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Induction of an immune network cascade in cancer patients treated with monoclonal antibodies (ab1)

II. Is induction of anti-idiotype reactive T cells (T3) of importance for tumor response to mAb therapy?

  • Original Articles
  • Monoclonal Antibodies Network Response Anti-idiotype Antibodies, T Cells, Colon Carcinoma
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The antitumor effector functions of unconjugated monoclonal antibodies (mAb) in cancer therapy are not fully understood. Direct cytotoxic mechanisms such as antibody-dependent cellular cytotoxicity, complement-dependent cytolysis and apoptosis have been suggested. Induction of anti-idiotypic (ab2) and anti-anti-idiotypic (ab3) antibodies as well as the corresponding T cells (T2 and T3) has also been proposed to be of therapeutic significance. In this study induction of an immune network cascade in ten patients with colorectal carcinoma, treated with mAb 17-1A (ab1) was assessed. After treatment, all ten patients had anti-idiotypic antibodies and anti-anti-idiotypic antibodies with ab1-like binding specificity while only five of ten patients had T cells corresponding to ab3 (T3) as assessed by a proliferation assay (DNA synthesis), and an assay of interferon γ production (ELISPOT) (Enzyme-linked immuno SPOT) in vitro or by a delayed-type hypersensitivity reaction in vivo. Purified T cells from four of the five patients with a positive T3 test responded with DNA synthesis after stimulation using human anti-mAb 17-1A anti-idiotypic monoclonal antibodies. These four patients had a clinical response showing a tumor reduction after therapy, while all six patients lacking a proliferative response failed to show tumor regression. Induction of a cell-mediated immune network cascade might accordingly be an important anti-tumor effector function of mAb and should be considered in the future design of mAb-based therapy protocols in cancer patients.

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References

  1. Adams DO, Hall T, Steplewski Z, Koprowski H (1984) Tumors undergoing rejection induced by monoclonal antibodies of the IgG2A isotype containing increased numbers of macrophages activated for distinctive form of antibody dependent cytolysis. Proc Natl Acad Sci USA 81: 3506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Atzpodien J, Körfer A, Franks CR, Poliwoda H, Kirchner H (1990) Home therapy with recombinant interleukin-2 and interferon-α2b in advanced human malignancies. Lancet 335: 1509

    Article  CAS  PubMed  Google Scholar 

  3. Bergenbrant S, Österborg A, Holm G, Mellstedt H, Lefvert A-K (1991) Anti-idiotypic antibodies in patients with monoclonal gammopathies: relation to the tumour load. Br J Haematol 78: 66

    Article  CAS  PubMed  Google Scholar 

  4. Böyum A (1983) Isolation of human blood monocytes with Nycodenz, a new non-ionic iodinated gradient medium. Scand J Immunol 17: 429

    Article  PubMed  Google Scholar 

  5. Bruck C, Sung Co M, Slaoui M, Gaulton GN, Smith T, Fields BN, Mullins JI, Greene MI (1986) Nucleic acid sequence of an internal image-bearing monoclonal anti-idiotype and its comparison to the sequence of the external antigen. Proc Natl Acad Sci USA 83: 6578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cheung N-KV, Lazarus H, Miraldi FD, Abramowsky CR, Kallick S, Saarinen UM, Spitzer T, Stransjord SE, Coccia PF, Berger NA (1987) Ganglioside GD2 specific monoclonal antibody 3F8: a phase-I study in patients with neuroblastoma and malignant melanoma. J Clin Oncol 5: 1430

    Article  CAS  PubMed  Google Scholar 

  7. Cleave VH van, Naeve CW, Metzger DW (1988) Do antibodies recognize amino acid side chains of protein antigens independently of the carbon backbone? J Exp Med 167: 1841

    Article  PubMed  Google Scholar 

  8. Courtenay-Luck NS, Epenetos AA, Sivolapenko GB, Barkans JR, Larche M, Ritter MA (1988) Development of anti-idiotypic anti-bodies against tumor antigens and auto-antigens in ovarian cancer patients treated intraperitoneally, with mouse monoclonal antibodies. Lancet II: 894

    Article  Google Scholar 

  9. Czerkinsky C, Andersson G, Ehre H-P, Nilsson L-Å, Klareskog L, Ouchterlony Ö (1988) Reverse ELISPOT assay for clonal analysis of cytokine production. I. Enumeration of gamma-interferon-secreting cells. J Immunol Methods 110: 29

    Article  CAS  PubMed  Google Scholar 

  10. Fagerberg J, Frödin J-E, Wigzell H, Mellstedt H (1993) Induction of an immune network cascade in cancer patients treated with monoclonal antibodies (ab2). I. May induction of ab1 reactive T cells and anti-anti-idiotypic antibodies (ab3) lead to tumor regression after mAb therapy? Cancer Immunol Immunother 37: 264

    Article  CAS  PubMed  Google Scholar 

  11. Fagreus A, Espmark JÅ, Jonsson J (1965) Mixed haemadsorption: a mixed anti-globulin reaction applied to antigens on a glass surface. Immunology 9: 161

    Google Scholar 

  12. Friguet B, Chaffotte A, Djavadi-Ohaniance L, Goldberg M (1985) Measurements of the true affinity constant in solution of antigen-antibody complexes by enzyme-linked immunosorbent assay. J Immunol Methods 77: 305

    Article  CAS  PubMed  Google Scholar 

  13. Frödin J-E, Pihlstedt P, Lefvert A-K, Mellstedt H (1987) Isolation and characterization of autologous blood mononuclear cells used for auto-infusion together with monoclonal antibodies in tumor treatment. Hybridoma 6: 555

    Article  PubMed  Google Scholar 

  14. Frödin J-E, Harmenberg U, Biberfeld P, Christensson B, Lefvert A-K, Rieger Ä, Shetye J, Wahren B, Mellstedt H (1988) Clinical effects of monoclonal antibodies (mAb 17-1A) in patients with metastatic colorectal carcinoma. Hybridoma 7: 309

    Article  PubMed  Google Scholar 

  15. Frödin J-E, Lefvert A-K, Mellstedt H (1990) Pharmacokinetics of the mouse monoclonal antibody 17-1A in cancer patients receiving various treatment schedules. Cancer Res 50: 4866

    PubMed  Google Scholar 

  16. Frödin J-E, Faxas M-E, Hagström B, Lefvert A-K, Masucci G, Nilsson B, Steinitz M, Unger P, Mellstedt H (1991) Induction of anti-idiotypic (ab2) and anti-anti-idiotypic (ab3) antibodies in patients treated with the mouse monoclonal antibody 17-1A (ab1). Relation to the clinical outcome — an important antitumoral effector function? Hybridoma 10: 421

    Article  PubMed  Google Scholar 

  17. Hearing VJ, Leong SPL, Vieira WD, Law LW (1991) Suppression of established pulmonary metastases by murine melanoma-specific monoclonal antibodies. Int J Cancer 47: 148

    Article  CAS  PubMed  Google Scholar 

  18. Hellström K, Hellström I (1990) Antitumor vaccines. I. Why cancer vaccines? Woodrow GC, Levine MM (eds) New generation vaccines. Dekker, New York, p 855

    Google Scholar 

  19. Herlyn DM, Koprowski H (1981) Monoclonal anticolon carcinoma antibodies in complement-dependent cytotoxicity. Int J Cancer 27: 769

    Article  CAS  PubMed  Google Scholar 

  20. Herlyn M, Steplewski Z, Herlyn D, Koprowski H (1979) Colorectal carcinoma-specific antigen detection by means of monoclonal antibodies. Proc Natl Acad Sci USA 76: 1438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Herlyn DM, Steplewski Z, Herlyn MF, Koprowski H (1980) Inhibition of growth of colorectal carcinoma in nude mice by monoclonal antibody. Cancer Res 40: 717

    CAS  PubMed  Google Scholar 

  22. Herlyn D, Sears H, Iliopoulos D, Lubeck M, Douillard J-Y, Sindelar W, Tempero M, Mellstedt H, Maher M, Koprowski H (1986) Anti-idiotypic antibodies to monoclonal antibody CO17-1A. Hybridoma 5: 51

    Google Scholar 

  23. Herlyn D, Wettendorff M, Schmoll E, Iliopoulos D, Schedel I, Dreikhausen U, Raab R, Ross AH, Jaksche H, Scriba M, Koprowski H (1987) Anti-idiotype immunization of cancer patients: Modulation of the immune response. Proc Natl Acad Sci USA 84: 8055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Houghton AN, Mintzner D, Cordon-Cardo C, Welt S, Fliegel F, Vadham S, Carswell E, Melamed MR, Oettgen HF, Old LY (1985) Mouse monoclonal IgG3 antibody detecting GD3 ganglioside: a phase I trial in patients with malignant melanoma. Proc Natl Acad Sci USA 82: 1242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hunter WM, Greenwood FC (1962) Preparation of iodine-131 labelled human growth hormone of high specific activity. Nature 194: 495

    Article  CAS  PubMed  Google Scholar 

  26. Iriei RF, Morton DL (1986) Regression of cutaneous metastatic melanoma by intralesional injection with human monoclonal antibody to ganglioside GD2. Proc Natl Acad Sci USA 83: 8694

    Article  Google Scholar 

  27. Jerne NK (1974) Towards a network theory of the immune system. Ann Immunol 125: 373

    CAS  Google Scholar 

  28. Kabilan L, Troye-Blomberg M, Perlmann H, Andersson G, Högh B, Petersen E, Björkman A, Perlmann P (1988) T-cell epitopes in Pf155/RESA, a major candidate for aPlasmodium falciparum malaria vaccine. Proc Natl Acad Sci USA 85: 5659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kabilan L, Troye-Blomberg M, Andersson G, Riley EM, Ehre HP, Whittle HC, Perlmann P (1990) Number of cells fromPlasmodium falciporum-immune donors that produce gamma interferon in vitro in response to PF155/RESA, a malaria vaccine candidate antigen. Infect Immun 58: 2989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Koprowski H, Herlyn D, Lubeck M, DeFreitas E, Sears HF (1984) Human anti-idiotype antibodies in cancer patients: is the modulation of the immune response beneficial for the patient? Proc Natl Acad Sci USA 81: 216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kosmas C, Man S, Epenetos AA, Courtenay-Luck NS (1990) The role of humoral and cellular immunity in patients developing human anti-murine immunoglobulin, antibody responses after radioimmunotherapy. Br J Cancer 62: 85

    Google Scholar 

  32. Lanzavecchia A, Abrignani S, Scheidegger D, Obrist R, Dörken B, Moldenhauer G (1988) Antibodies as antigens. The use of mouse monoclonal antibodies to focus human T cells against selected targets. Exp Med 167: 345

    Article  CAS  Google Scholar 

  33. Lehmann HP, Zwicky C, Waibel R, Stahel R (1992) Tumor-antigen-specific humoral immune response of animals to anti-idiotypic antibodies and comparative serological analysis of patients with small-cell lung carcinoma. Int J Cancer 50: 86

    Article  CAS  PubMed  Google Scholar 

  34. Lehtinen T, Perlmann P, Hellström U, Hammarström S (1980) Proliferative and cytolytic reactivities of human lymphocytes fractionated on wheat germ agglutinin-sepharose columns before or after allo-activation in mixed lymphocyte culture. Scand J Immunol 12: 309

    Article  CAS  PubMed  Google Scholar 

  35. LoBuglio AF, Salch MN, Lee J, Khazaeci MB, Carrano R, Holden H, Wheeler RH (1988) Phase I trial of multiple large doses of murine monoclonal antibody CO17-1A. I. Clinical aspects. J Natl Cancer Inst 12: 932

    Article  Google Scholar 

  36. Mellstedt H, Frödin J-E, Biberfeld P, Fagerberg J, Giscombe R, Hernandez A, Masucci G, Li S-L, Steinitz M (1991) Patients treated with a monoclonal antibody (ab1) to the colorectal carcinoma antigen 17-1A develop a cellular response (DTH) to “the internal image of the antigen” (ab2). Int J Cancer 48: 344

    Article  CAS  PubMed  Google Scholar 

  37. Mellstedt H, Frödin J-E, Masucci G, Ragnhammar P, Fagerberg J, Hjelm A-L, Shetye J, Wersäll P, Österborg A (1991) The therapeutic use of monoclonal antibodies in colorectal carcinoma. Semin Oncol 18: 462

    CAS  PubMed  Google Scholar 

  38. Neville AM, Gusterson BA (1985) Monoclonal antibodies and human tumours: Pathological and clinical aspects. Eur J Cancer Clin Oncol 21: 355

    Article  CAS  PubMed  Google Scholar 

  39. Ragnhammar P, Fagerberg J, Frödin J-E, Hjelm A-L, Lindemalm C, Magnusson I, Masucci G, Mellstedt H (1993) Effect of the monoclonal antibody 17-1A and GM-csf in patients with advanced colorectal carcinoma-long lasting, complete remissions can be induced. Int J Cancer 53: 751

    Article  CAS  PubMed  Google Scholar 

  40. Raychaudhuri S, Kang C-Y, Kaveri S-V, Kieber-Emmons T, Köhler H (1990) tumor idiotype vaccines. VII. Analysis and correlation of structural, idiotypic, and biologic properties of protective and nonprotective Ab2. J Immunol 145: 760

    Article  CAS  PubMed  Google Scholar 

  41. Robins RA, Denton GWL, Hardcastle JD, Austin EB, Baldwin RW, Durrant LG (1991) Antitumor immune response and interleukin-2 production induced in colorectal cancer patients by immunization with human monoclonal anti-idiotypic antibody. Cancer Res 51: 5425

    CAS  PubMed  Google Scholar 

  42. Sears HF, Mattis J, Herlyn D, Hayry P, Atkinson B, Ermst C, Steplewski Z, Koprowski H (1982) Phase I clinical trial of monoclonal antibody treatment of gastrointestinal tumors. Lancet 1: 762

    Article  CAS  PubMed  Google Scholar 

  43. Sears HF, Herlyn D, Steplewski Z, Koprowski H (1985) Phase II clinical trial of a murine monoclonal antibody cytotoxic for gastrointestinal adenocarcinoma. Cancer Res 45: 5910

    CAS  PubMed  Google Scholar 

  44. Shaw D, Khazaeli MB, Suu L, Ghrayeb J, Daddona P, McKinney S, Lobuglio A (1987) Characterization of a mouse/human chimeric monoclonal antibody (17-1A) to a colon cancer tumor-associated antigen. J Immunol 138: 4534

    Article  CAS  PubMed  Google Scholar 

  45. Steinitz M, Tamir S, Frödin J-E, Lefvert A-K, Mellstedt H (1988) Human monoclonal anti-idiotypic antibodies. I. Establishment of immortalized cell lines from a tumor patient treated with mouse monoclonal antibodies. J Immunol 141: 3516

    Article  CAS  PubMed  Google Scholar 

  46. Steinitz M, Tamir S, Frödin J-E, Mellstedt, H (1990) Human monoclonal anti-idiotypic antibodies against, a murine monoclonal antibody (mAb17-1A) as an anti-tumor vaccine. In: Borrebaeck CAK, Larrick JW (eds) Therapeutic monoclonal antibodies. Stockton Press, London, p 159

    Chapter  Google Scholar 

  47. Steplewski Z, Lubeck MD, Koprowski H (1983) Human macrophages armed with murine IgG2a anti-tumor immunoglobulins destroy human cancer cells. Science 221: 865

    Article  CAS  PubMed  Google Scholar 

  48. Strassburg CP, Kasai Y, Seng BA, Miniou P, Zaloudik J, Herlyn D, Koprowski H, Linnenbach AJ (1992) Baculovirus recombinant expressing a secreted form of a transmembrane carcinoma-associated antigen. Cancer Res 52: 815

    CAS  PubMed  Google Scholar 

  49. Sun L, Curtis P, Rabrowicz-Szulezyska E, Ghrayeb J, Morrison S, Chang N, Koprowski H (1986) Chimeric antibodies with 17-1A derived variable and human constant regions. Hybridoma 5: [Suppl 1]: 17

    Google Scholar 

  50. Szala S, Froehlich M, Scollon M, Kasai Y, Steplewski Z, Koprowski H, Linnenbach AJ (1990) Molecular cloning of cDNA for the carcinoma-associated antigen GA733-2. Proc Natl Acad Sci USA 87: 3542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Traub UC, DeJager RL, Primus FJ, Losman M, Goldenberg DM (1988) Anti-idiotype antibodies in cancer patients receiving monoclonal antibody to carcinoembryonic antigen. Cancer Res 48: 4002

    CAS  PubMed  Google Scholar 

  52. Trauth BC, Klas C, Peters AMJ, Matzku S, Möller P, Falk W, Debatin KM, Krummer PH (1989) Monoclonal antibody mediated tumor regression by induction of apoptosis. Science 245: 301

    Article  CAS  PubMed  Google Scholar 

  53. Waller M, Curry N, Mallory J (1968) Immunochemical and serological studies of enzymatically fractionated human IgG immunoglobulins. I. Hydrolysis with pepsin papain, ficin and bromelin. Immunochemistry 5: 577

    Article  CAS  PubMed  Google Scholar 

  54. Wettendorff M, Iliopoulos D, Tempero M, Kay D, DeFreitas E, Koprowski H, Herlyn D (1989) Idiotypic cascades in cancer patients treated with monoclonal antibody CO17-1A. Proc Natl Acad Sci USA 86: 3787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology (Radiumhemmet) and Immunological Research Laboratory, Karolinska Hospital, S-10401, Stockholm, Sweden

    J. Fagerberg, J. -E. Frödin, P. Ragnhammar & H. Mellstedt

  2. Department of Pathology, Hebrew University, Jerusalem, Israel

    M. Steinitz

  3. Department of Immunology, Karolinska Institute, Stockholm, Sweden

    H. Wigzell

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  1. J. Fagerberg
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  2. J. -E. Frödin
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  3. P. Ragnhammar
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  4. M. Steinitz
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  5. H. Wigzell
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  6. H. Mellstedt
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Fagerberg, J., Frödin, J.E., Ragnhammar, P. et al. Induction of an immune network cascade in cancer patients treated with monoclonal antibodies (ab1). Cancer Immunol Immunother 38, 149–159 (1994). https://doi.org/10.1007/BF01525635

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  • DOI: https://doi.org/10.1007/BF01525635

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