Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells,” Experimental Hematology, vol. 21, no. 13, pp. 1673–1679, 1993.
[14]
M. Franceschetti, A. Pievani, G. Borleri et al., “Cytokine-induced killer cells are terminallydifferentiated activated CD8 cytotoxic T-EMRA lymphocytes,” Experimental Hematology, vol. 37, no. 5, pp. 616–628, 2009.
[15]
M. R. Verneris, M. Ito, J. Baker, A. Arshi, R. S. Negrin, and J. A. Shizuru, “Engineering hematopoietic grafts: purified allogeneic hematopoietic stem cells plus expanded CD8+ NK-T cells in the treatment of lymphoma,” Biology of Blood and Marrow Transplantation, vol. 7, no. 10, pp. 532–542, 2001.
[16]
M. R. Verneris, M. Karami, J. Baker, A. Jayaswal, and R. S. Negrin, “Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells,” Blood, vol. 103, no. 8, pp. 3065–3072, 2004.
[17]
V. Groh, R. Rhinehart, H. Secrist, S. Bauer, K. H. Grabstein, and T. Spies, “Broad tumor-associated expression and recognition by tumor-derived γδ T cells of MICA and MICB,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 12, pp. 6879–6884, 1999.
[18]
H. R. Salih, H. Antropius, F. Gieseke et al., “Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia,” Blood, vol. 102, no. 4, pp. 1389–1396, 2003.
[19]
D. Pende, P. Rivera, S. Marcenaro et al., “Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity,” Cancer Research, vol. 62, no. 21, pp. 6178–6186, 2002.
[20]
V. Herrera and J. Parsonnet, “Helicobacter pylori and gastric adenocarcinoma,” Clinical Microbiology and Infection, vol. 15, no. 11, pp. 971–976, 2009.
[21]
J. Jiang, N. Xu, C. Wu et al., “Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells,” Anticancer Research, vol. 26, no. 3B, pp. 2237–2242, 2006.
[22]
L. Shi, Q. Zhou, J. Wu, et al., “Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer,” Cancer Immunology, Immunotherapy, vol. 61, no. 12, pp. 2251–2259, 2012.
[23]
Z. M. Wang, R. Y. Zhuang, Y. Chen, Y. Feng, Q. Li, and T. S. Liu, “A pilot study of chemotherapy combined with intraperitoneal perfusion of cytokine-induced killer cells for advanced gastric cancer patients with ascites,” Zhonghua Wei Chang Wai Ke Za Zhi, vol. 16, no. 1, pp. 28–31, 2013.
[24]
J. Jiang, C. Wu, L. Shi, et al., “Side effects during treatment of advanced gastric carcinoma by chemotherapy combined with CIK-cell transfusion in elderly people,” Chinese Journal of Clinical Oncology, vol. 5, no. 2, pp. 79–82, 2008.
[25]
J. T. Jiang, Y. P. Shen, C. P. Wu et al., “Increasing the frequency of CIK cells adoptive immunotherapy may decrease risk of death in gastric cancer patients,” World Journal of Gastroenterology, vol. 16, no. 48, pp. 6155–6162, 2010.
[26]
H. Zhao, Y. Fan, H. Li, et al., “Immunotherapy with cytokine-induced killer cells as an adjuvant treatment for advanced gastric carcinoma: a retrospective study of 165 patients,” Cancer Biotherapy & Radiopharmaceuticals, vol. 28, no. 4, pp. 303–309, 2013.
[27]
D. Yadav and A. B. Lowenfels, “The epidemiology of pancreatitis and pancreatic cancer,” Gastroenterology, vol. 144, no. 6, pp. 1252–1261, 2013.
[28]
A. B. Lowenfels and P. Maisonneuve, “Epidemiology and risk factors for pancreatic cancer,” Best Practice and Research, vol. 20, no. 2, pp. 197–209, 2006.
[29]
D. Li, K. Xie, R. Wolff, and J. L. Abbruzzese, “Pancreatic cancer,” The Lancet, vol. 363, no. 9414, pp. 1049–1057, 2004.
[30]
H. G. Beger, B. Rau, F. Gansauge, B. Poch, and K. H. Link, “Treatment of pancreatic cancer: challenge of the facts,” World Journal of Surgery, vol. 27, no. 10, pp. 1075–1084, 2003.
[31]
Y. Qiu, M. M. Yun, M. B. Xu, Y. Z. Wang, and S. Yun, “Pancreatic carcinoma-specific immunotherapy using synthesised alpha-galactosyl epitope-activated immune responders: findings from a pilot study,” International Journal of Clinical Oncology, vol. 18, no. 4, pp. 657–665, 2012.
[32]
R. Buonomano, C. Tinguely, R. Rieben, P. J. Mohacsi, and U. E. Nydegger, “Quantitation and characterization of antiGalα1-3Gal antibodies in sera of 200 healthy persons,” Xenotransplantation, vol. 6, no. 3, pp. 173–180, 1999.
[33]
W. Li, L. P. Xu, L. D. Zhao, et al., “Cytokine-induced killer cell therapy for advanced pancreatic adenocarcinoma: a case report and review of the literature,” Oncology Letters, vol. 5, no. 4, pp. 1427–1429, 2013.
[34]
T. Takayama, T. Sekine, M. Makuuchi et al., “Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial,” The Lancet, vol. 356, no. 9232, pp. 802–807, 2000.
[35]
M. Shi, B. Zhang, Z. R. Tang et al., “Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma,” World Journal of Gastroenterology, vol. 10, no. 8, pp. 1146–1151, 2004.
[36]
S. Kakumu, S. Ito, T. Ishikawa et al., “Decreased function of peripheral blood dendritic cells in patients with hepatocellular carcinoma with hepatitis B and C virus infection,” Journal of Gastroenterology and Hepatology, vol. 15, no. 4, pp. 431–436, 2000.
[37]
M. C. Rissoan, V. Soumelis, N. Kadowaki et al., “Reciprocal control of T helper cell and dendritic cell differentiation,” Science, vol. 283, no. 5405, pp. 1183–1186, 1999.
[38]
Y. S. Zhang, F. J. Yuan, G. F. Jia et al., “CIK cells from patients with HCC possess strong cytotoxicity to multidrug-resistant cell line Bel-7402/R,” World Journal of Gastroenterology, vol. 11, no. 22, pp. 3339–3345, 2005.
[39]
M. Zhao, P. H. Wu, Y. X. Zeng et al., “Cytokine-induced killer cell fusion to lower recurrence of hepatocellular carcinoma after transcatheter arterial chemoembolization sequentially combined with radiofrequency ablation: a randomized trial,” Zhonghua Yi Xue Za Zhi, vol. 86, no. 26, pp. 1823–1828, 2006.
[40]
D. S. Weng, J. Zhou, Q. M. Zhou et al., “Minimally invasive treatment combined with cytokine-induced killer cells therapy lower the short-term recurrence rates of hepatocellular carcinomas,” Journal of Immunotherapy, vol. 31, no. 1, pp. 63–71, 2008.
[41]
C. C. Pan, Z. L. Huang, W. Li et al., “Serum alpha-fetoprotein measurement in predicting clinical outcome related to autologous cytokine-induced killer cells in patients with hepatocellular carcinoma undergone minimally invasive therapy,” Chinese Journal of Cancer, vol. 29, no. 6, pp. 596–602, 2010.
[42]
Z. M. Huang, W. Li, S. Li, et al., “Cytokine-induced killer cells in combination with transcatheter arterial chemoembolization and radiofrequency ablation for hepatocellular carcinoma patients,” Journal of Immunotherapy, vol. 36, no. 5, pp. 287–293, 2013.
[43]
R. Lencioni and J. M. Llovet, “Modified recist (mRECIST) assessment for hepatocellular carcinoma,” Seminars in Liver Disease, vol. 30, no. 1, pp. 52–60, 2010.
[44]
M. Z. Hao, H. L. Lin, Q. Chen, Y. B. Ye, Q. Z. Chen, and M. S. Chen, “Efficacy of transcatheter arterial chemoembolization combined with cytokine-induced killer cell therapy on hepatocellular carcinoma: a comparative study,” Chinese Journal of Cancer, vol. 29, no. 2, pp. 172–177, 2010.
[45]
X. P. Wang, M. Xu, H. F. Gao, J. F. Zhao, and K. C. Xu, “Intraperitoneal perfusion of cytokine-induced killer cells with local hyperthermia for advanced hepatocellular carcinoma,” World Journal of Gastroenterology, vol. 19, no. 19, pp. 2956–2962, 2013.
[46]
D. Hui, L. Qiang, W. Jian, Z. Ti, and K. Da-Lu, “A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma,” Digestive and Liver Disease, vol. 41, no. 1, pp. 36–41, 2009.
[47]
Y. Qiu, M. B. Xu, M. M. Yun et al., “Hepatocellular carcinoma-specifc immunotherapy with synthesized α1,3- galactosyl epitope-pulsed dendritic cells and cytokine-induced killer cells,” World Journal of Gastroenterology, vol. 17, no. 48, pp. 5260–5266, 2011.
[48]
I. G. H. Schmidt-Wolf, S. Finke, B. Trojaneck et al., “Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-1 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma,” British Journal of Cancer, vol. 81, no. 6, pp. 1009–1016, 1999.
[49]
World Health Organization, WHO Handbook for Reporting Results of Cancer Treatment, World Health Organization, Geneva, Switzerland, 1979.
[50]
C. Hontscha, Y. Borck, H. Zhou, D. Messmer, and I. G. H. Schmidt-Wolf, “Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC),” Journal of Cancer Research and Clinical Oncology, vol. 137, no. 2, pp. 305–310, 2011.