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Immunotherapy of B lymphoma by anti-idiotype antibodies: Characterization of variant tumour cells appearing a long time after the initial tumour inoculation

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Summary

Immunotherapy of a murine B-cell lymphoma by antibodies to idiotypic determinants of its IgM, resulted in surviving tumour-free mice. Several of these mice, however, did develop tumours a long time after the initial inoculation of the tumour cells, or upon rechallange of the survivors with B-lymphoma cells. The presence of tumour cells during this long latent period may have been due to the development in the host of an anti-idiotype immune response. These late-developing tumours were detected by a radioimmunoassay and characterized by immunofluorescent staining and sodium dodecyl sulphate/polyacrylamide gel electrophoresis. Cells of some late-developing tumours lost the idiotype recognized by the antibodies used for the immunotherapy. Several of these tumours expressed IgM on the cell surface, while others did not, because of the absence of light chains. They were identical in the structure of their rearranged µ chain genes proving their derivation from the original inoculation. Cell lines obtained from the late-developing tumours differed in their tumorigenicity. The appearance of idiotype-negative tumour cells as a result of anti-idiotype immunotherapy has a great impact in our efforts to cure lymphoma by this modality.

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References

  1. Ber R, Eriksson I (1979) Isolation of ouabain-resistant human lymphoblastoid cell lines by multi-step selection. Mutat Res 61: 411

    PubMed  Google Scholar 

  2. Bergman Y, Haimovich J (1977) Characterization of a carcinogeninduced murine B lymphocyte cell line of C3H/eB origin. Eur J Immunol 7: 413

    PubMed  Google Scholar 

  3. Bergman Y, Haimovich J (1978) B-lymphocytes contain three species of µ chains. Eur J Immunol 8: 876

    PubMed  Google Scholar 

  4. Berinstein N, Levy R (1987) Treatment of a murine B cell lymphoma with monoclonal antibodies and IL-2. J Immunol 139: 971

    PubMed  Google Scholar 

  5. Campbell MJ, Esserman L, Levy R (1988) Immunotherapy of established murine B cell lymphoma. J Immunol 141: 3227

    PubMed  Google Scholar 

  6. Ciavara RP, Vitetta ES, Forman J (1986) Growth inhibition of B cell leukemia: evidence implicating an anti-idiotype immune response for protective tumor immunity. J Immunol 137: 1371

    PubMed  Google Scholar 

  7. Cleary ML, Meeker TC, Levy S, Lee E, Trela M, Sklar J, Levy R (1986) Clustering of extensive somatic mutation in the variable region of an immunoglobulin heavy chain gene from a human B cell lymphoma. Cell 44: 97

    PubMed  Google Scholar 

  8. Fu SM, Winchester RJ, Feizi T, Walzer PK, Kunkel HG (1974) Idiotype specificity of surface immunoglobulin and the maturation of leukemic bone-marrow-derived lymphocytes. Proc Natl Acad Sci USA 71: 4487

    PubMed  Google Scholar 

  9. George AJT, Tutt AL, Stevenson FK (1987) Anti-idiotypic mechanism involved in suppression of a mouse B cell lymphoma BCL1. J Immunol 138: 628

    PubMed  Google Scholar 

  10. George AJT, Spellerberg MB, Stevenson FK (1988) Idiotype vaccination leads to the emergence of a stable surface Ig-negative variants of the mouse lymphoma BCL1, with different growth characteristics. J Immunol 140: 1695

    PubMed  Google Scholar 

  11. Ghosh SK, Bankert RB (1989) Generation of somatic variants of a B cell hybrid mediated by a non-cytolytic\(L_3 T_{4^ + } \) idiotype-specific T cells. J Immunol 142: 409

    PubMed  Google Scholar 

  12. Glennie MJ, McBride HM, Stirpe F, Thorpe PE, Worth AT, Stevenson GT (1987) Emergance of immunoglobulin variants following treatment of a B-cell leukemia with an immunotoxin composed of anti-idiotype antibody and saporin J Exp Med 166: 43

    PubMed  Google Scholar 

  13. Glennie MJ, Brennand DM, Bryden F, McBride HM, Stirpe F, Worth AT, Stevenson GT (1988) Bispecific F(ab′)2 antibody for the delivery of saporin in the treatment of lymphoma. J Immunol 141: 3662

    PubMed  Google Scholar 

  14. Hannestad K, Kao MS, Eisen HN (1972) Cell-bound myeloma proteins on the surface of myeloma cells, potential target for the immune system. Proc Natl Acad Sci USA 69: 2295

    PubMed  Google Scholar 

  15. Haughton GI, Lanier L, Babcock GF, Lynes MA (1978) Antigen-induced murine B lymphomas. II. Exploitation of the surface idiotype as tumor specific antigen. J Immunol 121: 2358

    PubMed  Google Scholar 

  16. Hunter WM (1973) Radioimmunoassay. In: Handbook of experimental Immunology, 2nd edn. Blackwell Scientific, Oxford, p 17.1

    Google Scholar 

  17. Hurwitz E, Kashi R, Burowsky D, Arnon R, Haimovich J (1983) Site directed chemotherapy with a drug bound to anti-idiotypic antibody to a lymphoma cell-surface IgM. Int J Cancer 31: 745

    PubMed  Google Scholar 

  18. Hurwitz E, Burowski D, Kashi R, Hollander N, Haimovich J (1986) A synergistic effect between anti-neoplastic drugs in the therapy of a murine B-cell tumor. Int J Cancer 37: 739

    PubMed  Google Scholar 

  19. Kessler SW (1975) Rapid isolation of antigens from cells with a staphylococcal protein A-antibody adsorbent: parameters of the interactions of antibody-antigen complex with protein A. J Immunol 115: 1617

    PubMed  Google Scholar 

  20. Krolick KA, Isakson PC, Uhr JW, Vitetta ES (1979) BCL1 a murine model for chronic lymphocytic leukemia: use of the surface immunoglobulin idiotype for the detection and treatment of tumors. Immunol Rev 48: 81

    PubMed  Google Scholar 

  21. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680

    PubMed  Google Scholar 

  22. Levy R, Warnke R, Dorfman RF, Haimovich J (1977) The monoclonality of human B cell lymphoma. J Exp Med 145: 1014

    PubMed  Google Scholar 

  23. Levy S, Campbell MJ, Levy R (1989) Functional immunoglobulin light chain genes are replaced by ongoing rearrangement of germline Vk genes to downstream Jk segments in a murine B cell line. J Exp Med 170: 1

    PubMed  Google Scholar 

  24. Lynch RG, Rohrer JW, Odermatt B, Gebel HM, Autry JR, Hoover RG (1979) Immunoregulation of murine myeloma cell growth and differentiation: a monoclonal model of B cell differentiation. Immunol Rev 48: 45

    PubMed  Google Scholar 

  25. Maloney DG, Kaminski MS, Burowski D, Haimovich J, Levy R (1985) Monoclonal anti-idiotype antibodies against the murine B cell lymphoma 38c-13: characterization and use as probes for the biology of the tumor in vivo and in vitro. Hybridoma 4: 191

    PubMed  Google Scholar 

  26. Maniatis T, Fritsch EF, Sambrook J (1982) In: Molecular cloning. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York p 382

    Google Scholar 

  27. Meeker TC, Lowder J, Cleary ML, Stewart S, Warnke R, Sklar J, Levy R (1985) Emergence of idiotype variants during treatment of B-cell lymphoma with anti-idiotype antibodies. N Engl J Med 312: 1658

    PubMed  Google Scholar 

  28. Meeker TC, Lowder J, Maloney DG, Miller RA, Thielemans K, Warnke R, Levy R (1985) A clinical trial of anti-idiotype therapy for B cell malignancy. Blood 65: 1349

    PubMed  Google Scholar 

  29. Melchers F, Andersson J (1973) Synthesis, surface deposition and secretion of immunoglobulin M in bone marrow derived lymphocytes before and after mitogen stimulation. Transplant Rev 14: 76

    PubMed  Google Scholar 

  30. Miller RA, Maloney DG, Warnke R, Levy R (1982) Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N Engl J Med 306: 517

    PubMed  Google Scholar 

  31. Nelson KJ, Haimovich J, Perry RP (1983) Characterization of productive and sterile transcripts from the immunoglobulin heavy chain locus: processing of µm and µs mRNA. Mol Cell Biol 3: 1317

    PubMed  Google Scholar 

  32. Nowell PC (1976) The clonal evaluation of tumor cell population. Science 194: 23

    PubMed  Google Scholar 

  33. Perek Y, Hurwitz E, Burowski D, Haimovich J (1983) Immunotherapy of a murine B-cell tumor with antibodies and F(ab′)2 against idiotype determinants of its cell surface IgM. J Immunol 131: 1600

    PubMed  Google Scholar 

  34. Peto R, Pike CM, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG (1977) Logrank test. Br J Cancer 35: 1

    PubMed  Google Scholar 

  35. Rankin EM, Hekman A, Somers R, Huinink WT (1988) Treatment of two patients with B cell lymphoma with monoclonal anti-idiotype antibodies. Blood 65: 1373

    Google Scholar 

  36. Roth MS, Weiner GJ, Allen EA, Terry WH, Harnden CE, Beohnke M, Kaminski MS, Ginsburg D (1990) Molecular characterization of anti-idiotype antibody-resistant variant of murine B cell lymphoma. J Immunol 145: 768

    PubMed  Google Scholar 

  37. Salmon SE, Seligman M (1974) B cell neoplasia in man. Lancet 2: 1230

    PubMed  Google Scholar 

  38. Salsano R, Froland SS, Natvig JB, Michaelsen TE (1974) Same idiotype of B-lymphocyte membrane IgD and IgM. Formal evidence for monoclonality of chronic lymphocytic leukemia cells. Scand J Immunol 3: 841

    PubMed  Google Scholar 

  39. Schroer KR, Briles DE, Vanboxel JA, Davie JM (1974) Idiotype uniformity of cell surface immunoglobulin in chronic lymphocytic leukemia: evidence for monoclonal proliferation. J Exp Med 140: 1416

    PubMed  Google Scholar 

  40. Starnes CO, Carrol WL, Campbell MJ, Houston LL, Apell G, Levy R (1988) Heterogeneity of a murine B cell lymphoma. J Immunol 141: 333

    PubMed  Google Scholar 

  41. Stevenson GT, Stevenson FK (1975) Antibody to a molecularly defined antigen confined to a tumor cell surface. Nature 254: 714

    PubMed  Google Scholar 

  42. Stevenson GT, Glennie MM, Hamblin TJ, Lane AC, Stevenson FK (1988) Problems and prospects in the use of lymphoma idiotypes as therapeutic targets Int J Cancer [Suppl] 3: 9

    Google Scholar 

  43. Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98: 503

    PubMed  Google Scholar 

  44. Uhr JW (1983) Immunotoxins: a new approach to cancer therapy. Science 219: 649

    Google Scholar 

  45. Vitetta ES, Yuan D, Krolick KA, Isakson P, Knapp M, Slavin S, Strober S (1979) Characterization of the spontaneous murine B cell leukemia (BCL1): III. Evidence for monoclonality using an anti-idiotype antibody. J Immunol 122: 1649

    PubMed  Google Scholar 

  46. Weiner GJ Kaminski MS (1989) Idiotype variants emerging after anti-idiotype monoclonal antibody therapy of a murine B cell lymphoma. J Immunol 142: 343

    PubMed  Google Scholar 

  47. Wheelock EF, Weinhold KJ, Levich J (1981) The tumor dormant state. Adv Cancer Res 34: 107

    PubMed  Google Scholar 

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Taya, M., Haimovich, J. Immunotherapy of B lymphoma by anti-idiotype antibodies: Characterization of variant tumour cells appearing a long time after the initial tumour inoculation. Cancer Immunol Immunother 34, 43–48 (1991). https://doi.org/10.1007/BF01741323

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