title: Synergistic antitumor effect of combining metronomic chemotherapy with adoptive cell immunotherapy in nude mice.
abstract: Adoptive cell immunotherapy with cytokine-induced killer cell (CIK cell) represents a promising non-toxic anticancer therapy. However, the clinical efficacy of CIK cells is limited because of abnormal tumor vasculature. Metronomic chemotherapy shows promising anticancer activity by its potential antiangiogenic effect and reduced toxicity. We hypothesized that metronomic chemotherapy with paclitaxel could improve the antitumor effect of adoptive CIK cell immunotherapy. Mice health status was analyzed by measuring mice weight and observing mice behavior. Immunohistochemistry was used to investigate the recruitment of CIK cells, the expression of endothelial cell molecules, as well as the hypoxic tumor area. Metronomic paclitaxel synergized with adoptive CIK cell immunotherapy to inhibit the growth of non-small cell lung cancer (NSCLC). Metronomic paclitaxel reduced hypoxic tumor area and increased CIK cell infiltration. Hypoxia impeded the adhesion of CIK cells and reduced the expression of endothelial cell adhesion molecules. In vivo studies demonstrated that more CIK cells were found in endothelial cell adhesion molecules high expressed area. Our study provides a new rationale for combining metronomic chemotherapy with adoptive cell immunotherapy in the treatment of xenograft NSCLC tumors in immunodeficient mice. Further clinical trials integrating translational research are necessary to better evaluate the clinical benefit of this promising approach.
authors.affiliation: Medical Oncology Department of Jinling Hospital, Medical school of Nanjing University, Nanjing, China.
authors.forename: Shujing
authors.initials: S
authors.lastname: Shi
authors.forename: Leilei
authors.initials: L
authors.lastname: Tao
authors.forename: Haizhu
authors.initials: H
authors.lastname: Song
authors.forename: Longbang
authors.initials: L
authors.lastname: Chen
authors.forename: Guichun
authors.initials: G
authors.lastname: Huang
mesh_terms: D059250:Administration, Metronomic; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D055612:Cytokine-Induced Killer Cells; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C573420:ICAM1 protein, human; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D017239:Paclitaxel
keywords: Adoptive CIK cell transfer; antiangiogenesis therapy; endothelial cell adhesion molecule; hypoxia; metronomic paclitaxel; vascular normalization