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

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 Mip1α 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.

Serial immunomonitoring of cancer patients receiving combined antagonistic anti-CD40 and chemotherapy reveals consistent and cyclical modulation of T cell and dendritic cell parameters

“…Similarly, whilst profound immediate and short term effects of CP-870,893 on B cells were identified, these parameters returned to baseline by day 8 after treatment [4]. Therefore it is possible that any increase was transient and not detected by us 7 days after treatment [11]. …”

“…Previous studies have also reported detectable modulation of DC by CP-870,893; in particular, depletion of CD11c + CD123 dim CD14 − DC from peripheral blood, and in vitro increases in HLA-DR expression by monocyte-derived DC [10, 11]. Weekly CP-870,893 monotherapy halved circulating lymphocyte concentrations after 48 h before returning to pre-treatment levels; this depletion was not observed when dosing occurred every three weeks [4, 10].…”

Ex Vivo Assays of Dendritic Cell Activation and Cytokine Profiles as Predictors of In Vivo Effects in an Anti-Human CD40 Monoclonal Antibody ChiLob 7/4 Phase I Trial

“…Although other agonistic anti-CD40 antibodies entering the clinic have been shown to activate dendritic cells with the use of model systems (19)(20)(21), we have used ex vivo assays to uniquely show biologic activity of ChiLob 7/4 on unmanipulated peripheral dendritic cells and conducted a direct comparison with a first-in-human study. Ex vivo, we have shown that ChiLob 7/4 is most potent when cross-linked and is able to activate dendritic cell to the level induced by the potent TLR ligand LPS.…”

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

“…We and others have shown that CP-870,893 activates human B cells and dendritic cells in vitro which in turn can induce T cell proliferation and cytokine production. 16-18 Here, we report that the combination of CD40 and CTLA-4 mAbs results in reinvigoration of T cells and is associated with clinical activity and acceptable toxicity in metastatic melanoma.…”