Immunogene therapy of tumors with vaccine based on xenogeneic epidermal growth factor receptor.
The breaking of immune tolerance against self epidermal growth factor receptor (EGFr) should be a useful approach for the treatment of receptor-positive tumors with active immunization. To test this concept, we constructed a plasmid DNA encoding extracellular domain of xenogeneic (human) EGFr (hEe-p) or corresponding control mouse EGFr (mEe-p) and empty vector (c-p). Mice immunized with hEe-p showed both protective and therapeutic antitumor activity against EGFr-positive tumor. Sera isolated from the hEe-p-immunized mice exhibited positive staining for EGFr-positive tumor cells in flow cytometric analysis and recognized a single 170-kDa band in Western blot analysis. Ig subclasses responded to rEGFr proteins were elevated in IgG1, Ig2a, and Ig2b. There was the deposition of IgG on the tumor cells. Adoptive transfer of the purified Igs showed the antitumor activity. The increased killing activity of CTL against EGFr-positive tumor cells could be blocked by anti-CD8 or anti-MHC class I mAb. In vivo depletion of CD4(+) T lymphocytes could completely abrogate the antitumor activity, whereas the depletion of CD8(+) cells showed partial abrogation. The adoptive transfer of CD4-depleted (CD8(+)) or CD8-depleted (CD4(+)) T lymphocytes isolated from mice immunized with hEe-p vaccine showed the antitumor activity. In addition, the increase in level of both IFN-gamma and IL-4 was found. Taken together, these findings may provide a new vaccine strategy for the treatment of EGFr-positive tumors through the induction of the autoimmune response against EGFr in a cross-reaction between the xenogeneic homologous and self EGFr.
Lu
You
Y
Key Laboratory of Biotherapy of Human Diseases, Ministry of Education and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, The People's Republic of China.
Wei
Yu-quan
YQ
Tian
Ling
L
Zhao
Xia
X
Yang
Li
L
Hu
Bin
B
Kan
Bin
B
Wen
Yan-jun
YJ
Liu
Feng
F
Deng
Hong-xin
HX
Li
Jiong
J
Mao
Yong-qiu
YQ
Lei
Song
S
Huang
Mei-juan
MJ
Peng
Feng
F
Jiang
Yu
Y
Zhou
Hao
H
Zhou
Li-qun
LQ
Luo
Feng
F
D019264:Adoptive Transfer; D000818:Animals; D015478:Antigens, Heterophile / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D001323:Autoantibodies / Q000032:analysis / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000276:immunology / Q000628:therapy; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D066246:ErbB Receptors / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D006801:Humans; D007111:Immunity, Cellular; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019444:Vaccines, DNA / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use
D015478:Antigens, Heterophile; D001323:Autoantibodies; D019496:Cancer Vaccines; D016207:Cytokines; D019444:Vaccines, DNA; D066246:ErbB Receptors