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

I. May induction of ab1-reactive T cells and anti-anti-idiotypic antibodies (ab3) lead to tumor regression after mAb therapy?

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

Abstract

The antitumor effector functions of unconjugated monoclonal antibodies in cancer therapy are complex. 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 T cell (T2 and T3 respectively) responses have also been proposed to be of clinical importance. In this study induction of an immune network cascade in patients with colorectal carcinoma, treated with mAb 17-1A (ab1) was assessed. All patients developed anti-idiotypic antibodies (ab2) of the IgG class after treatment with ab1 and four of nine patients showed induction of mouse Ig reactive T cells [a proliferative response to F(ab′)2 fragments of ab1]. Patients with such a T cell response developed anti-anti-idiotypic antibodies (ab3), while those lacking the T cell reactivity failed to mount an ab3 response. Three of four patients with a T cell response achieved a tumor response to mAb therapy. Thus, all responding patients belonged to the group of individuals developing ab3. Induction of mAb(ab1)-reactive T cells as well as an immune network cascade might be important antitumor effector functions 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

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  3. 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 comparision to the sequence of the external antigen. Proc Natl Acad Sci USA 83: 6578

    PubMed  Google Scholar 

  4. Bruggen van der P, Traversari C, Chomez P, Lurquin C, Plaen de E, Eynde van den B, Knuth A, Boon T (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254: 1643

    PubMed  Google Scholar 

  5. Cheung NKV, 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

    PubMed  Google Scholar 

  6. Cleave van VH, 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

    PubMed  Google Scholar 

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

    Google Scholar 

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

    PubMed  Google Scholar 

  9. Frödin JE, Pihlstedt P, Lefvert AK, 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

    PubMed  Google Scholar 

  10. Frödin JE, Harmenberg U, Biberfeld P, Christensson B, Lefvert AK, Rieger Å, Shetye J, Wahren B, Mellstedt H (1988) Clinical effects of monoclonal antibodies (MAb 17-1A) in patients with metastatic colorectal carcinoma. Hybridoma 7: 309

    PubMed  Google Scholar 

  11. Frödin JE, Faxas ME, Hagström B, Lefvert AK, Masucci G, Nilsson B, Steinitz M, Unger P, Mellstedt H (1991) Induction of anti-idio-typic (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

    PubMed  Google Scholar 

  12. 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

    PubMed  Google Scholar 

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

    Google Scholar 

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

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  16. 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

    PubMed  Google Scholar 

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

    Google Scholar 

  18. Herlyn DM, 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

    PubMed  Google Scholar 

  19. 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 6D3 ganglioside: a phase I trial in patients with malignant melanoma. Proc Natl Acad Sci USA 82: 1242

    PubMed  Google Scholar 

  20. Irie 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

    PubMed  Google Scholar 

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

    Google Scholar 

  22. 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

    PubMed  Google Scholar 

  23. 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

    PubMed  Google Scholar 

  24. Kosmas C, Epenetos AA, Courtenay-Luck NS (1991) Patients receiving murine monoclonal antibody therapy for malignancy develop T cells that proliferate in vitro in response to these antibodies as antigens. Br J Cancer 64: 492

    Google Scholar 

  25. 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. J Exp Med 167: 345

    PubMed  Google Scholar 

  26. 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

    PubMed  Google Scholar 

  27. Lindemalm C, Mellstedt H, Biberfeld P, Björkholm M, Christensson B, Holm G, Johansson B, Sundblad R (1983) Blood and lymph node T lymphocyte subsets in non-Hodgkin lymphomas. Scand J Heamatol 30: 68

    Google Scholar 

  28. LoBuglio AF, Saleh 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 80: 932

    PubMed  Google Scholar 

  29. Mellstedt H, Holm G (1973) In vitro studies of lymphocytes from patients with plasma cell myeloma. I. Stimulation by mitogens and cytotoxic activities. Clin Exp Immunol 15: 309

    PubMed  Google Scholar 

  30. Mellstedt H, Frödin JE, Biberfeld P, Fagerberg J, Giscombe R, Hernandez A, Masucci G, Li SL, 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

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  33. 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

    PubMed  Google Scholar 

  34. 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 I: 762

    Google Scholar 

  35. 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

    PubMed  Google Scholar 

  36. Shaw D, Khazaeli MB, Suu L, Ghrayeb J, Dadonna 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

    PubMed  Google Scholar 

  37. Steinitz M, Tamir S, Frödin JE, Lefvert AK, 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

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  39. Steplweski Z, Blaszezyle M, Herlyn D, Herlyn M, Koprowski H (1985) Effector cells in ADCC with antibreast cancer monoclonal antibodies: In. Monoclonal antibodies and breast cancer. Nijhoff, Boston, p 134

    Google Scholar 

  40. 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 

  41. 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

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  43. 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

    PubMed  Google Scholar 

  44. 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

    PubMed  Google Scholar 

  45. Woo DV, Li D, Mattis JA, Steplewski Z (1989) Selective chromosomal damage and cytotoxicitiy of125I-labeled monoclonal antibody 17-1a in human cancer cells. Cancer Res 49: 2952

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology (Radiumhemmet) & Immunological Research Laboratory, Karolinska Hospital, S-104 01, Stockholm, Sweden

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

  2. 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. H. Wigzell
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  4. H. Mellstedt
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Fagerberg, J., Frödin, JE., Wigzell, H. et al. Induction of an immune network cascade in cancer patients treated with monoclonal antibodies (ab1). Cancer Immunol Immunother 37, 264–270 (1993). https://doi.org/10.1007/BF01518521

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  • DOI: https://doi.org/10.1007/BF01518521

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