Induction of cellular immunity in chimpanzees to human tumor-associated antigen mucin by vaccination with MUC-1 cDNA-transfected Epstein-Barr virus-immortalized autologous B cells.
Aberrant glycosylation of the mucin molecule (encoded by the gene MUC-1) on human epithelial cell tumors leads to the exposure of tumor-associated epitopes recognized by patients' antibodies and cytotoxic T cells. Consequently, these epitopes could be considered targets for immunotherapy. We designed a cellular vaccine, employing, instead of tumor cells, autologous Epstein-Barr virus (EBV)-immortalized B cells as carriers of tumor-associated mucin, to take advantage of their costimulatory molecules for T-cell activation. The vaccine was tested in chimpanzees because of the identity of the human and chimpanzee MUC-1 tandem repeat sequence. EBV-immortalized B cells derived from two chimpanzees were transfected with MUC-1 cDNA, treated with glycosylation inhibitor phenyl-N-acetyl-alpha-D-galactosaminide to expose tumor-associated epitopes, irradiated, and injected subcutaneously four times at 3-week intervals. One vaccine preparation also contained cells transduced with the interleukin 2 (IL-2) cDNA and producing low levels of IL-2. Already after the first injection we found in the peripheral blood measurable frequency of cytotoxic T-cell precursors specific for underglycosylated mucin. The highest frequency observed was after the last boost, in the lymph node draining the vaccination site. Delayed-type hypersensitivity reaction to the injected immunogens was also induced, whereas no appearance of mucin-specific antibodies was seen. Long-term observation of the animals yielded no signs of adverse effects of this immunization. Autologous antigen-presenting cells, like EBV-immortalized B cells, expressing tumor-associated antigens are potentially useful immunogens for induction of cellular anti-tumor responses in vivo.
Pecher
G
G
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, PA 15261, USA.
Finn
O J
OJ
D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000528:radiation effects / Q000637:transplantation; D002461:Cell Line, Transformed / Q000276:immunology / Q000528:radiation effects / Q000637:transplantation; D018076:DNA, Complementary / Q000235:genetics; D006031:Glycosylation; D004854:Herpesvirus 4, Human; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000209:etiology / Q000276:immunology; D007111:Immunity, Cellular; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D018396:Mucin-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002679:Pan troglodytes / Q000276:immunology*; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014611:Vaccination / Q000379:methods*
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D018076:DNA, Complementary; D007376:Interleukin-2; D018396:Mucin-1; D011994:Recombinant Proteins