Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells.

Purpose: Tremelimumab is a fully human monoclonal antibody specific for CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but has not been evaluated in patients with breast cancer.

Experimental Design: In a phase 1 study, 26 patients with advanced, hormone-responsive breast cancer received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane 25 mg daily. The objectives were to determine safety and the maximum tolerated dose (MTD) of tremelimumab with exemestane and, secondarily, to assess tumor response, pharmacokinetics, and immune pharmacodynamics.

Increased IL-12 inhibits B cells' differentiation to germinal center cells and promotes differentiation to short-lived plasmablasts.

B cells activated by antigen in T cell-dependent immune responses can become short-lived plasma cells, which remain in the spleen, or germinal center-derived memory or plasma cells, which show evidence of affinity maturation and, in the case of plasma cells, migrate to the bone marrow. We show that this cell fate decision can be governed by the cytokine environment engendered by activated dendritic cells (DCs). DCs from mice lacking the Fc receptor gamma chain exhibited an activated phenotype in vitro.

Anti-CD40 agonist antibodies: preclinical and clinical experience.

The cell-surface molecule CD40, a member of the tumor necrosis factor receptor superfamily, broadly regulates immune activation and mediates tumor apoptosis. CD40 is expressed by antigen-presenting cells (APC) and engagement of its natural ligand on T cells activates APC including dendritic cells and B cells. Agonistic CD40 antibodies have been shown to substitute for T cell help provided by CD4+ lymphocytes in murine models of T cell-mediated immunity.

Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody.

Purpose: The cell-surface molecule CD40 activates antigen-presenting cells and enhances immune responses. CD40 is also expressed by solid tumors, but its engagement results in apoptosis. CP-870,893, a fully human and selective CD40 agonist monoclonal antibody (mAb), was tested for safety in a phase I dose-escalation study.

The naive B cell repertoire predisposes to antigen-induced systemic lupus erythematosus.

It is clear that the development of an autoimmune disease usually depends on both a genetic predisposition and an environmental trigger. In this study, we demonstrate that BALB/c mice develop a lupus-like serology following immunization with a peptide mimetope of DNA, while DBA/2 mice do not. We further demonstrate that the critical difference resides within the B cell compartment and that the naive B cell repertoire of DBA/2 mice has fewer B cells specific for the DNA mimetope.