Immunization and immunotherapy for cancers involving infection by a human papillomavirus in a mouse model.
We describe a protocol for generating a potent cellular immune response against viral-infected cells, and demonstrate its efficacy and safety in a mouse model of human cancer associated with infection by a human papillomavirus (HPV). In the mouse model, the mouse tumor TC-1, which expresses the E7 oncoprotein from HPV-16, is used as a surrogate for human tumors infected with HPV-16. The antigen for the protocol is composed of the E7 oncoprotein conjugated to the Fc region of a mouse IgG1 Ig (E7-mFc). The mFc domain should bind to Fc receptors on dendritic cells, enhancing the processing and presentation of E7 peptides by dendritic cells to T cells, which mediate a cellular immune attack against tumors expressing E7. The E7-mFc antigen was encoded in a replication-incompetent adenoviral vector, called Ad(E7-mFc), for infection of the human kidney cell line 293. The infected 293 cells synthesize the E7-mFc antigen and also infectious Ad(E7-mFc) vector particles for approximately equal 2 days, until the cells lyse and the vector particles are released. To test the protocol for immunization against formation of a TC-1 tumor, the mice first were injected s.c. with 293 cells infected with Ad(E7-mFc), followed by two challenges with TC-1 cells. The immunized mice remained healthy and tumor-free for the 6-month duration of the experiment, and the autopsies showed no toxicity. In the control mice immunized with 293 cells infected with an adenoviral vector that does not encode the E7-mFc antigen, the TC-1 tumor grew continuously and the mice had to be killed within 1 month. To test the protocol for immunotherapy, the mice first were injected with TC-1 cells, followed by s.c. injections of 293 cells infected with Ad(E7-mFc). Tumor growth was prevented or strongly retarded in these mice, in contrast to the continuous tumor growth in the controls. These results suggest that the protocol could be adapted for immunization against human cancers associated with an HPV infection, notably cervical cancer, and for immunotherapy to prevent recurrence of a tumor after surgery.
Li
Jin
J
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
Sun
Ying
Y
Garen
Alan
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D002460:Cell Line; D002472:Cell Transformation, Viral; D003602:Cytotoxicity, Immunologic; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005813:Genes, Synthetic; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000235:genetics; D007167:Immunotherapy; D007668:Kidney; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy* / Q000821:virology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D027383:Papillomaviridae / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D050725:Papillomavirus E7 Proteins; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012867:Skin / Q000821:virology; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection; D014765:Viral Vaccines / Q000276:immunology / Q000627:therapeutic use*
D000956:Antigens, Viral; D018076:DNA, Complementary; D007074:Immunoglobulin G; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011993:Recombinant Fusion Proteins; D014765:Viral Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16