Summary
The development of recombinant vaccines for specific immunotherapy of carcinoma represents a novel approach for the treatment of breast cancer and other tumor types. This article reviews the various parameters that should be considered in the development of recombinant vaccines. Several breast cancer associated antigens are also discussed which may provide potential target molecules. The human carcinoembryonic antigen (CEA), which is expressed on approximately 50% of breast cancers, represents one such target for immunotherapy. To enhance the immunogenicity of this antigen, a recombinant CEA-vaccinia vaccine, designated rV-CEA, was produced. To study the effects of this vaccine in an animal model, a murine colon carcinoma cell line was transduced with CEA and transplanted into immunocompetent mice for protection and therapy studies. Pre-clinical toxicity studies were also conducted in non-human primates. The results of these studies showed the rV-CEA vaccine to be immunogenic and safe in both rodents and primates, and to elicit good anti-tumor responses in the rodent model. In a Phase I clinical trial in metastatic breast, lung, and colorectal cancer patients involving three immunizations of rV-CEA, at three dose levels, enhancement of T-cell and antibody responses to vaccinia virus proteins were observed with no toxicity. Specific T-cell responses were studied via stimulation of peripheral blood lymphocytes with specific peptide epitopes from the CEA molecule. These studies demonstrated clear cut differences in establishment of T-cell lines pre- versus post-immunization. The T-cell lines were shown to be CD8+ and/or CD4+/CD8+, to lyse EBV transformed B-cells transduced with the CEA gene, and to lyse CEA positive carcinoma cells in a HLA restricted manner. Thus, in a Phase I clinical trial the rV-CEA vaccine has been shown to stimulate a CTL response specific for CEA defined epitopes in cancer patients.
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Pietras RJ, Fendly BM, Chazin VR, Pegram MD, Howell SB, Slamon DJ: Antibody to HER-2/neu receptor blocks DNA repairs after cisplatin in human breast and ovarian cancer cells. Oncogene 9:1829–1838, 1994
Bernards R, Destree A, McKenzie S, Gordon E, Weinberg RA, Panicali D: Effective tumor immunotherapy directed against an oncogene-encoded product using a vaccinia virus vector. Proc Natl Acad Sci USA 84:6854–6858, 1987
Disis ML, Smith JW, Murphy AE, Chen W, Cheever MA: In vitro generation of human cytolytic T-cells specific for peptides derived from the HER-2/neu protooncogene protein. Cancer Res 54:1071–1076, 1994
Yanuck M, Carbone DP, Pendleton CD, Tsukui T, Winter SF, Minna JD, Berzofsky JA: A mutant p53 tumor suppressor protein is a target for peptideinduced CD8+ cytotoxic T-cells. Cancer Res 53: 3257–3261, 1993
Abe M, Kufe D: Characterization of cis-acting elements regulating transcription of the human DF3 breast carcinoma-associated antigen (MUC1) gene. Proc Natl Acad Sci USA 90:282–286, 1993
Barnd DL, Lan MS, Metzgar RS, Finn OJ: Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells. Proc Natl Acad Sci USA 86:7159–7163, 1989
Rughetti A, Turchi V, Ghetti CA, Scambia G, Panici PB, Roncucci G, Mancuso S, Frati L, Nuti M: Human B-cell immune response to the polymorphic epithelial mucin. Cancer Res 53:2457–2459, 1993
Hareuveni M, Gautier C, Kieny M-P, Wreschner D, Chambon P, Lathe R: Vaccination against tumor cells expressing breast cancer epithelial tumor antigen. Proc Natl Acad Sci USA 87:9498–9502, 1990
Hareuveni M, Wreschner DH, Kieny M-P, Dott K, Gautier C, Tomasetto C, Keydar I, Chambon P, Lathe R: Vaccinia recombinants expressing secreted and transmembrane forms of breast cancer-associated epithelial tumour antigen (ETA). Vaccine 9:618–626, 1991
Thor A, Ohuchi N, Szpak CA, Johnston WW, Schlom J: Distribution of oncofetal antigen tumor-associated glycoprotein-72 defined by monoclonal antibody B72.3. Cancer Res 46:3118–3124, 1986
Longenecker BM, Reddish M, Koganty R, MacLean GD: Immune responses of mice and human breast cancer patients following immunization with synthetic sialyl-Tn conjugated to KLH plus Detox adjuvant. Ann NY Acad Sci 690:276–291, 1993
MacLean GD, Reddish M, Koganty RR, Wong T, Gandhi S, Smolenski M, Samuel J, Nabholtz JM, Longenecker BM: Immunization of breast cancer patients using a synthetic sialyl-Tn glycoconjugate plus Detox adjuvant. Cancer Immunol Immunother 36:215–222, 1993
Robbins PF, Eggensperger D, Qi C-F, Schlom J: Definition of the expression of the human carcinoembryonic antigen and non-specific cross-reacting antigen in human breast and lung carcinomas. Int J Cancer 53:892–897, 1993
Esteban JM, Felder B, Ahn C, Simpson JF, Battifora H, Shively JE: Prognostic relevance of carcinoembryonic antigen and estrogen receptor status in breast cancer patients. Cancer 74:1575–1583, 1994
Bhattacharya-Chatterjee M, Foon KA, Kohler H: Anti-idiotpye monoclonal antibodies as vaccines for human cancer. Int Rev Immunol 7:289–302, 1991
Kantor J, Irvine K, Abrams S, Kaufman H, DiPietro J, Schlom J: Antitumor activity and immune responses induced by a recombinant carcinoembryonic antigenvaccinia virus vaccine. J Natl Cancer Inst 84:1084–1091, 1992
Van der Bruggen P, Traversari C, Chomez P, Larquin C, DePlaen E, Van den Eynde B, Kunth A, Boon T: A gene encoding an antigen recognized by cytolytic T lymphocytes on human melanoma. Science 254:1643–1647, 1991
Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Sakaguchi K, Appella E, Yannelli JR, Adema GJ, Miki T, Rosenberg SA: Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci USA 91:6458–6462, 1994
Ruby J, Ramsay A, Karupiah G, Ramshaw I: Recombinant virus vectors that coexpress cytokines — a new vaccine strategy. Vaccine Res 1:347–356, 1992
Schwartz RH: Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell 71:1065–1068, 1992
Chen L, Ashe S, Brady WA, Hellstrom I, Hellstrom KE, Ledbetter JA, McGowan P, Linsley PS: Costimulation of antitumor immunity by the B7 counter-receptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 71:1093–1102, 1992
Freeman GJ, Freedman AS, Segil JM, Lee G, Whitman JF, Nadler LM: B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells. J Immunol 143:2714–2722, 1989
Salgaller ML, Bei R, Schlom J, Poole DJ, Robbins PF: Baculovirus recombinants expressing the human carcinoembryonic antigen gene. Cancer Res 53:2154–2161, 1993
Jenner E: An inquiry into the causes and effects of the variolae vacciniae, a disease discovered in some of the western counties of England, particularly Gloucestershire, and known by the name of the cow pox. Sampson Low, London, 1978
World Health Organization. Declaration of global eradication of smallpox. Wkly Epidemiol Rec 55:145–152, 1980
Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID: Smallpox and its eradication. World Health Org, Geneva, 1988
Moss B: Vaccinia virus vectors.In: Ellis RW (ed) Vaccines: New Approaches to Immunological Problems. Butterworth-Heinemann, 1992, pp 369–511
Kaufman H, Schlom J, Kantor J: A recombinant vaccinia virus expressing human carcinoembryonic antigen (CEA). Int J Cancer 48:900–907, 1991
Fuchs C, Krapf F, Kern P, Hoferichter S, Jager W, Kalden JR: CEA-containing immune complexes in sera of patients with colorectal and breast cancer — analysis of complexed immunoglobulin classes. Cancer Immunol Immunother 26:180–184, 1988
Abeyounis CJ, Wilhelm SA, Rittenhouse KW, Milgrom F: Is carcinoembryonic antigen an autoantigen? Transplan Proc 16:489–491, 1984
MacSween JM: The antigenicity of carcinoembryonic antigen in man. Int J Cancer 15:246–252, 1975
Steele G, Lahey S, Rodrick M, Ross D, Deasy J, Zamcheck N, Osteen R, Wilson R: Circulating immune complexes in patients with colorectal cancer. Am J Surg 145:549–553, 1983
Horan Hand P, Robbins PF, Salgaller ML, Poole DJ, Schlom J: Evaluation of human carcinoembryonicantigen (CEA)-transduced and non-transduced murine tumors as potential targets for anti-CEA therapies. Cancer Immunol Immunother 36:65–75, 1993
Kantor J, Irvine K, Abrams S, Snoy P, Olsen R, Greiner J, Kaufman H, Eggensperger D, Schlom J: Immunogenicity and safety of a recombinant vaccinia virus vaccine expressing the carcinoembryonic antigen gene in a nonhuman primate. Cancer Res 52:6917–6925, 1992
Hamilton JM, Chen AP, Nguyen B, Grem J, Abrams S, Chung Y, Kantor J, Phares JC, Bastian A, Brooks C, Morrison G, Allegra CJ, Schlom J: Phase I study of recombinant vaccinia virus (rV) that expresses human carcinoembryonic antigen (CEA) in adult patients with adenocarcinomas [abstract]. ASCO Proc, 961, 1994
Tsang K, Zaremba S, Hamilton JM, Schlom J: Analysis of T-cell responses to carcinoembryonic antigen (CEA) in carcinoma patients following immunization with a recombinant vaccinia CEA vaccine. J Natl Cancer Inst 87:982–990, 1995
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Schlom, J., Kantor, J., Abrams, S. et al. Strategies for the development of recombinant vaccines for the immunotherapy of breast cancer. Breast Cancer Res Tr 38, 27–39 (1996). https://doi.org/10.1007/BF01803781
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DOI: https://doi.org/10.1007/BF01803781