Immunization with a recombinant adenovirus encoding a lymphoma idiotype: induction of tumor-protective immunity and identification of an idiotype-specific T cell epitope.
The Ig Id of a B cell lymphoma is a tumor-specific Ag, although as a self-Ag it is likely to be a weak immunogen. Provision of a foreign gene may enhance the immunogenicity of the idiotype. Viral vectors allow highly efficient transfer of genetic material and are themselves innately immunogenic. We have investigated the ability of recombinant adenoviral vectors, encoding the idiotypic gene with or without fusion to the human Fc region, to produce anti-idiotypic Ab- and T cell-mediated responses in a syngeneic BALB/c A20 murine lymphoma model. The idiotypic V(H) and V(L) sequences were assembled as a single chain variable fragment (scFv) and adenoviral vectors encoding the A20 scFv (Ad.A20) and A20 scFv linked to the Fc fragment of human IgG1 (Ad.A20hFc) were constructed. A single immunization of BALB/c mice with Ad.A20hFc but not Ad.A20 induced a specific anti-idiotypic Ab response. T cell lines generated from mice vaccinated with either vector displayed specific cytotoxicity, proliferation, and IFN-gamma release against a syngeneic dendritic cell line transduced using a retroviral vector to express the A20 scFv idiotype (XS52.A1.A20). Importantly, both T cell lines lysed the A20 lymphoma cells. An immunodominant H-2K(d)-restricted CD8(+) T cell peptide, DYWGQGTEL (A20[106-114]), was identified as a naturally occurring A20 scFv epitope. A single immunization with Ad.A20hFc but not Ad.A20 provided protection in >40% of animals challenged with a lethal dose of the A20 tumor line and was more effective, in this model, than a previously optimized plasmid vaccine.
Armstrong
Anne C
AC
Department of Medical Oncology and Immunology, Cancer Research Campaign, Paterson Institute of Cancer Research, Christie Hospital National Health Service Trust, Manchester, United Kingdom.
Dermime
Said
S
Allinson
Christopher G
CG
Bhattacharyya
Tapan
T
Mulryan
Kate
K
Gonzalez
Karin R
KR
Stern
Peter L
PL
Hawkins
Robert E
RE
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002999:Clone Cells; D003001:Cloning, Molecular; D018984:Epitopes, T-Lymphocyte / Q000032:analysis* / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007115:Immunization Schedule; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D007130:Immunoglobulin Idiotypes / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011995:Recombination, Genetic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000637:transplantation; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
D000888:Antibodies, Anti-Idiotypic; D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D016056:Immunodominant Epitopes; D007130:Immunoglobulin Idiotypes; D007135:Immunoglobulin Variable Region; D010446:Peptide Fragments; D014765:Viral Vaccines