cytotoxic T lymphocytes. Evidence for shared tumor antigens. J Immunol 142:3329-3335, 1989 (25) RiBl E: Beneficial modification of the endotoxin molecule. J Biol Response Mod 3:1-9, 1984 (26) TANIYAMA T, AZUMA I, YAMAMURA Y: Ad-
juvant activity of mycobacterial fractions. III. Adjuvant effect of cell wall of Mycobacterium bovis BCG on cell-mediated cytotoxicity in mice. Jpn J Microbiol 19:255-264, 1975 (27) OCDEN BE, HILL HR: Histamine regulates
transfer of delayed hypersensitivity was also demonstrated using lymphocytes from mice primed with 105AD7. These Findings show that the human monoclonal anti-idiotypic antibody 105AD7 is likely to induce cellular immune responses to tumors in cancer patients. [J Natl Cancer Inst 83:1245-1248,1991]
lymphocyte mitogenic responses through activation of specific Hi and H2 histamine receptors. Immunology 41:107-114, 1980 (25)
LIVINGSTON PO, JONES M, OETTGEN HF, ET
AL: Augmentation of the serological response to Meth A antigen by cyclophosphamide and endotoxin. Proc Am Assoc Cancer Res 25:279, 1984 (29) VOSIKA G, GIDDINGS C, GRAY GR: Phase I
(50)
MITCHELL MS, KAN-MITCHELL J, KEMPF RA,
ET AL: Active specific immunotherapy for melanoma: Phase I trial of allogeneic lysates and a novel adjuvant. Cancer Res 48:58835893,1988
Induction of Delayed Hypersensitivity to Human Tumor Cells With a Human Monoclonal Anti-idiotypic Antibody E. B. Austin* R. A. Robins, R. W. Baldwin, L. G. Durrant
There is considerable interest in the development of anti-idiotypic antibodies as vaccines in a number of diseases, including cancer. We have developed a human anti-idiotypic monoclonal antibody (105AD7) which binds at or very near to the binding site of mouse antitumor monoclonal antibody 791T/36. The 791T/36 antibody binds to a tumor-associated antigen (gp72) expressed on a number of human tumors, including colorectal and ovarian carcinomas and osteogenic sarcoma. This study shows that, in rats and mice, 105AD7 induces delayedtype hypersensitivity to human tumor cells bearing the gp72 antigen. Local Vol. 83, No. 17, September 4, 1991
Materials and Methods Anti-idiotypic antibodies have been shown to induce or modulate immune responses to various infectious agents (7). This approach has gained interest in the field of tumor immunotherapy, especially because idiotypic manipulation has the potential to overcome suppression of an immune response against the nominal tumor antigen. Cancer patients injected with murine monoclonal antibodies have anti-idiotypic responses, and the indication that these patients have a more favorable clinical outcome has encouraged the view that idiotypic manipulation could be used to induce immunity to human cancer (2). Although anti-idiotypic antibody-induced antitumor antibodies may play a role in tumor therapy, T helper and cytotoxic T lymphocyte clones, which recognize tumor cells, may provide a more effective rejection mechanism. The induction of T-cell responses by antiidiotypic antibody has been investigated in several systems (3). For example, in a mouse lymphoma system, T cells obtained from lymph nodes of mice given an injection of anti-idiotypic antibodies were shown to be cytotoxic for the lymphoma cells (4). Induction of T-cell responses by anti-idiotype has also been demonstrated by testing for the ability of anti-idiotypic antibody to prime a tumorspecific, delayed-type hypersensitivity response to experimental tumors (5-8). Heterologous goat (9) and mouse (70) anti-idiotypic antibodies have so far been used to immunize cancer patients. However, after repeated immunization with a foreign antibody, the immune response may become dominated by antibodies to the constant regions of heterologous antibody with no further therapeutic effect. Immunization with a human anti-idiotypic antibody would be expected to induce only anti-idiotypic responses, and thus allow repeated immunizations. We
Tumor cell lines. The cell lines used in these studies were maintained in Dulbecco's modified Eagle medium (GIBCO, Grand Island, N.Y.) containing 10% newborn calf serum without antibiotics and were periodically checked for mycoplasma contamination. The cells were subcultured every 3 days using 0.25% trypsin/edetic acid (Difco Laboratories, Detroit, Mich.; Sigma Chemical Co., St. Louis, Mo.) to release attached cells. The tumor cell lines used were the osteogenic sarcoma cell line 791T (W. A. Nelson Rees, U.S. Naval Biomedical Center, Oakland, Calif.), which expresses high levels of the 72-kd membrane glycoprotein (gp72) identified by the mouse antibody 791T/36 (12,13); the bladder carcinoma line T24 (Franks LM, Imperial Cancer Research Fund Laboratories, London: personal communication), which expresses low levels of gp72; and the colorectal carcinoma cell line Colo 205 (14), negative for gp72. Animals. Female BALB/c mice and male Wistar rats were housed under normal animal-house conditions following United Kingdom Coordinating Committee for Cancer Research guidelines and kept on a standard diet and on water ad libitum. Antibodies. Human monoclonal antibody 105AD7, an immunoglobulin Gl (IgGl), was purified from hybridoma tis-
Received October 10, 1990; revised May 10, 1991; accepted May 16, 1991. Supported by a grant from the Cancer Research Campaign, U.K. E. B. Austin, R. A. Robins, R. W. Baldwin, L. G. Durrani, Cancer Research Campaign Laboratories, Nottingham University, Nottingham, U.K. We thank Teresa Morris for technical assistance and Owen Roberts for help with photography. 'Correspondence to: E. B. Austin, M.D., Cancer Research Campaign Laboratories, Nottingham University, Nottingham NG7 2RD, UK.
REPORTS 1245
Downloaded from http://jnci.oxfordjournals.org/ at University of Sussex on August 17, 2015
study of intravenous mycobactenal cell wall skeleton and trehalose dimycolate attached to oil droplets. J Biol Response Mod 3:620-626, 1984
have developed a human monoclonal anti-idiotypic antibody (77) directed against the anti-tumor antibody 791T/36 which may have potential use in the therapy of cancer patients. In this report, the ability of human anti-idiotypic antibody 105AD7 to induce cellular immune responses to human tumor cells has been screened in experimental animals.
Results Cell-mediated immunity was assessed by tests for delayed hypersensitivity to human tumor cells in mice immunized by
1246
injection of anti-idiotypic antibody without adjuvant, using a modification of the method of Nepom et al. (
juvant activity of mycobacterial fractions. III. Adjuvant effect of cell wall of Mycobacterium bovis BCG on cell-mediated cytotoxicity in mice. Jpn J Microbiol 19:255-264, 1975 (27) OCDEN BE, HILL HR: Histamine regulates
transfer of delayed hypersensitivity was also demonstrated using lymphocytes from mice primed with 105AD7. These Findings show that the human monoclonal anti-idiotypic antibody 105AD7 is likely to induce cellular immune responses to tumors in cancer patients. [J Natl Cancer Inst 83:1245-1248,1991]
lymphocyte mitogenic responses through activation of specific Hi and H2 histamine receptors. Immunology 41:107-114, 1980 (25)
LIVINGSTON PO, JONES M, OETTGEN HF, ET
AL: Augmentation of the serological response to Meth A antigen by cyclophosphamide and endotoxin. Proc Am Assoc Cancer Res 25:279, 1984 (29) VOSIKA G, GIDDINGS C, GRAY GR: Phase I
(50)
MITCHELL MS, KAN-MITCHELL J, KEMPF RA,
ET AL: Active specific immunotherapy for melanoma: Phase I trial of allogeneic lysates and a novel adjuvant. Cancer Res 48:58835893,1988
Induction of Delayed Hypersensitivity to Human Tumor Cells With a Human Monoclonal Anti-idiotypic Antibody E. B. Austin* R. A. Robins, R. W. Baldwin, L. G. Durrant
There is considerable interest in the development of anti-idiotypic antibodies as vaccines in a number of diseases, including cancer. We have developed a human anti-idiotypic monoclonal antibody (105AD7) which binds at or very near to the binding site of mouse antitumor monoclonal antibody 791T/36. The 791T/36 antibody binds to a tumor-associated antigen (gp72) expressed on a number of human tumors, including colorectal and ovarian carcinomas and osteogenic sarcoma. This study shows that, in rats and mice, 105AD7 induces delayedtype hypersensitivity to human tumor cells bearing the gp72 antigen. Local Vol. 83, No. 17, September 4, 1991
Materials and Methods Anti-idiotypic antibodies have been shown to induce or modulate immune responses to various infectious agents (7). This approach has gained interest in the field of tumor immunotherapy, especially because idiotypic manipulation has the potential to overcome suppression of an immune response against the nominal tumor antigen. Cancer patients injected with murine monoclonal antibodies have anti-idiotypic responses, and the indication that these patients have a more favorable clinical outcome has encouraged the view that idiotypic manipulation could be used to induce immunity to human cancer (2). Although anti-idiotypic antibody-induced antitumor antibodies may play a role in tumor therapy, T helper and cytotoxic T lymphocyte clones, which recognize tumor cells, may provide a more effective rejection mechanism. The induction of T-cell responses by antiidiotypic antibody has been investigated in several systems (3). For example, in a mouse lymphoma system, T cells obtained from lymph nodes of mice given an injection of anti-idiotypic antibodies were shown to be cytotoxic for the lymphoma cells (4). Induction of T-cell responses by anti-idiotype has also been demonstrated by testing for the ability of anti-idiotypic antibody to prime a tumorspecific, delayed-type hypersensitivity response to experimental tumors (5-8). Heterologous goat (9) and mouse (70) anti-idiotypic antibodies have so far been used to immunize cancer patients. However, after repeated immunization with a foreign antibody, the immune response may become dominated by antibodies to the constant regions of heterologous antibody with no further therapeutic effect. Immunization with a human anti-idiotypic antibody would be expected to induce only anti-idiotypic responses, and thus allow repeated immunizations. We
Tumor cell lines. The cell lines used in these studies were maintained in Dulbecco's modified Eagle medium (GIBCO, Grand Island, N.Y.) containing 10% newborn calf serum without antibiotics and were periodically checked for mycoplasma contamination. The cells were subcultured every 3 days using 0.25% trypsin/edetic acid (Difco Laboratories, Detroit, Mich.; Sigma Chemical Co., St. Louis, Mo.) to release attached cells. The tumor cell lines used were the osteogenic sarcoma cell line 791T (W. A. Nelson Rees, U.S. Naval Biomedical Center, Oakland, Calif.), which expresses high levels of the 72-kd membrane glycoprotein (gp72) identified by the mouse antibody 791T/36 (12,13); the bladder carcinoma line T24 (Franks LM, Imperial Cancer Research Fund Laboratories, London: personal communication), which expresses low levels of gp72; and the colorectal carcinoma cell line Colo 205 (14), negative for gp72. Animals. Female BALB/c mice and male Wistar rats were housed under normal animal-house conditions following United Kingdom Coordinating Committee for Cancer Research guidelines and kept on a standard diet and on water ad libitum. Antibodies. Human monoclonal antibody 105AD7, an immunoglobulin Gl (IgGl), was purified from hybridoma tis-
Received October 10, 1990; revised May 10, 1991; accepted May 16, 1991. Supported by a grant from the Cancer Research Campaign, U.K. E. B. Austin, R. A. Robins, R. W. Baldwin, L. G. Durrani, Cancer Research Campaign Laboratories, Nottingham University, Nottingham, U.K. We thank Teresa Morris for technical assistance and Owen Roberts for help with photography. 'Correspondence to: E. B. Austin, M.D., Cancer Research Campaign Laboratories, Nottingham University, Nottingham NG7 2RD, UK.
REPORTS 1245
Downloaded from http://jnci.oxfordjournals.org/ at University of Sussex on August 17, 2015
study of intravenous mycobactenal cell wall skeleton and trehalose dimycolate attached to oil droplets. J Biol Response Mod 3:620-626, 1984
have developed a human monoclonal anti-idiotypic antibody (77) directed against the anti-tumor antibody 791T/36 which may have potential use in the therapy of cancer patients. In this report, the ability of human anti-idiotypic antibody 105AD7 to induce cellular immune responses to human tumor cells has been screened in experimental animals.
Results Cell-mediated immunity was assessed by tests for delayed hypersensitivity to human tumor cells in mice immunized by
1246
injection of anti-idiotypic antibody without adjuvant, using a modification of the method of Nepom et al. (
