Original paper Cellular immunotherapy| Volume 17, ISSUE 7, P979-988, July 2015

Combined cellular immunotherapy and chemotherapy improves clinical outcome in patients with gastric carcinoma

Published:April 15, 2015DOI:


      Background aims

      Despite the availability of multiple treatment strategies, patients with gastric carcinoma (GC) have a dismal prognosis. The aim of this study was to evaluate the efficacy and safety of cellular immunotherapy (CIT) with the use of autologous natural killer cells, γδT cells and cytokine-induced killer cells in combination with chemotherapy in patients with GC.


      In this open-label pilot cohort study, patients were treated with the combination therapy (chemo/CIT group) or chemotherapy alone (control group). Progression-free survival (PFS), overall survival (OS), quality of life (QOL) and adverse events were investigated.


      Fifty-eight patients were analyzed, 30 in the chemo/CIT group and 28 in the control group. The median PFS of the chemo/CIT group was significantly longer compared with the control group (P = 0.021). In subgroup analysis, in patients with stage III GC, node-positive metastasis or poorly differentiated carcinoma, the 2-year PFS rate in chemo/CIT versus control groups was 62.5% versus 26.7% (P = 0.022), 50% versus 27.3% (P = 0.016) and 56.3% versus 28.6% (P = 0.005), respectively. The median OS in either group has not yet been reached, and there was no significant difference in OS between the groups. The QOL was improved in the patients treated with chemo/CIT compared with the control group. CIT was well tolerated and not related to any significant adverse events.


      A combination of CIT and chemotherapy for patients with GC was safe, improved QOL, and might prevent recurrence, especially in GC patients with advanced stage, poorly differentiated carcinoma or lymph node metastasis.

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        • Jemal A.
        • Bray F.
        • Center M.M.
        • Ferlay J.
        • Ward E.
        • Forman D.
        Global cancer statistics.
        CA Cancer J Clin. 2011; 61: 69-90
        • Macdonald J.S.
        • Smalley S.R.
        • Benedetti J.
        • Hundahl S.A.
        • Estes N.C.
        • Stemmermann G.N.
        • et al.
        Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction.
        N Engl J Med. 2001; 345: 725-730
        • Kiessling R.
        • Wasserman K.
        • Horiguchi S.
        • Kono K.
        • Sjöberg J.
        • Pisa P.
        • et al.
        Tumor-induced immune dysfunction.
        Cancer Immunol Immunother. 1999; 48: 353-362
        • Xie Z.J.
        • Liu Y.
        • Jia L.M.
        • He Y.C.
        Heparanase expression, degradation of basement membrane and low degree of infiltration by immunocytes correlate with invasion and progression of human gastric cancer.
        World J Gastroenterol. 2008; 14: 3812-3818
        • Dudley M.E.
        • Rosenberg S.A.
        Adoptive-cell-transfer therapy for the treatment of patients with cancer.
        Nat Rev Cancer. 2003; 3: 666-675
        • Gilboa E.
        How tumors escape immune destruction and what we can do about it.
        Cancer Immunol Immunother. 1999; 48: 382-385
        • Fisch P.
        • Moris A.
        • Rammensee H.G.
        • Handgretinger R.
        Inhibitory MHC class I receptors on gammadelta T cells in tumour immunity and autoimmunity.
        Immunol Today. 2000; 21: 187-191
        • Mimura K.
        • Kamiya T.
        • Shiraishi K.
        • Kua L.
        • Shabbir A.
        • So J.
        • et al.
        Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer.
        Int J Cancer. 2014; 135: 1390-1398
        • Maniar A.
        • Zhang X.
        • Lin W.
        • Gastman B.R.
        • Pauza C.D.
        • Strome S.E.
        • et al.
        Human gam-madelta T lymphocytes induce robust NK cell-mediated antitumor cytotoxicity through CD137 engagement.
        Blood. 2010; 116: 1726-1733
        • Jiang J.
        • Wu C.
        • Lu B.
        Cytokine-induced killer cells promote antitumor Immunity.
        J Transl Med. 2013; 11: 83
        • Lu P.H.
        • Negrin R.S.
        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.
        J Immunol. 1994; 153: 1687-1696
        • Morisaki T.
        • Onishi H.
        • Katano M.
        Cancer immunotherapy using NKG2D and DNAM-1 systems.
        Anticancer Res. 2012; 32: 2241-2247
        • Peng Y.P.
        • Zhu Y.
        • Zhang J.J.
        • Xu Z.K.
        • Qian Z.Y.
        • Dai C.C.
        • et al.
        Comprehensive analysis of the percentage of surface receptors and cytotoxic granules positive natural killer cells in patients with pancreatic cancer, gastric cancer, and colorectal cancer.
        J Transl Med. 2013; 11: 262
        • Lake R.A.
        • Robinson B.W.
        Immunotherapy and chemotherapy–a practical partnership.
        Nat Rev Cancer. 2005; 5: 397-405
        • Gasser S.
        • Orsulic S.
        The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor.
        Nature. 2005; 436: 1186-1190
        • Kershaw M.H.
        • Devaud C.
        • John L.B.
        • westwood J.A.
        • Darcy P.K.
        Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment.
        OncoImmunology. 2013; (1–6): e25962
        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • Schwartz L.H.
        • Sargent D.
        • Ford R.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247
        • Aaronson N.K.
        • Ahmedzai S.
        • Bergman B.
        • Bullinger M.
        • Cull A.
        • Duez N.J.
        • 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: 365-376
        • Vickey C.W.
        • Blazeby J.M.
        • Conroy T.
        • Arraras J.
        • Sezer O.
        • Koller M.
        • et al.
        Development of an EORTC disease-special quality of life modules for use in patients with gastric cancer.
        Eur J Cancer. 2001; 37: 966-971
        • Cui J.
        • Wang N.
        • Zhao H.
        • Jin H.
        • Wang G.
        • Niu C.
        • et al.
        Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma.
        Int J Cancer. 2014; 134: 342-351
        • Dewan M.Z.
        • Terunuma H.
        • Takada M.
        • Tanaka Y.
        • Abe H.
        • Sat T.
        Role of natural killer cells in hormone-independent rapid tumor formation and spontaneous metastasis of breast cancer cells in vivo.
        Breast Cancer Res Treat. 2007; 104: 267-275
        • Kondo M.
        • Sakuta K.
        • Noguchi A.
        • Ariyoshi N.
        • Sato K.
        • Sato S.
        • et al.
        Zoledronate facilitates large-scale ex vivo expansion of functional gammadelta T cells from cancer patients for use in adoptive immunotherapy.
        Cytotherapy. 2008; 10: 842-856
        • Wick M.
        • Dubey P.
        • Koeppen H.
        • Siegel C.T.
        • Fields P.E.
        • Chen L.
        • et al.
        Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy.
        J Exp Med. 1997; 186: 229
        • Pawelec G.
        • Zeuthen J.
        • Kiessling R.
        Escape from host-antitumor immunity.
        Crit Rev Oncog. 1997; 8: 111
        • Saito H.
        • Osaki T.
        • Ikeguchi M.
        Decreased NKG2D expression on NK cells correlates with impaired NK cell function in patients with gastric cancer.
        Gastric Cancer. 2012; 15: 27-33
        • Végh Z.
        • Wang P.
        • Vánky F.
        • Klein E.
        Selectively down-regulated expression of major histocompatibility complex class I alleles in human solid tumors.
        Cancer Res. 1993; 53: 2416-2420
        • Shi L.
        • Zhou Q.
        • Wu J.
        • Ji M.
        • Li G.
        • Jiang J.T.
        • et al.
        Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer.
        Cancer Immunol Immunother. 2012; 6: 2251-2259
        • McKernan M.
        • McMillan D.C.
        • Anderson J.R.
        The relationship between quality of life (EORTC QLQ-C30) and survival in patients with gastro-oesophageal cancer.
        Br J Cancer. 2008; 98: 888-893
        • Barsevick A.
        • Frost M.
        • Zwinderman A.
        • Hall P.
        • Halyard M.
        I'm so tired: biological and genetic mechanisms of cancer-related fatigue.
        Qual Life Res. 2012; 19: 1419-1427
        • Christopher G.
        • Digant G.
        • Carolyn A.L.
        • Maurie M.
        • Pankaj G.V.
        Role of nutritional status in predicting quality of life outcomes in cancer a systematic review of the epidemiological literature.
        Nutrition Journal. 2012; 11: 27