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Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin

Leukemia volume 14, pages 129–135 (2000)Cite this article

Abstract

The anti-CD25 immunotoxin RFT5.dgA was constructed by coupling the monoclonal antibody RFT5 via a sterically hindered disulfide linker to deglycosylated ricin A-chain and was administered to patients with relapsed Hodgkin's lymphoma in four bolus infusions over 7 days (day 1, 3, 5 and 7). The maximum tolerated dose in these patients as defined in a previous phase I study was 15 mg/m2. Subsequently, further patients were enrolled at the maximum tolerated dose and a total of 18 patients were treated at this level. All patients had signs of progressive disease and were heavily pretreated. Side-effects in this trial were moderate and related to vascular leak syndrome. Five of 18 patients experienced NCI grade III toxicities including weakness, edema, dyspnea, and myalgia. Eleven of 16 (69%) patients receiving two or more cycles produced human anti-ricin antibodies and human anti-mouse antibodies (⩾1.0 μg/ml). Seventeen of 18 patients were evaluable for clinical response. These included two partial remissions. One patient demonstrated minor response and five patients stable diseases. We conclude that RFT5.dgA is of moderate clinical efficacy in this group of heavily pretreated refractory patients.

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References

  1. De Vita VT, Molloy Hubbard S . Hodgkin's lymphoma New Engl J Med 1983 328: 560–565

    Google Scholar 

  2. Longo IL, Young RC, Wesley M . Twenty years of MOPP therapy for Hodgkin's lymphoma J Clin Oncol 1986 4: 1295–1306

    Article  CAS  PubMed  Google Scholar 

  3. Riethmüller G, Schneider-Gaedicke E, Schlimok G, Schmiegel W, Raab R, Hoeffken K, Gruber R, Pichlmaier H, Hirche H, Pichlmayr R, Buggisch P, Witte R and the German Cancer Aid . 17-1A Study Group. Randomized trial of monoclonal antibody for adjuvant therapy of resected Dukes'C colorectal carcinoma Lancet 1994 343: 1177–1183

    Article  PubMed  Google Scholar 

  4. Ro DC, Griffin JD, Belvin M, Blaettler WA, Lambert JM, Ritz J . Anti-My9-blocked ricin: an immunotoxin for selective targeting of acute myeloid leukemia cells Blood 1991 77: 2404–2412

    Google Scholar 

  5. Gribben JG, Freedman AS, Neuberg D, Roy DC, Blake KW, Woo SD, Grossbard ML, Rabinowe SN, Coral F, Freeman GJ, Ritz J, Nadler LM . Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma New Engl J Med 1991 325: 1525–1533

    Article  CAS  PubMed  Google Scholar 

  6. Kanzler H, Hansmann M-L, Kapp U, Wolf J, Diehl V, Rajewsky K, Kueppers R . Molecular single cell analysis demonstrates the derivation of a peripheral blood derived cell line (L1236) from the Hodgkin/Reed–Sternberg cells of a Hodgkin's lymphoma patient Blood 1996 87: 3429–3436

    CAS  PubMed  Google Scholar 

  7. Wolf J, Kapp U, Bohlen H, Kornacker M, Schoch C, Stahl B, Muecke S, von Kalle C, Fonatsch C, Schaefer HE, Hansmann M-L, Diehl V . Peripheral blood mononuclear cells of a patient with advanced Hodgkin's lymphoma give rise to permanently growing Hodgkin/Reed–Sternberg cells Blood 1996 87: 3418–3428

    CAS  PubMed  Google Scholar 

  8. Simonsson B . Treatment of minimal residual disease in acute myelogenous leukemia (AML): focus on immunotherapeutic options Leukemia 1996 10: (Suppl. 2) 44–52

    Google Scholar 

  9. Grossbard ML, Gribben JG, Freedman AS, Lambert J, Kinsella J, Rabinowe S, Eliseo L, Taylor J, Blatter W, Epstein C, Nadler L . Adjuvant immunotoxin therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with B-cell non-Hodgkin's lymphoma Blood 1993 81: 2263–2271

    CAS  PubMed  Google Scholar 

  10. Schnell R, Barth S, Diehl V, Engert A . Hodgkin's disease. Future treatment strategies: fact or fiction. In Diehl V (ed). Bailliéres Clinical Haematology Bailliére Tindall: London 1996 pp 573–593

    Google Scholar 

  11. Hsu SM, Jaffe ES . Leu M1 and peanut agglutinin stain the neoplastic cells of Hodgkin's lymphoma Am J Clin Pathol 1984 82: 29–32

    Article  CAS  PubMed  Google Scholar 

  12. Hsu SM, Ho YS, Hsu PL . Effect of monoclonal antibodies anti-2H9, anti-IRac, and anti-HeFi-1 on the surface antigens of Reed–Sternberg cells J Natl Cancer Inst 1987 79: 1091–1097

    CAS  PubMed  Google Scholar 

  13. Stein H, Mason DY, Gerdes J, O'Conner N, Wainscoat J, Pallesen G, Gatter K, Falini B, Delsol G, Lemke H, Schwarting R, Lennert K . The expression of the Hodgkin's-disease-associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Sternberg–Reed cells and histocytic malignancies are derived from activated lymphoid cells Blood 1985 66: 848–858

    CAS  PubMed  Google Scholar 

  14. Agnarsson BA, Kadin ME . The immunophenotype of Reed–Sternberg cells. A study of 50 cases of Hodgkin's lymphoma using fixed frozen tissue Cancer 1989 63: 2083–2087

    Article  CAS  PubMed  Google Scholar 

  15. Kennedy IC, Hart DN, Colls BM . Nodular sclerosing, mixed cellularity and lymphocyte-depleted variants of Hodgkin's lymphoma are probable dendritic cell malignancies Clin Exp Immunol 1989 76: 324–331

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Delabie J, Ceuppens JL, Vandenberghe P, de Boer M, Coorevits L, de Wolf-Peeters C . The B7/BB1 antigen is expressed by Reed–Sternberg cells of Hodgkin's lymphoma and contributes to the stimulating capacity of Hodgkin's lymphoma-derived cell lines Blood 1993 82: 2845–2852

    CAS  PubMed  Google Scholar 

  17. Barth S, Schnell R, Diehl V, Engert A . Development of immunotoxins for potential clinical use in Hodgkin's disease Ann Oncol 1996 7: (Suppl. 4) 135–141

    Article  PubMed  Google Scholar 

  18. Taniguchi T, Minami Y . The IL-2/IL-2 receptor system: a current overview Cell 1993 73: 5–8

    Article  CAS  PubMed  Google Scholar 

  19. Kreitman RJ, Pastan I . Recombinant single-chain immunotoxins against T and B cell leukemias Leuk Lymphoma 1994 13: 1–10

    CAS  PubMed  Google Scholar 

  20. Strauchen JA, Breakstone BA . IL-2 receptor expression in human lymphoid lesions. Immunohistochemical study of 166 cases Am J Pathol 1987 126: 506–512

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Engert A, Martin G, Amlot P, Wijdenes J, Diehl V, Thorpe P . Immunotoxins constructed with CD25 monoclonal antibodies and deglycosylated ricin A-chain have potent antitumor effects against human Hodgkin cells in vitro and solid Hodgkin tumors in mice Int J Cancer 1991 49: 450–456

    Article  CAS  PubMed  Google Scholar 

  22. Winkler U, Gottstein C, Schön G, Kapp U, Wolf J, Hansmann ML, Bohlen H, Thorpe P, Diehl V, Engert A . Successful treatment of disseminated human Hodgkin's disease in SCID mice with deglycosylated ricin A-chain immunotoxins Blood 1994 83: 466–475

    CAS  PubMed  Google Scholar 

  23. Engert A, Diehl V, Schnell R, Radszuhn A, Hatwig MT, Drillich S, Schön G, Bohlen H, Tesch H, Hansmann ML, Barth S, Schindler J, Ghetie V, Uhr J, Vitetta E . A phase I study of an anti-CD25 ricin A-chain immunotoxin (RFT5-SMPT-dgA) in patients with refractory Hodgkin's lymphoma Blood 1997 89: 403–410

    CAS  PubMed  Google Scholar 

  24. Thorpe PE, Wallace PM, Knowles PP, Relf MG, Browmn ANF, Watson GJ, Blakes DC, Newell DR . Improved antitumor effects of immunotoxins prepared with deglycosylated ricin A-chain and hindered disulfide linkages Cancer Res 1988 48: 6396–6403

    CAS  PubMed  Google Scholar 

  25. Simon R . Optimal two-stage designs for phase II clinical trials Control Clin Trials 1989 10: 1–10

    Article  CAS  PubMed  Google Scholar 

  26. Merz H, Malisius R, Mannweiler S, Zhou R, Hartmann W, Orscheschek K, Moubayed P, Feller AC . ImmunoMax. A maximized immunohistochemical method for the retrieval and enhancement of hidden antigens Lab Invest 1995 73: 149–156

    CAS  PubMed  Google Scholar 

  27. Sausville EA, Headlee D, Stetler-Stevenson M, Jaffe ES, Solomon D, Figg WD, Herdt J, Kopp WC, Rager H, Steinberg SM, Ghetie V, Schindler J, Uhr JW, Wittes RE, Vitetta ES . Continuous infusion of the anti-CD22 immunotoxin IgG-RFB4-SMPT-dgA in patients with B-cell lymphoma: a phase I study Blood 1995 85: 3457–3465

    CAS  PubMed  Google Scholar 

  28. Schumaker RC . A basic interactive complex program for statistical and pharmacokinetic analysis of data Drug Metab Rev 1986 17: 331–342

    Article  Google Scholar 

  29. Vitetta ES, Stone M, Amlot P, Fay J, May R, Till M, Newman J, Clark P, Collins R, Cunningham D, Ghetie V, Uhr J, Thorpe P . Phase-I immunotoxin trial in patients with B-cell lymphoma Cancer Res 1991 51: 4052–4058

    CAS  PubMed  Google Scholar 

  30. Amlot P, Stone MJ, Cunningham D, Fay J, Newman J, Collins R, May R, McCarthy M, Richardson J, Ghetie V, Ramillo O, Thorpe P, Uhr J, Vitetta ES . A phase I study of an anti-CD22-deglycosylated ricin A-chain immunotoxin in the treatment of B-cell lymphomas resistant to conventional therapy Blood 1993 82: 2624–2633

    CAS  PubMed  Google Scholar 

  31. Stone MJ, Sausville EA, Fay JW, Headlee D, Collins RH, Figg WD, Stetler-Stevenson M, Jain V, Jaffe ES, Solomon D, Lush RM, Senderowilz A, Ghetie V, Schindler J, Uhr JW, Vitetta ES . A phase I study of bolus vs. continuous infusion of the anti-CD19 immunotoxin, IgG-HL37-dgA in patients with B cell lymphoma Blood 1996 88: 1188–1197

    CAS  PubMed  Google Scholar 

  32. Vitetta ES, Thorpe PE, Uhr JW . Immunotoxins: magic bullets or misguided missiles? Immunol Today 1993 14: 252–259

    Article  CAS  PubMed  Google Scholar 

  33. Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, Grillo-Lopez A, Levy R . Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma Blood 1994 84: 2457–2466

    CAS  PubMed  Google Scholar 

  34. Mansfield E, Amlot P, Pastan I, FitzGerald DJ . Recombinant RFB4 immunotoxins exhibit potent cytotoxic activity for CD22-bearing cells and tumors Blood 1997 90: 2020–2026

    CAS  PubMed  Google Scholar 

  35. Woodard SL, Fraser SA, Winkler U, Jackson DS, Kam CM, Powers JC, Hudig D . Purification and characterization of lymphocyte chymase I, a granzyme implicated in perforin-mediated lysis J Immunol 1998 160: 4988–4993

    CAS  PubMed  Google Scholar 

  36. Kreitman RJ, Chaudhary VK, Kozak RW, FitzGerald DJP, Waldmann TA, Pastan I . Recombinant toxins containing the variable domains of the anti-tac monoclonal antibody to the interleukin-2 receptor kill malignant cells from patients with chronic lymphocytic leukemia Blood 1992 80: 2344–2352

    CAS  PubMed  Google Scholar 

  37. Kreitman RJ, Chaudhary VK, Waldmann TA, Hanchard B, Cranston B, FitzGerald DJP, Pastan I . Cytotoxic activities of recombinant immunotoxins composed of Pseudomonas toxin or Diphtheria toxin toward lymphocytes from patients with adult T cell leukemia Leukemia 1993 7: 553–562

    CAS  PubMed  Google Scholar 

  38. Foss FM, Borkowski TA, Gilliom M, Stetler-Stevenson MA, Jaffe ES, Figg WD, Tompkins A, Bastian A, Nylen P, Woodworth T, Udey MC, Sausville EA . Chimeric fusion protein toxin DAB486IL-2 in advanced mycosis fungoides and the Sezary syndrome: correlation of activity and interleukin-2 receptor expression in a phase II study Blood 1994 84: 1765–1774

    CAS  PubMed  Google Scholar 

  39. LeMaistre CF, Mansoor NS, Kuzel TM, Foss F, Platanias LC, Schwarzt G, Ratain M, Rook A, Freytes CO, Craig F, Reuben J, Nichols JC . Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2 Blood 1998 91: 399–405

    CAS  PubMed  Google Scholar 

  40. Williams DP, Parker K, Bacha P, Bishai W, Borowski M, Genbauffe F, Strom TB, Murphy JR . Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein Prot Eng 1987 1: 493–498

    Article  CAS  Google Scholar 

  41. LeMaistre CF, Craig FE, Meneghetti CM, McMullin B, Parker K, Reuben J, Boldt DH, Rosenblum M, Woodworth T . Phase-I trial of a 90-minute infusion of the fusion toxin DAB486IL-2 in hematological cancers Cancer Res 1993 53: 3930–3934

    CAS  PubMed  Google Scholar 

  42. LeMaistre CF, Meneghetti C, Rosenblum M, Reuben J, Parker K, Shaw J, Dieisseroth A, Woodworth T, Parkinson DR . Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor Blood 1992 79: 2547–2554

    CAS  PubMed  Google Scholar 

  43. Tepler I, Schwartz G, Parker K, Charette J, Kadin ME, Woodworth TG, Schnipper LE . Phase-I trial of an interleukin-2 fusion toxin (DAB486IL-2) in hematologic malignancies: complete response in a patient with Hodgkin's disease refractory to chemotherapy Cancer 1994 73: 1276–1285

    Article  CAS  PubMed  Google Scholar 

  44. Tazzari PL, Bolognesi A, de Totero D, Falini B, Lemoli RM, Soria MR, Pileri S, Gobbi M, Stein H, Flenghi L, Martelli MF, Stirpe F . Ber-H2 (anti-CD30)-saporin immunotoxin: a new tool for the treatment of Hodgkin's lymphoma and CD30+ lymphoma: in vitro evaluation Br J Haematol 1992 81: 203–211

    Article  CAS  PubMed  Google Scholar 

  45. Falini B, Bolognesi A, Flenghi L, Tazzari PL, Broe MK, Stein H, Dürkopp H . Response of refractory Hodgkin's lymphoma to monoclonal anti-CD30 immunotoxin Lancet 1992 339: 1195–1196

    Article  CAS  PubMed  Google Scholar 

  46. Falini B, Pasqualucci L, Flenghi L, Bologneri A, Kadin M, Stein H, Martinelli MF, Stirpe F . Anti-CD30 immunotoxins: experimental and clinical studies Abstracts of the Fourth International Symposium on Immunotoxins 1995 160A

  47. Engert A, Burrows F, Jung W, Tazzari PL, Stein H, Pfreundschuh M, Diehl V, Thorpe P . Evaluation of ricin A-chain-containing immunotoxins directed against the CD30 antigen as potential reagents for the treatment of Hodgkin's lymphoma Cancer Res 1990 50: 84–88

    CAS  PubMed  Google Scholar 

  48. Horn-Lohrens O, Tiemann M, Lange H, Kobarg J, Hafner M, Hansen H, Sterry W, Parwaresch RM, Lemke H . Shedding of the soluble form of CD30 from the Hodgkin-analogous cell line L540 is strongly inhibited by a new CD30-specific antibody (Ki-4) Int J Cancer 1995 60: 539–544

    Article  CAS  PubMed  Google Scholar 

  49. Schnell R, Linnartz C, Schön G, Katouzi A, Bohlen H, Horn-Lohrens O, Parwaresch R, Diehl V, Lemke H, Engert A . Development of new ricin A-chain immunotoxins with potent anti-tumor effects against human Hodgkin cells in vitro and disseminated Hodgkin tumors in SCID mice using high-affinity monoclonal antibodies directed against the CD30 antigen Int J Cancer 1995 63: 238–244

    Article  CAS  PubMed  Google Scholar 

  50. Engert A, Gottstein C, Bohlen H, Winkler U, Schön G, Manske O, Schnell R, Diehl V, Thorpe P . Cocktails of ricin A-chain immunotoxins against different antigens of Hodgkin and Sternberg–Reed cells have superior anti-tumor effects against H-RS cells in vitro and solid Hodgkin tumors in mice Int J Cancer 1995 63: 304–309

    Article  CAS  PubMed  Google Scholar 

  51. Katz FE, Janossy G, Cumber A, Ross W, Blacklock HA, Tax W, Thorpe PE . Elimination of T cells from human peripheral blood and bone marrow using a cocktail of three anti-T cell immunotoxins Br J Haematol 1987 67: 407–411

    Article  CAS  PubMed  Google Scholar 

  52. Ghetie MA, Tucker K, Richardson J, Uhr JW, Vitetta ES . The antitumor activity of an anti-CD 22 immunotoxin in SCID mice with disseminated Daudi lymphoma is enhanced by either an anti-CD19 antibody or an anti-CD19 immunotoxin Blood 1992 80: 2315–2320

    CAS  PubMed  Google Scholar 

  53. Hartmann F, Renner C, Jung W, Deisting C, Juwana M, Eichentopf B, Kloft M, Pfreundschuh M . Treatment of refractory Hodgkin's disease with an anti-CD16/CD30 bispecific antibody Blood 1997 89: 2042–2047

    CAS  PubMed  Google Scholar 

  54. Barth S, Engert A . Recombinant immunotoxins for the treatment of Hodgkin's lymphoma Leuk Lymphoma 1998 29: (Suppl. 1) O–10

    Google Scholar 

  55. Klimka A, Roovers RC, Barth S, Bot F, Engert A, Arends JW, Hoogenboom HR . Human anti-CD30 phage antibody by guided selection for imunotherapy of Hodgkin's lymphoma Leuk Lymphoma 1998 29: (Suppl. 1) P–112

    Google Scholar 

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Acknowledgements

This work was supported in part by the Deutsche Forschungsgemeinschaft, Grant Di 184/9–7, TP9, the Deutsche Krebshilfe Grant W 125/94/En2, National Institutes of Health Grants No. CA 28149 and CA 41081.

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  1. Klinik I fuer Innere Medizin, Universitaet zu Koeln, Koeln, Germany

    R Schnell, P Borchmann, S Barth, S Drillich, V Diehl & A Engert

  2. Cancer Immunobiology Center and Department of Microbiology, The University of Texas, Southwestern Medical Center, Dallas, Texas, USA

    E Vitetta, J Schindler & V Ghetie

  3. Institut fuer Pathologie, Universitaet zu Koeln, Koeln, Germany

    K Hell

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Schnell, R., Vitetta, E., Schindler, J. et al. Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin. Leukemia 14, 129–135 (2000). https://doi.org/10.1038/sj.leu.2401626

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