Cancer immunotherapy using in vitro genetically modified targeted dendritic cells.
Modest clinical outcomes of dendritic cell (DC) vaccine trials call for novel strategies. In this study, we have created a chimeric CD40 molecule that incorporates a single chain Fv (scFv) molecule specific for human ErbB2 antigen and fusing to the membrane spanning and cytosolic domains of murine CD40. After adenoviral transfer to bone marrow-derived DC, this chimeric receptor (CR) induced nuclear factor-kappaB (NF-kappaB)-dependent DC activation and effector function when cultured with immobilized ErbB2 protein or ErbB2-positive tumor cells in vitro. In vivo migration assays showed that approximately 40% injected CR-modified DC (scFv-CD40-DC) effectively migrated to ErbB2-positive tumors, where they were activated after ErbB2 antigen stimulation, and sequentially homed into the draining lymph nodes. In murine ErbB2-positive D2F2/E2 breast tumor (BALB/c) and EL4/E2 thymoma (C57BL/6) models, i.v. injection of 1 x 10(6) scFv-CD40-DC significantly inhibited tumor growth and cured established tumors. Importantly, the cured mice treated by injection of scFv-CD40-DC were effective in preventing both ErbB2-positive and parental ErbB2-negative tumor rechallenge. Analysis of the underlying mechanism revealed that i.v. infusion of scFv-CD40-DC elicited tumor-specific CTL responses, and the transfer of CTLs from scFv-CD40-DC-treated mice protected naive mice against a subsequent tumor challenge. These results support the concept that genetic modification of DC with tumor-associated antigen-specific CD40 chimeric receptor might be a useful strategy for treatment of human cancers.
Wei
Huafeng
H
International Joint Cancer Institute, The Second Military Medical University, and Shanghai Center for Cell Engineering and Antibody, Shanghai, People's Republic of China.
Wang
Hao
H
Lu
Bing
B
Li
Bohua
B
Hou
Sheng
S
Qian
Weizhu
W
Fan
Kexing
K
Dai
Jianxin
J
Zhao
Jian
J
Guo
Yajun
Y
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D019013:CD40 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D005260:Female; D005821:Genetic Techniques; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000628:therapy*; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D019013:CD40 Antigens