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Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1995 Jan;40(1):37–47. doi: 10.1007/BF01517234

Treatment of low-grade non-Hodgkin's lymphoma with continuous infusion of low-dose recombinant interleukin-2 in combination with the B-cell-specific monoclonal antibody CLB-CD19

L Tom Vlasveld 1,1, Annemarie Hekman 3, Florry A Vyth-Dreese 3, Cornelis J M Melief 3, Johan J Sein 3, Arie C Voordouw 3, Trees A M Dellemijn 3, Elaine M Rankin 3,
PMCID: PMC11037856  PMID: 7530170

Abstract

Seven patients with low-grade non-Hodgkin's lymphoma were treated with a combination of a murine monoclonal antibody directed against the B-cell-specific antigen CD19 (CLB-CD10), given twice weekly, and continuous infusion of low-dose recombinant interleukin-2 (rIL-2). We demonstrated stable serum CLB-CD19 levels throughout the 12 weeks of treatment, and homing of the antibody into the tumour sites. A variable degree of antigenic modulation was noted. Prolonged treatment resulted in a sustained increase in the number of natural killer cells in the circulation with enhanced cytotoxic capacity, including antibody-dependent cellular cytotoxicity. During the first weeks of treatment, T cell activation occurred in the majority of patients. Toxicity was related to the rIL-2 treatment and consisted of transient constitutional symptoms and a flu-like syndrome without organ dysfunction. A partial remission occurred in one patient, and in another patient who was primarily leukaemic a greater than 50% reduction of circulating B cells was noted. An antitumour effect occurred early during treatment and could not be related to rIL-2-induced modulation of natural killer cell or T lymphocyte activation.

Key words: Interleukin-2, Anti-CD19 antibody, Monoclonal therapy

References

  • 1.Allison MAK, Jones SE, McGuffy P. Phase II trial of outpatient interleukin-2 in malignant lymphoma, chronic lymphocytic leukemia, and selected solid tumors. J Clin Oncol. 1989;7:75. doi: 10.1200/JCO.1989.7.1.75. [DOI] [PubMed] [Google Scholar]
  • 2.Bajorin DF, Chapman PB, Wong G, Coit DG, Kunicka J, Dimaggio J, Cordon-Cardo C, Urmacher C, Dantes L, Templeton MA, Liu J, Oettgen HF, Houghton AN. Phase I evaluation of a combination of monclonal antibody R24 and interleukin 2 in patients with metastatic melanoma. Cancer Res. 1990;50:7490. [PubMed] [Google Scholar]
  • 3.Berinstein N, Levy R. Treatment of a murine B cell lymphoma with monoclonal antibodies and IL-2. J Immunol. 1987;139:971. [PubMed] [Google Scholar]
  • 4.Berinstein N, Starnes CO, Levy R. Specific enhancement of the therapeutic effect of anti-idiotype antibodies on a murine B cell lymphoma by IL-2. J Immunol. 1988;140:2839. [PubMed] [Google Scholar]
  • 5.Bernstein ZP, Vaickus L, Friedman N, Goldrosen MH, Watanabe H, Rahman R, Arbuck SG, Sweeney J, Vesper D, Henderson ED, Zeffren J, Dennin RA, Levitt D, Foon KA. Interleukin-2 lymphokine-activated killer cell therapy of non-Hodgkin's lymphoma and Hodgkin's disease. J Immunother. 1991;10:141. doi: 10.1097/00002371-199104000-00008. [DOI] [PubMed] [Google Scholar]
  • 6.Blottiere HM, Douillard J-Y, Koprowski H, Steplewski Z. Humoral and cellular responses of colorectal patients treated with monoclonal antibodies and interferon-γ. Cancer Immunol Immunother. 1990;32:29. doi: 10.1007/BF01741721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Brown SL, Miller RA, Horning SJ, Czerwinsky D, Hart SM, McElderry R, Basham T, Warnke RA, Merigan TC, Levy R. Treatment of B-cell lymphomas with anti-idiotype antibodies alone or in combination with alpha interferon. Blood. 1989;73:651. [PubMed] [Google Scholar]
  • 8.Caligiuri MA, Murray C, Soiffer RJ, Klumpp TR, Seiden M, Cochran K, Cameron C, Ish C, Buchanan L, Perillo D, Smith K, Ritz J. Extended continuous infusion low-dose recombinant interleukin-2 in advanced cancer: prolonged immunomodulation without significant toxicity. J Clin Oncol. 1991;9:2110. doi: 10.1200/JCO.1991.9.12.2110. [DOI] [PubMed] [Google Scholar]
  • 9.Caligiuri MA, Murray C, Robertson MJ, Wang E, Cochran K, Cameron C, Schow P, Ross ME, Klumpp TR, Soiffer RJ, Smith KA, Ritz J. Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. J Clin Invest. 1993;91:123. doi: 10.1172/JCI116161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.De Rie MA, Schumacher TNM, Van Schijndel GMW, Van Lier RAW, Miedema F. Regulatory role of CD19 molecules in B-cell activation and differentiation. Cell Immunol. 1989;118:368. doi: 10.1016/0008-8749(89)90385-7. [DOI] [PubMed] [Google Scholar]
  • 11.Dillmann RO. Monoclonal antibodies for treating cancer. Ann Intern Med. 1989;111:592. doi: 10.7326/0003-4819-111-7-592. [DOI] [PubMed] [Google Scholar]
  • 12.Duggan DB, Santarelli MT, Zamkoff K, Lichtman S, Ellerton J, Cooper R, Poies B, Anderson JR, Bloomfield CD, Peterson BA, Gottlieb AJ. A phase II study of recombinant interleukin-2 with or without recombinant interferon-β in non-Hodgkin's lymphoma. A study of the Cancer and Leukemia Group B. J Immunother. 1992;12:115. doi: 10.1097/00002371-199208000-00006. [DOI] [PubMed] [Google Scholar]
  • 13.Gottlieb DJ, Prentice HG, Heslop HE, Bello C, Brenner MK. IL-2 infusion abrogates humoral immune responses in humans. Clin Exp Immunol. 1992;87:493. doi: 10.1111/j.1365-2249.1992.tb03025.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Grossbard ML, Freedman AS, Ritz J, Coral F, Goldmacher VS, Eliseo L, Spector N, Dear K, Lambert JM, Blättler WA, Taylor JA, Nadler LM. Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: a phase I trial of daily bolus infusion. Blood. 1992;79:576. [PubMed] [Google Scholar]
  • 15.Grossbard ML, Press OW, Appelbaum FR, Bernstein ID, Nadler LM. Monoclonal antibody-based therapies of leukemia and lymphoma. Blood. 1992;80:863. [PubMed] [Google Scholar]
  • 16.Hekman A, Honselaar A, Vuist WMJ, Sein JJ, Rodenhuis S, Ten Bokkel Huinink WW, Somers R, Rümke P, Melief CJM. Initial experience with treatment of human B cell lymphoma with anti-CD19 monoclonal antibody. Cancer Immunol Immunother. 1991;32:364. doi: 10.1007/BF01741331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Hu F, Epstein A, Naeve GS, Gill I, Martin S, Sherrod A, Nichols P, Chen D, Mazumder A, Levine AM. A phase la clinical trial of Lym-1 monoclonal antibody serotherapy in patients with refractory B cell malignancies. Hematol Oncol. 1989;7:155. doi: 10.1002/hon.2900070207. [DOI] [PubMed] [Google Scholar]
  • 18.Klempner MS, Noring R, Mier JW, Atkins B. An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy. N Engl J Med. 1990;322:959. doi: 10.1056/NEJM199004053221404. [DOI] [PubMed] [Google Scholar]
  • 19.Kosmas C, Epenetos AA, Courtenay-Luck NS. Patients receiving murine monoclonal antibody therapy for malignancy develop T cells that proliferate in vitro in response to these antibodies targets. J Exp Med. 1991;167:345. doi: 10.1038/bjc.1991.337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Levy R, Miller RA. Therapy of lymphoma directed at idiotypes. J Natl Cancer Inst Monogr. 1990;10:61. [PubMed] [Google Scholar]
  • 22.Lim SH, Giles FJ, Smith MP, Goldstone AH. Bacterial infections in lymphoma patients treated with recombinant interleukin-2. Acta Haematol. 1991;85:135. doi: 10.1159/000204875. [DOI] [PubMed] [Google Scholar]
  • 23.Margolin KA, Aronson FR, Sznol M, Atkins MB, Ciobaum N, Fisher RI, Weiss GR, Doroshow JH, Bar MH, Hawkins MJ, Mier JW, Paietta E, Gaynor EP, Boldt DH. Phase II trial of high-dose interleukin-2 and lymphokine-activated killer cells in Hodgkin's disease and non-Hodgkin's lymphoma. J Immunother. 1991;10:214. doi: 10.1097/00002371-199106000-00008. [DOI] [PubMed] [Google Scholar]
  • 24.Meeker TC, Lowder J, Maloney DG, Miller RA, Thielemans K, Warnke R, Levy R. A clinical trial of anti-idiotype therapy for B cell malignancy. Blood. 1985;65:1349. [PubMed] [Google Scholar]
  • 25.Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207. doi: 10.1002/1097-0142(19810101)47:1<207::aid-cncr2820470134>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  • 26.Munn DH, Cheung N-KV. Interleukin-2 enhancement of monoclonal antibody-mediated cellular cytotoxicity against human melanoma. Cancer Res. 1987;47:6600. [PubMed] [Google Scholar]
  • 27.Non-Hodgkin's lymphoma pathologic classification project National Cancer Institute sponsored study of classfication of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. Cancer. 1982;49:2112. doi: 10.1002/1097-0142(19820515)49:10<2112::aid-cncr2820491024>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  • 28.Ortaldo JR, Woodhouse C, Morgan AC, Herberman RB, Cheresh DA, Reisfeld R. Analysis of effector cells in human antibody dependent cellular cytotoxicity with murine monoclonal antibodies. J Immunol. 1987;381:3566. [PubMed] [Google Scholar]
  • 29.Pezzutto A, Dörken B, Rabinovitch PS, Ledbetter JA, Moldenhauer G, Clark EA. CD19 monoclonal antibody HD37 inhibits anti-immunoglobulin-induced B cell activation and proliferation. J Immunol. 1987;138:2793. [PubMed] [Google Scholar]
  • 30.Press OW, Appelbaum F, Ledbetter JA, Marin PJ, Zarlin J, Kidd P, Thomas ED. Monoclonal antibody IF5 [anti-CD20] serotherapy of human B cell lymphomas. Blood. 1987;69:584. [PubMed] [Google Scholar]
  • 31.Press OW, Eary JF, Badger CC, Martin PJ, Appelbaum FR, Levy R, Miller R, Brown S, Nelp WB, Krohn KA, Fisher D, DeSanted K, Porter B, Kidd P, Thomas ED. Treatment of refractory non-Hodgkin's lymphoma with radiolabeled MB-1 (anti-CD37) antibody. J Clin Oncol. 1989;7:1027. doi: 10.1200/JCO.1989.7.8.1027. [DOI] [PubMed] [Google Scholar]
  • 32.Press OW, Farr AG, Borroz KI, Anderson SK, Martin PJ. Endocytosis and degradation of monoclonal antibodies targeting human B-cell malignancies. Cancer Res. 1989;49:4906. [PubMed] [Google Scholar]
  • 33.Pross HF, Baines MG, Rubin P, Shragge P, Patterson MS. Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity. J Clin Immunol. 1981;1:51. doi: 10.1007/BF00915477. [DOI] [PubMed] [Google Scholar]
  • 34.Ritz J, Pesando JM, Sallan SE, Clawell LA, Notis-McConarty J, Rosenthal P, Schlossman SF. Serotherapy of acute lymphoblastic leukemia with monoclonal antibody. Blood. 1981;58:141. [PubMed] [Google Scholar]
  • 35.Sanda MG, Bolton E, Mulé JJ, Rosenberg SA. In vivo administration of recombinant macrophage colony-stimulating factor induces macrophage-mediated antibody-dependent cytotoxicity of tumor cells. J Immunother. 1992;12:132. doi: 10.1097/00002371-199208000-00008. [DOI] [PubMed] [Google Scholar]
  • 36.Scheinberg DA. Current applications of monoclonal antibodies for the therapy of hematopoietic cancers. Curr Opin Immunol. 1991;3:679. doi: 10.1016/0952-7915(91)90096-j. [DOI] [PubMed] [Google Scholar]
  • 37.Scheinberg DA, Straus DJ, Yeh SD, Divgi C, Garin-Chesa P, Graham M, Pentlow K, Coit D, Oettgen HF, Old LJ. A phase I toxicity, pharmacology, and dosimetry trial of monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma: effects of tumor burden and antigen expression. J Clin Oncol. 1990;8:792. doi: 10.1200/JCO.1990.8.5.792. [DOI] [PubMed] [Google Scholar]
  • 38.Soiffer RJ, Murray C, Cochran K, Cameron C, Wang E, Schow PW, Daley JF, Ritz J. Clinical and immunologic effects of prolonged infusion of low-dose recombinant interleukin-2 after autologous and T-cell-depleted allogeneic bone marrow transplantation. Blood. 1992;79:517. [PubMed] [Google Scholar]
  • 39.Tourani J-M, Levy V, Briere J, Levy R, Franks C, Andrieu J-M. Interleukin-2 therapy for refractory and relapsing lymphomas. Eur J Cancer. 1991;27:1676. doi: 10.1016/0277-5379(91)90444-i. [DOI] [PubMed] [Google Scholar]
  • 40.Uckun FM, Jascz W, Ambrus JL, Fauci AS, Gajl-Pecszalska K, Song CW, Wick MR, Myers DE, Waddick K, Ledbetter JA. Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins. Blood. 1988;71:13. [PubMed] [Google Scholar]
  • 41.Vaickus L, Biddle W, Cemerlik D, Foon KA. Interferon gamma augments Lym-1 dependent granulocyte-mediated tumor cell lysis. Blood. 1990;75:2408. [PubMed] [Google Scholar]
  • 42.Van Endert PM, Heilig B, Hämmerling G, Moldenhauer G. Monoclonal antibodies to idiotype inhibit in vitro growth of human-B-cell lymphomas. Blood. 1992;79:129. [PubMed] [Google Scholar]
  • 43.Vlasveld LT, Rankin EM, Hekman A, Rodenhuis S, Beijnen JH, Hilton AM, Dubbelman AC, Vyth-Dreese FA, Melief CJM. A phase I study of prolonged continuous infusion of low dose recombinant interleukin-2 in melanoma and renal cell cancer. Part I clinical aspects. Br J Cancer. 1992;65:744. doi: 10.1038/bjc.1992.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Vlasveld LT, Hekman A, Vyth-Dreese FA, Rankin EM, Scharenberg JGM, Voordouw AC, Sein JJ, Dellemijn TAM, Rodenshuis S, Melief CJM. A phase I study of prolonged continuous infusion of low dose recombinant interleukin-2 in melanoma and renal cell cancer. Part II: immunologic aspects. Br. J Cancer. 1993;68:559. doi: 10.1038/bjc.1993.386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Vuist WMJ, Van Buitenen F, De Rie MA, Hekman A, Rümke P, Melief CJM. Potentiation by interleukin 2 of Burkintt's lymphoma therapy with anti-pan B (anti-CD19) monoclonal antibody in a mouse xenotransplantation model. Cancer Res. 1988;49:3783. [PubMed] [Google Scholar]
  • 46.Vyth-Dreese FA, Van der Reijden HJ, De Vries JE. Phorbol-ester-mediated induction and augmentation of mitogenesis and interleukin-2 production in human T-cell lymphoproliferative disease. Blood. 1982;60:1437. [PubMed] [Google Scholar]
  • 47.Weber JS, Yang JC, Topalian SL, Schwartzentruber DJ, White DE, Rosenberg SA. The use of interleukin-2 and lymphokine-activated killer cells for the treatment of patients with non-Hodgkin's lymphoma. J Clin Oncol. 1992;10:33. doi: 10.1200/JCO.1992.10.1.33. [DOI] [PubMed] [Google Scholar]
  • 48.Ziegler LD, Palazzolo P, Cunningham J, Janus M, Itoh K, Hayakawa K, Hellström I, Hellström KE, Nicaise C, Dennin R, Murray JL. Phase 1 trial of murine monoclonal antibody L6 in combination with subcutaneous interleukin-2 in patients with advanced carcinoma of the breast, colorectum, and lung. J Clin Oncol. 1992;10:1470. doi: 10.1200/JCO.1992.10.9.1470. [DOI] [PubMed] [Google Scholar]
  • 49.Zola H. The surface antigens of human B lymphocytes. Immunol Today. 1987;8:308. doi: 10.1016/0167-5699(87)90018-1. [DOI] [PubMed] [Google Scholar]

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