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

• Published in: Proceedings of the National Academy of Sciences - PNAS 1996-02, Vol.93 (4), p.1699-1704
• Main Authors: Pecher, Gabriele, Finn, Olivera J.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies, Neoplasm - biosynthesis; Antigens; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; B lymphocytes; B-Lymphocytes - immunology; B-Lymphocytes - radiation effects; B-Lymphocytes - transplantation; Cell Line, Transformed - immunology; Cell Line, Transformed - radiation effects; Cell Line, Transformed - transplantation; Cellular biology; DNA, Complementary - genetics; Epithelial cells; Epitopes; Epstein-Barr virus; Glycosylation; Herpesvirus 4, Human; Humans; Hypersensitivity, Delayed - etiology; Hypersensitivity, Delayed - immunology; Immunity (Disease); Immunity, Cellular; Interleukin-2 - biosynthesis; Interleukin-2 - genetics; Lymphocyte Activation; Male; Molecules; Monkeys & apes; Mucin-1 - genetics; Mucin-1 - immunology; Mucin-1 - metabolism; Mucins; Pan troglodytes; Pan troglodytes - immunology; Protein Processing, Post-Translational; Recombinant Proteins - immunology; Recombinant Proteins - metabolism; T lymphocytes; T-Lymphocytes, Cytotoxic - immunology; Tumors; Vaccination; Vaccination - methods; Vaccines; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.4.1699

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-α -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.