An agonist antibody specific for CD40 induces dendritic cell maturation and promotes autologous anti-tumour T-cell responses in an in vitro mixed autologous tumour cell/lymph node cell model

Scand J Immunol. 2007 May;65(5):479-86. doi: 10.1111/j.1365-3083.2007.01927.x.

Abstract

CD40-mediated interactions play an important role in the response to a variety of diseases, including cancer. Engagement of CD40 on antigen-presenting cells, namely dendritic cells (DC), by CD40L leads to maturation and up-regulation of co-stimulatory molecules B7.1 and B7.2 (CD80 and CD86). These molecules are requisite to subsequent antigen-specific activation of T cells. T-cell activation is a critical aspect of specific anti-tumour immune responses that have become the focus of a variety of cancer immunotherapy approaches. Clinical trials involving immunologic interventions have shown clinical responses confirming that the immune system can be harnessed for the treatment of cancer. However, the clinical response rate has been low, signifying the need for new immunotherapeutic strategies. To this end, an agonist antibody specific for CD40, CP-870,893, has been developed. A fully autologous mixed tumour cell/lymph node cell model was utilized to demonstrate that CP-870,893 promotes the responsiveness of lymph node-derived T cells to autologous tumour. Specifically, T cells from the tumour-draining lymph nodes are not responsive to autologous tumour cells; however, in the presence of CP-870,893, this unresponsiveness is reversed, as indicated by lymph node cell proliferation and cytokine secretion. Monocyte-derived DC treated with CP-870,893 consistently display a mature phenotype: up-regulation of CD80, CD83, CD86 and HLA-DR expression, increased Mip1alpha and IL-12 secretion, and the loss of exogenous antigen-presenting capability subsequent to treatment with the antibody. These data indicate that CP-870,893 binds to and activates DC, ultimately driving a specific anti-tumour T-cell response.

MeSH terms

  • Antibodies, Monoclonal / biosynthesis
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antibody Specificity*
  • Antineoplastic Agents / therapeutic use*
  • CD40 Antigens / agonists
  • CD40 Antigens / immunology*
  • Cell Differentiation / immunology*
  • Cell Proliferation
  • Cells, Cultured
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Epitopes, T-Lymphocyte / immunology
  • Humans
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology*
  • Lymphocyte Culture Test, Mixed
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / pathology

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • CD40 Antigens
  • Epitopes, T-Lymphocyte
  • selicrelumab