title: Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo.
abstract: 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.
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Carol M
authors.initials: CM
authors.lastname: Lewis
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Lou
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Peng
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Gelbard
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gregory
authors.initials: G
authors.lastname: Lizée
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D017951:Antigen Presentation / Q000276:immunology; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000819:agonists / Q000276:immunology*; D002460:Cell Line; D005260:Female; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D058951:gp100 Melanoma Antigen / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; D007376:Interleukin-2; D058951:gp100 Melanoma Antigen