DNA vaccines targeting tumor antigens to B7 molecules on antigen-presenting cells induce protective antitumor immunity and delay onset of HER-2/Neu-driven mammary carcinoma.

Purpose: Presentation of tumor antigens by professional antigen-presenting cells (APC) is critical for the induction of tumor-specific T-cell responses. To facilitate targeted delivery of tumor antigens to APC, we generated DNA vaccines that encode secreted fusion proteins consisting of the extracellular domain of CTLA-4 for binding to costimulatory B7 molecules on APC, fused to residues 1 to 222 of human ErbB2 (HER-2) or a corresponding 224 residues fragment of its rat homologue Neu.

Experimental Design: Induction of humoral and cellular immune responses and antitumoral activity of the DNA vaccines were tested in murine tumor models with transfected renal carcinoma cells expressing the respective antigens and in transgenic BALB-neuT mice developing spontaneous Neu-driven mammary carcinomas.

Transgenic mice replicating hepatitis B virus but lacking expression of the major HBsAg.

Hepatitis B Virus (HBV) transgenic mice replicating the viral genome at high level but lacking expression of the small envelope protein (HBsAg) have been produced using a terminally redundant viral DNA construct (HBV 1.4). The generation of viable infectious progeny was dependent on sex and age of mice.

Activation of dendritic cells by local ablation of hepatocellular carcinoma.

Background/aims: Local ablation methods are an effective treatment for hepatocellular carcinoma (HCC). The rate of recurrence or development of intra-hepatic metastases may be lowered by antitumoral immune responses. Since HCCs are in general only weakly immunogenic, cell injury induced by local tumor ablation (PEI/RFTA) may increase HCC immunogenicity and may release endogenous adjuvants that activate dendritic cells (DC).

Targeted delivery of the ErbB2/HER2 tumor antigen to professional APCs results in effective antitumor immunity.

Activation of T cells by professional APCs that present peptide epitopes of tumor-associated Ags is critical for the induction of cell-mediated immunity against tumors. To facilitate targeted delivery of the ErbB2 (HER2, neu) tumor Ag to APCs in vivo, we have generated chimeric proteins that contain the extracellular domain of CTLA-4 for binding to B7 molecules on the APC surface, which is genetically fused to a human ErbB2 fragment as an antigenic determinant. Bacterially expressed CTLA-4-ErbB2 fusion protein and a similar molecule harboring in addition the translocation domain of Pseudomonas exotoxin A as an endosome escape function displayed specific binding to B7-expressing cells, followed by protein internalization and intracellular degradation.

A novel bispecific tetravalent antibody fusion protein to target costimulatory activity for T-cell activation to tumor cells overexpressing ErbB2/HER2.

Persistent activation of T-lymphocytes requires two signals: one is initiated by T-cell receptor binding to antigenic peptide presented by MHC molecules. In addition, binding of the B7 family members CD80 or CD86 on professional antigen presenting cells to CD28 on T cells is considered to provide an important costimulatory signal. Activation without costimulation induces T-cell unresponsiveness or anergy.

Immunoregulation of dendritic and T cells by alpha-fetoprotein in patients with hepatocellular carcinoma.

Background/aims: Novel immunotherapeutic and other strategies are being explored for the treatment of hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) may be a target antigen for immunotherapy. Little is known, however, about the immunobiology of AFP.

Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection.

The antiviral T cell failure of patients with chronic hepatitis B virus (HBV) infection was suggested to be caused by a T cell stimulation defect of dendritic cells (DC). To address this hypothesis, monocyte derived DC (MDDC) of patients with chronic or resolved acute HBV infection and healthy controls were studied phenotypically by FACS analyses and functionally by mixed lymphocyte reaction, ELISA, ELISpot and proliferation assays of MDDC cultures or co-cultures with an allogeneic HBc-specific Th cell clone. HBV infection of MDDC was studied by quantitative PCR.