Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) immunotherapy for the treatment of prostate cancer

Abstract

Costimulatory pathway ligands and receptors can deliver either positive or negative signals to help determine the ultimate fate of activated T lymphocytes. Cytotoxic T lymphocyte antigen-4 (CTLA-4) represents one of the most extensively studied receptors in the costimulatory pathway and has recently been shown to function as a potent inhibitor of T cell-mediated immunity. T-cell expression of CTLA-4 indirectly facilitates tumor progression by restraining host antitumoral immunity. In contrast, administration of a monoclonal antibody to block CTLA-4 function can alleviate restraints on T-cell activity to promote immune-mediated tumor regression. We review the preclinical and clinical experience with CTLA-4 blockade as a promising immunotherapeutic approach to treat patients with advanced prostate cancer.

Fig. 1

T-cell activation requires 2 independent signals. First, antigen is presented to the T-cell receptor (TCR) via an antigen/major histocompatibility complex (MHC). A second antigen independent signal, termed costimulation, is required to govern the fate of the T cell. (A) When the T-cell receptor CD28 interacts with its counter-receptor B7-1/2, a positive T-cell response is generated. (B) In the presence of CTLA-4, T-cell responses are abrogated, and tolerance of presented antigen is allowed. (Color version of figure is available online.)

Fig. 2

Although required for T-cell activation, the antigen-T-cell receptor interaction does not govern the fate of the T cell. Positive costimulatory molecules, such as CD28, 4-1BB, inducible costimulator, and OX40 can stimulate a T-cell response specific for the antigen presented. On the other hand, negative costimulatory molecules, such as CTLA-4, B7-H1/PD-1. B7-H4, and BLTA can inhibit T-cell activation, and may induce anergy (tolerance) to the presented antigen. (Color version of figure is available online.)

Fig. 3

Monoclonal antibody blockade of CTLA-4 allows CD28 to interact with its B7 family counter-receptor, thus stimulating a tumor specific T-cell response. (Color version of figure is available online.)