Immune-modulating Effects of the Newest Cetuximab-based Chemoimmunotherapy Regimen in Advanced Colorectal Cancer Patients

被引:33
作者
Botta, Cirino [3 ]
Bestoso, Elena [3 ]
Apollinari, Serena [3 ]
Cusi, Maria Grazia [4 ]
Pastina, Pierpaolo [3 ]
Abbruzzese, Alberto [1 ]
Sperlongano, Pasquale [2 ]
Misso, Gabriella [1 ]
Caraglia, Michele [1 ]
Tassone, Pierfrancesco [5 ,6 ]
Tagliaferri, Pierosandro [5 ,6 ]
Correale, Pierpaolo [3 ]
机构
[1] Univ Naples 2, Dept Biochem & Biophys, I-80138 Naples, Italy
[2] Univ Naples 2, Dept Anesthesiol & Special Surg, I-80138 Naples, Italy
[3] Siena Univ Hosp, Ist Toscano Tumori, Med Oncol Unit, Dept Oncol, Siena, Italy
[4] Siena Univ Hosp, Ist Toscano Tumori, Microbiol Sect, Dept Mol Biol, Siena, Italy
[5] Magna Graecia Univ Catanzaro, Med Oncol Unit, Catanzaro, Italy
[6] Tommaso Campanella Canc Ctr, Catanzaro, Italy
关键词
cetuximab; epidermal growth factor receptor; colorectal cancer; polychemotherapy; DEPENDENT CELLULAR CYTOTOXICITY; ANTITUMOR-ACTIVITY; T-CELLS; CARCINOEMBRYONIC ANTIGEN; RECEPTOR FAMILY; CARCINOMA CELLS; IN-VITRO; ANTIBODY; COLON; EXPRESSION;
D O I
10.1097/CJI.0b013e31825943aa
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Cetuximab is a human-murine chimeric monoclonal antibody to the epidermal growth factor receptor, active for advanced colorectal cancer treatment in combination with chemotherapy. Cetuximab mainly acts by inhibiting epidermal growth factor receptor-mediated pathways in cancer cells; however, in the human host, its IgG(1) backbone may offer additional antitumor activity that includes Fc gamma Rs-mediated antibody-dependent cell cytotoxicity, phagocytosis, cross priming, and tumor-specific T-cell-mediated immune response. These mechanisms are still under active investigation. At this purpose, we have performed an immunologic investigation in advanced colon cancer patients enrolled in an ongoing phase II trial aimed to test the toxicity and the biological and antitumor activity of a novel biochemotherapy regimen combining polychemotherapy with gemcitabine, irinotecan, levofolinic acid, and fluorouracil with cetuximab and with subcutaneous low-dose metronomic aldesleukin (GILFICet regimen). The peripheral blood mononuclear cells of the first 20 patients enrolled in the GILFICet trial were collected at baseline and after 6 treatment cycles and examined for immune-phenotype change by flow cytometry. Colon cancer-specific T-cell lines were also generated ex vivo from these samples and subsequently characterized for immune phenotype, functional activity, and antigen specificity. We found a treatment-related increase of circulating dendritic cells, natural killer cells, central memory T cells, and activated T cells with a T-helper 1 (Th1)-cytotoxic phenotype. In addition, the ex-vivo characterization of antigen-specific T cells derived from the treated patients revealed a significant increase in proliferating cytotoxic T-lymphocyte precursors specific for carcinoembryonic antigen and thymidylate synthase derivative epitope peptides. On these basis, we concluded that the GILFICet regimen exerts substantial immune-modulating activity that significantly affects tumor antigen-specific T-cell compartment with potential antitumor activity.
引用
收藏
页码:440 / 447
页数:8
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