TY - JOUR
T1 - Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo
AU - Liu, Chengwen
AU - Lewis, Carol M.
AU - Lou, Yanyan
AU - Xu, Chunyu
AU - Peng, Weiyi
AU - Yang, Yan
AU - Gelbard, Alexander H.
AU - Lizée, Gregory
AU - Zhou, Dapeng
AU - Overwijk, Willem W.
AU - Hwu, Patrick
PY - 2012/4
Y1 - 2012/4
N2 - CD40, a member of the tumor necrosis factor receptor superfamily, is broadly expressed on antigen-presenting cells and other cells, including fibroblasts and endothelial cells. Binding of CD40 and its natural ligand CD40L (CD154) triggers cytokine secretion, and increased expression of costimulatory molecules is required for T-cell activation and proliferation. However, to our knowledge, the use of agonistic antibodies to CD40 to boost adoptively transferred T cells in vivo has not been investigated. The purpose of this study was to determine whether anti-CD40 monoclonal antibody (mAb) in combination with interleukin (IL)-2 could improve the efficacy of in vitro-activated T cells to enhance antitumor activity. Mice bearing B16 melanoma tumors expressing the gp100 tumor antigen were treated with cultured, activated T cells transgenic for a T-cell receptor specifically recognizing gp100, with or without anti-CD40 mAb. In this model, the combination of anti-CD40 mAb with IL-2 led to expansion of adoptively transferred T cells and induced a more robust antitumor response. Furthermore, the expression of CD40 on bone marrow-derived cells and the presence of CD80/CD86 in the host were required for the expansion of adoptively transferred T cells. The use of neutralizing mAb to IL-12 provided direct evidence that enhanced IL-12 secretion induced by anti-CD40 mAb was crucial for the expansion of adoptively transferred T cells. Collectively, these findings provide a rationale to evaluate the potential application of anti-CD40 mAb in adoptive T-cell therapy for cancer.
AB - CD40, a member of the tumor necrosis factor receptor superfamily, is broadly expressed on antigen-presenting cells and other cells, including fibroblasts and endothelial cells. Binding of CD40 and its natural ligand CD40L (CD154) triggers cytokine secretion, and increased expression of costimulatory molecules is required for T-cell activation and proliferation. However, to our knowledge, the use of agonistic antibodies to CD40 to boost adoptively transferred T cells in vivo has not been investigated. The purpose of this study was to determine whether anti-CD40 monoclonal antibody (mAb) in combination with interleukin (IL)-2 could improve the efficacy of in vitro-activated T cells to enhance antitumor activity. Mice bearing B16 melanoma tumors expressing the gp100 tumor antigen were treated with cultured, activated T cells transgenic for a T-cell receptor specifically recognizing gp100, with or without anti-CD40 mAb. In this model, the combination of anti-CD40 mAb with IL-2 led to expansion of adoptively transferred T cells and induced a more robust antitumor response. Furthermore, the expression of CD40 on bone marrow-derived cells and the presence of CD80/CD86 in the host were required for the expansion of adoptively transferred T cells. The use of neutralizing mAb to IL-12 provided direct evidence that enhanced IL-12 secretion induced by anti-CD40 mAb was crucial for the expansion of adoptively transferred T cells. Collectively, these findings provide a rationale to evaluate the potential application of anti-CD40 mAb in adoptive T-cell therapy for cancer.
KW - adoptive cell transfer (ACT)
KW - anti-CD40 mAb
KW - immunotherapy
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UR - http://www.scopus.com/inward/citedby.url?scp=84863382868&partnerID=8YFLogxK
U2 - 10.1097/CJI.0b013e31824e7f43
DO - 10.1097/CJI.0b013e31824e7f43
M3 - Article
C2 - 22421945
AN - SCOPUS:84863382868
SN - 1524-9557
VL - 35
SP - 276
EP - 282
JO - Journal of Immunotherapy
JF - Journal of Immunotherapy
IS - 3
ER -