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. 1993 Nov;37(6):400–407. doi: 10.1007/BF01526797

Local antitumour treatment in carcinoma patients with bispecific-monoclonal-antibody-redirected T cells

B J Kroesen 1,✉, A ter Haar 1, H Spakman 1, P Willemse 2, D Th Sleijfer 2, E G E de Vries 2, N H Mulder 2, H H Berendsen 3, P C Limburg 1, T H The 1, L de Leij 1
PMCID: PMC11038386  PMID: 7902211

Abstract

In a pilot clinical study carcinoma patients with malignant ascites or pleural exudates have been treated locally with autologous lymphocytes activated ex vivo and redirected towards tumour cells with bispecific monoclonal antibodies. BIS-1, the bispecific monoclonal antibody used in this study, combines specificity against a tumour-associated antigen, AMOC-31, present on carcinomas, with a specificity against the CD3 complex on T lymphocytes. Patients selected for treatment had malignant pleural or peritoneal effusions. Treatment consisted of isolating autologous peripheral blood lymphocytes, ex vivo activation, incubation with bispecific monoclonal antibodies and injection at the effusion site of these BIS-1-redirected lymphocytes. To evaluate the effects of the bispecific monoclonal antibody, five patients received treatments with activated lymphocytes without bispecific antibodies. Effusion samples taken before and at various times after treatment were analysed by immunocytology and for the presence of the soluble factors carcinoembryonic antigen (CEA), interleukin-6 (IL-6), tumour necrosis factor (TNF), C-reactive protein and soluble CD8. In this way both immune activation and anti-tumour activity could be monitored. Conjugate formation between tumour cells and activated lymphocytes was seen as soon as 4 h after injection of BIS-1-redirected activated lymphocytes, followed by a disappearance or reduction of tumour cells after 24–48 h. In parallel with this, the soluble tumour marker CEA decreased in the effusion fluid following injection with the BIS-1-redirected lymphocytes. Furthermore, a steep increase in local granulocyte numbers was observed in the effusion fluid, which reached a maximum 24–48 h after the start of the treatment. Also levels of IL-6 and TNF were greatly elevated. The data suggest tha the treatment induces both antitumour activity and a strong local inflammatory reaction. This is accompanied by no or only minor local and systemic toxicity, i.e. mild fever, which disappeared as the local inflammatory reaction diminished 48–72 h after treatment.

Key words: Immunotherapy, Bispecific monoclonal antibodies, T cell targeting, Inflammation, T cell activation, Carcinoma

References

  • 1.Appelgate KG, Balch CM, Pellis NR. in vitro migration of lymphocytes through collagen matrix: arrested locomotion in tumorinfiltrating lymphocytes. Cancer Res. 1990;50:7153. [PubMed] [Google Scholar]
  • 2.Bolhuis RLH, Sturm E, Braakman E. T cell targeting in cancer therapy. Cancer Immunol Imunother. 1991;34:1. doi: 10.1007/BF01741317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Blakely DC, Thorpe PE. An overview of therapy with immunotoxins containing ricin or its A-chain. Antibody Immunocon Radiopharmacol. 1988;1:1. [Google Scholar]
  • 4.Braakman E, Goedegebuure PS, Vreugdenhil RJ, Segal DM, Shaw S, Bolhuis RLH. ICAM-1-melanoma cells are relatively resistant to CD3-mediated T-cell lysis. Int J Cancer. 1990;46:475. doi: 10.1002/ijc.2910460325. [DOI] [PubMed] [Google Scholar]
  • 5.Brissinck J, Demanet C, Moser M, Leo O, Thielemans K. Treatment of mice bearing BCL lymphoma with bispecific antibodies. J Immunol. 1991;147:4019. [PubMed] [Google Scholar]
  • 6.Ferrini S, Prigione I, Miotti S, Ciccone E, Cantoni C, Chen Q, Colnaghi MI, Moretta L. Bispecific monoclonal antibodies to CD and to a tumor associated antigen induce target-cell lysis by resting NK cells and by a subset of NK clones. Int J Cancer. 1991;48:227. doi: 10.1002/ijc.2910480213. [DOI] [PubMed] [Google Scholar]
  • 7.Garrido MA, Valdayo MJ, Winkler DF, Titus JA, Hecht TT, Perez P, Segal DM, Wunderlich JR. Refocussing the immune system to react with human tumors by targeting human lymphocytes with bispecific antibodies. Dev Biol Stand. 1990;71:33. [PubMed] [Google Scholar]
  • 8.Garrido MA, Perez P, Titus JA, Valdayo MJ, Winkler DF, Barbieri SA, Wunderlich JR, Segal DM. Targeted cytotoxic cells in human peripheral blood lymphocytes. J Immunol. 1990;144:2891. [PubMed] [Google Scholar]
  • 9.Helle M, Boeye L, de Groot E, de Vos A, Aarden L. Sensitive ELISA for I-6; detection of IL-6 in biological fluids, synovial fluids and sera. J Immunol Methods. 1991;138:47. doi: 10.1016/0022-1759(91)90063-l. [DOI] [PubMed] [Google Scholar]
  • 10.Herlyn M, Steplewski Z, Herlyn D, Koprowski H. Colorectal carcinoma-specific antigen: detection by means of monoclonal antibodies. Proc Natl Acad Sci USA. 1979;75:1438. doi: 10.1073/pnas.76.3.1438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Kerr L, Huntoon C, Donohue J, Leibson PJ, Bander NH, Ghose T, Luner SJ, Vessella R, McKean DJ. Hetero conjugate antibodydirected killing of autologous human renal carcinoma cells by in vitro-activated lymphocytes. J Immunol. 1990;144:4060. [PubMed] [Google Scholar]
  • 12.de Lau WBM, van Loon AE, Heije K, Valerio D, Bast EJEG. production of hybrid hybridomas based on HATs-neomycinr double mutants. J Immunol Methods. 1989;117:1. doi: 10.1016/0022-1759(89)90111-7. [DOI] [PubMed] [Google Scholar]
  • 13.de Leij L, Postmus PE, Poppema S, Elema JE, The TH. The use of monoclonal antibodies for the pathological diagnosis of lungcancer. In: Hansen HH, editor. Lung cancer: basic and clinical aspects. The Hague: Nijhof; 1986. p. 31. [Google Scholar]
  • 14.Mackay CR, Marston WL, Dudler L, Spertini O, Tedder TF, Hein WR. Tissue specific migration pathways by phenotipically distinct subpopulations of memory T cells. Eur J Immunol. 1992;22:887. doi: 10.1002/eji.1830220402. [DOI] [PubMed] [Google Scholar]
  • 15.Makgoba MW, Sanders ME, Shaw S. The CD2-LFA3 and LFA1-ICAM pathways: relevance to T-cell recognition. Immunol Today. 1989;10:417. doi: 10.1016/0167-5699(89)90039-X. [DOI] [PubMed] [Google Scholar]
  • 16.Mezzanzanica D, Canevari S, Colnaghi MI. Retargeting of human lymphocytes against human ovarian carcinoma cells by bispecific antibodies: from laboratory to clinic. Int J Clin Lab Res. 1991;21:159. doi: 10.1007/BF02591636. [DOI] [PubMed] [Google Scholar]
  • 17.Mezzanzanica D, Garido MA, Neblock DS, Daddona PE, Andrew SM, Zurawski VR, Segal DM, Wunderlich JR. Human T-lymphocytes targeted against an established human ovarian carcinoma with a bispecific F(ab')2 antibody prolong host survival in a murine xenograft model. Cancer Res. 1991;51:57. [PubMed] [Google Scholar]
  • 18.Milstein C, Cuello AC. Hybrid hybridomas and the production of bi-specific monoclonal antibodies. Immunol Today. 1984;5:299. doi: 10.1016/0167-5699(84)90155-5. [DOI] [PubMed] [Google Scholar]
  • 19.Nishimura T, Nakamura Y, Tsulamoto H, Takeuchi Y, Tokuda Y, Iwasawa M, Yamamoto T, Masuko T, Hashimoto Y, Habu S. Humanc-erbB-2 proto-ongogene product as a target for bispecificantibody directed adoptive tumor immunotherapy. Int J Cancer. 1992;50:800. doi: 10.1002/ijc.2910500523. [DOI] [PubMed] [Google Scholar]
  • 20.Nitta T, Sato K, Okumura K, Ishii S. Induction of cytotoxicity in human T cells coated with anti-glioma X anti-CD3 bispecific antibody against human glioma cells. J Neurosurg. 1990;72:476. doi: 10.3171/jns.1990.72.3.0476. [DOI] [PubMed] [Google Scholar]
  • 21.Nitta T, Sato K, Yagita H, Okumura K, Ishii S. Preliminary trial of specific targeting therapy against malignant glioma. Lancet. 1990;335:368. doi: 10.1016/0140-6736(90)90205-j. [DOI] [PubMed] [Google Scholar]
  • 22.Perez P, Titus JA, Lotze MT, Cuttitta F, Longo DL, Groves ES, Rabin H, Durda PJ, Segal DM. Specific lysis of human tumor cells by T cells coated with anti-T3 cross-linked to anti-tumor antibody. J Immunol. 1986;137:2069. [PubMed] [Google Scholar]
  • 23.Rivoltini L, Cattoretti G, Arienti F, Mastroianni A, Melani C, Colombo MP, Parmiani G. The high lysability by LAK cells of colon-carcinoma cells resistant to doxorubicin is associated with a high expression of ICAM-1, LFA-3, NCA and a less differentiated phenotype. Int J Cancer. 1991;47:746. doi: 10.1002/ijc.2910470521. [DOI] [PubMed] [Google Scholar]
  • 24.Roosnek EE, van Lier RA, Aarden LA. Two monoclonal anti-CD3 antibodies can induce different events in human T lymphocyte activation. Eur J Immunol. 1987;17:1507. doi: 10.1002/eji.1830171019. [DOI] [PubMed] [Google Scholar]
  • 25.Rosenberg SA, Lotze MT, Muul LM. A progess reprot on the treatment of 157 patients with advanced cancer using lymphokine activated killer cells and IL-2 or high dose IL-2 alone. N Engl J Med. 1987;316:889. doi: 10.1056/NEJM198704093161501. [DOI] [PubMed] [Google Scholar]
  • 26.Rosenberg SA, Schwarz SL, Spiess PJ. Combination immunotherapy for cancer: synergistic anti tumour interactions of interleukin-2, alfa interferon and tumour infiltrating lymphocytes. J Natl Cancer Inst. 1988;80:139. doi: 10.1093/jnci/80.17.1393. [DOI] [PubMed] [Google Scholar]
  • 27.Ségal DM, Qian JH, Andrew SM, Titus JA, Mezzanzanica D, Garrido MA, Wunderlich JR. Cytokine release by peripheral blood lymphocytes targeted with bispecific antibodies, and its role in blocking tumor growth. Ann NY Acad Sci. 1991;636:228. doi: 10.1111/j.1749-6632.1991.tb33459.x. [DOI] [PubMed] [Google Scholar]
  • 28.Shaw S, Luce GEG, Quinones R, Gress RE, Springer TA, Sanders ME. Two antigen-independent adhesion pathways used by human cytotoxic T-cell clones. Nature. 1986;323:262. doi: 10.1038/323262a0. [DOI] [PubMed] [Google Scholar]
  • 29.Shimizu Y, Newman W, Tanaka Y, Shaw S. Lymphocyte interactions with endothelial cells. Immunol Today. 1992;13:106. doi: 10.1016/0167-5699(92)90151-V. [DOI] [PubMed] [Google Scholar]
  • 30.Spits H, Schoten W, Keizer H, van Seventer G, van de Rijn M, Terhorst D, de Vries JE. Alloantigen recognition is preceded by non specific adhesion of cytotoxic T cells and target cells. Science. 1986;232:403. doi: 10.1126/science.3485822. [DOI] [PubMed] [Google Scholar]
  • 31.Spronk PE, ter Borg EJ, Limburg PC, Kallenberg CGM. Plasma concentration of IL-6 in systemic lupus erythematosus; an indicator of disease activity. Clin Exp Immunol. 1992;90:106. doi: 10.1111/j.1365-2249.1992.tb05840.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Spurr NK, Durbin H, Sheer D, Parkar M, Bobrow L, Bodmer WF. Characterization and chromosomal assignment of a human cell surface antigen defined by the monoclonal antibody AUA-I. Int J Cancer. 1986;38:631. doi: 10.1002/ijc.2910380503. [DOI] [PubMed] [Google Scholar]
  • 33.Stearz UD, Bevan MJ. Hybrid hybridoma producing a bispecific monoclonal antibody that can focus effector T-cell activity. Proc Natl Acad Sci USA. 1986;83:1453. doi: 10.1073/pnas.83.5.1453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Stearz UD, Kanagawa O, Bevan MJ. Hybrid antibodies can target sites for attack by T cells. Nature. 1985;31:628. doi: 10.1038/314628a0. [DOI] [PubMed] [Google Scholar]
  • 35.Stötter H, Wiebke EA, Tomita A, Belldegrun A, Topilian S, Rosenberg SA, Lotze MT. Cytokines alter target cell suseptibility to lysis. J Immunol. 1989;142:1767. [PubMed] [Google Scholar]
  • 36.Tax WJM, Reekers HW, Reekers PPM, Capel PJA, Koene RH. Polymorphism in mitogenic effect of IgG monoclonal antibodies against T3 antigen on human T-cell. Nature. 1983;304:445. doi: 10.1038/304445a0. [DOI] [PubMed] [Google Scholar]
  • 37.Tomita Y, Nishiyama T, Watanabe H, Fujiwara M, Sato S. Expression of intercellular adhesion molecule-I (ICAM-1) on renal-cell cancer: possible significance in host immune responses. Int J Cancer. 1990;46:1001. doi: 10.1002/ijc.2910460609. [DOI] [PubMed] [Google Scholar]
  • 38.Tomkinson BE, Brown MC, IP SH, Carabis S, Sullivan JL. Soluble CD8 during T cell activation. J Immunol. 1989;142:2230. [PubMed] [Google Scholar]
  • 39.van Wauwe JP, de Mey JR, Goosens JG. OKT3: a monoclonal anti-human T-lymphocyte antibody with potent mitogenic properties. J Immunol. 1980;124:2708. [PubMed] [Google Scholar]
  • 40.Weiner GJ, Hillstrom JR. Bispecific anti-idiotype/anti-CD3 antibody therapy of murine B cell lymphoma. J Immunol. 1991;147:4035. [PubMed] [Google Scholar]
  • 41.West WH, Tauer KW, Yannelli JR, Marshall GD, Orr DW, Thurman GB, Oldhan RK. Constant infusion interleukin 2 in adoptive immunotherapy of advanced cancer. N Engl J Med. 1987;3:898. doi: 10.1056/NEJM198704093161502. [DOI] [PubMed] [Google Scholar]
  • 42.Woo DV, Li D, Steplewski Z. Selective chromosomal damage and cytotoxicity of 125-I-labeled monoclonal antibody 17-1A in human cancer cells. Cancer Res. 1989;49:2952. [PubMed] [Google Scholar]

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