title: A DNA vaccine against cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) prevents tumor growth.
abstract: Co-stimulatory signaling pathway triggered by the binding of B7.1/B7.2 (CD80/86) of antigen-presenting cells (APCs) to CD28 of T cells is required for optimal T-cell activation. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T cell activation, which competes with CD28 for B7.1/B7.2 binding with a greater affinity. Ipilimumab, a monoclonal antibody against CTLA-4, has shown positive efficacy in a pivotal clinical trial for the treatment of metastatic melanoma and was approved by FDA. However, the cost of monoclonal antibody-based therapeutics might limit the number of patients treated. To develop a novel therapeutics specifically targeting CTLA-4, we constructed a DNA vaccine by cloning the sequence of CTLA-4 fused with a transmembrane domain sequence of placental alkaline phosphatase (PLAP) into a mammalian expression plasmid, pVAC-1. Immunization with the resulting construct, pVAC-1-hCTLA-4, elicited antibody specific to human CTLA-4 with cross reactivity to murine CTLA-4, which was sufficient for inhibiting B16F10 tumor growth in c57BL/6 mice in the absence of measurable toxicity. Coupling liposome with pVAC-1-mCTLA-4 could break tolerance to self-antigen in BALB/c mice and induce potent immunity against murine CTLA-4, and suppress growth of subcutaneous renal cell carcinoma (Renca).
authors.affiliation: Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Keng-Hsueh
authors.initials: KH
authors.lastname: Lan
authors.forename: Yu-Chang
authors.initials: YC
authors.lastname: Liu
authors.forename: Yi-Sheng
authors.initials: YS
authors.lastname: Shih
authors.forename: Chang-Liang
authors.initials: CL
authors.lastname: Tsaid
authors.forename: Sang-Hue
authors.initials: SH
authors.lastname: Yen
authors.forename: Keng-Li
authors.initials: KL
authors.lastname: Lan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000938:Antigen-Presenting Cells / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D000074324:Ipilimumab; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology* / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; D019444:Vaccines, DNA
keywords: Antigen-presenting cells (APC); Cytotoxic T-lymphocyte associated-antigen-4 (CTLA-4); Liposome; Vaccine