Skip to main content
NCBI home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1995 Nov;40(6):390–396. doi: 10.1007/BF01525390

CD8 T cell activation after intravenous administration of CD3×CD19 bispecific antibody in patients with non-Hodgkin lymphoma

Gijsbert C de Gast 1,✉, Inez-Anne Haagen 1, Anja A van Houten 2, Sigrid C Klein 3, Ashley J Duits 1, Roel A de Weger 3, Thea M Vroom 3, Mike R Clark 4, Jenny Phillips 4, Anette J G van Dijk 1, Wim B M de Lau 1, Bert J E G Bast 1
PMCID: PMC11037599  PMID: 7543021

Abstract

A bispecific antibody directed to T and B cells (CD3×CD19 bsAb) was daily infused intravenously in escalating doses from 10 μg up to 5 mg in three patients with chemotherapy-resistant non-Hodgkin lymphoma; in this way we aimed to activate T cells to kill the malignant B cells. Only limited toxicity was observed, consisting of moderate fever preceded by chills or shivers and mild thrombocytopenia. No human anti-(mouse Ig) antibodies were found. Pharmacokinetics showed at 1/2 of 10.5 h with peak levels of 200–300 ng/ml after infusion of 2.5 mg bsAb. bsAb in serum was functionally active in vitro. After bsAb infusion a rise in serum tumour necrosis factor α was observed, accompanied by an increase in soluble CD8 and to some extent in soluble interleukin-2 receptor (IL-2R), but not in interferon γ, IL-4 or soluble CD4. No evidence was found for monocyte activation (no increases in IL-6, IL-8 or IL-1ß in serum). No gross changess in histology or number of IL-2R+, CD4+ or CD8+ cells were found in the lymph nodes after therapy, but one patient showed activated CD8+ T cells within the tumour nodules. In conclusion, after intravenously administered CD3×CD19 bsAb only moderate toxicity was found, probably due to CD8+ T cell activation and cytokine release, without CD4+ T cell activation.

Key words: Bispecific antibody, Cytokines, Phase I study, Non-Hodgkin lymphoma, T cell activation

References

  • 1.Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993;328:1002. doi: 10.1056/NEJM199304083281404. [DOI] [PubMed] [Google Scholar]
  • 2.Segal DM, Qian JH, Mezzanzanica D, Garrido MA, Titus JA, George AJT, Jost CR, Perez P, Wunderlich JR. Targeting of anti-tumor responses with Bispecific antibodies. Immunobiology. 1992;185:390. doi: 10.1016/S0171-2985(11)80655-8. [DOI] [PubMed] [Google Scholar]
  • 3.Beun GDM, van de Velde CJH, Fleuren GJ. T-cell based cancer immunotherapy: direct or redirect tumor-cell recognition. Immunol Today. 1994;15:11. doi: 10.1016/0167-5699(94)90019-1. [DOI] [PubMed] [Google Scholar]
  • 4.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]
  • 5.Bolhuis RLH, Lamers CHJ, Goey SH, Eggermont AMM, Trimbos JBMZ, Stoter G, Lanzavecchia A, de Re E, Miotti S, Raspagliesi F, Rivoltini L, Colnaghi MI. Adoptive immunotherapy of ovarian carcinoma with Bs-Mab-targeted lymphocytes: a multi-center study. Int J Cancer. 1992;Suppl 7:78. [PubMed] [Google Scholar]
  • 6.Tibben JG, Boerman OC, Claessens RAMJ. Cytokine release in an ovarian carcinoma patient following intravenous administration of bispecific antibody OC/TR F(ab)2 . J Natl Cancer Inst. 1993;85:1003. doi: 10.1093/jnci/85.12.1003. [DOI] [PubMed] [Google Scholar]
  • 7.Uckun FM, Ledbetter JA. Immunobiologic differences between normal and leukemic human B-cell precursors. Proc Natl Ac Sci USA. 1988;85:8603. doi: 10.1073/pnas.85.22.8603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Haagen IA, van de Griend R, Clark M, Geerars A, Bast B, de Gast GC. Killing of human leukaemia/lymphoma B cells by activated cytotoxic T lymphocytes in the presence of a bispecific monoclonal antibody (αCD3/αCD19) Clin Exp Immunol. 1992;90:368. doi: 10.1111/j.1365-2249.1992.tb05853.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Haagen IA, Geerars AJ, de Lau WB, Clark MR, van de Griend RJ, Bast BJEG, de Gast GC. Killing of autologous Blineage malignancy using CD3×CD19 bispecific monoclonal antibody in end stage leukemia and lymphoma. Blood. 1994;84:556. [PubMed] [Google Scholar]
  • 10.Haagen IA, de Lau WBM, Bast BJEG, Geerars AJG, Clark MR, de GAst GC. Unprimed CD4+ and CD8+ T cells can be rapidly activated by a CD3×CD19 bispecific antibody to proliferate and become cytotoxic. Cancer Immunol Immunother. 1994;39:391. doi: 10.1007/BF01534426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Demanet C, Brissinck J, Mechelen Mv, Loe O, Thielemans K. Treatment of murine B cell lymphoma with bispecific monoclonal antibodies (anit-idiotype×anti-CD3) J Immunol. 1991;147:1091. [PubMed] [Google Scholar]
  • 12.Brissinck J, Demanet C, Moser M, Leo O, Thielemans K. Treatment of mice bearing BCL1 lymphoma with bispecific antibodies. J Immunol. 1991;147:4019–4026. [PubMed] [Google Scholar]
  • 13.Weiner GJ, Hillstrom JR. Bispecific anti-idiotype/anti-CD3 antibody therapy of murine B cell lymphoma. J Immunol. 1991;147:4035. [PubMed] [Google Scholar]
  • 14.Clark MR, Waldmann H. T-cell killing of target cells induced by hybrid antibodies: comparison of two bispecific monoclonal antibodies. J Natl Cancer Inst. 1987;79:1393. [PubMed] [Google Scholar]
  • 15.Clark MR, Bindon C, Dyer M, Friend P, Hale G, Cobbold R, Calne H, Waldmann H. The improved lytic function and in vivo efficacy of monovalent monoclonal CD3 antibodies. Eur J Immunol. 1989;19:381. doi: 10.1002/eji.1830190224. [DOI] [PubMed] [Google Scholar]
  • 16.Vroom TM, Scholte G, Ossendorp F, Borst J. Tissue distribution of human λδ T cells: no evidence for general epithelial tropism. J Clin Pathol. 1991;44:1012. doi: 10.1136/jcp.44.12.1012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Hekman A, Honselaar A, Vuist WMJ, Sein JJ, Rodenhuis S, ten Bokkel Huinink WW, Somers R, Rumke Ph, 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]
  • 18.Tomkinson BE, Brown MC, Ip SH, Carrabis S, Sullivan JL. Soluble CD8 during T cell activation. J Immunol. 1989;142:224. [PubMed] [Google Scholar]
  • 19.Norment AM, Lonberg N, Lacy E, Littman DR. Alternatively spliced mRNA encodes a secreted form of human CD8a. Characterization of the human CD8a gene. J Immunol. 1989;142:3312. [PubMed] [Google Scholar]
  • 20.Robb RJ, Kutny RM. Structure function relationships for the IL-2 receptor system. IV. Analysis of the sequence and ligand-binding properties of soluble Tac protein. J Immunol. 1987;139:855. [PubMed] [Google Scholar]
  • 21.Huizinga TWG, Van der Schoot CE, Jost C, Klaassen R, Kleijer M, Von dem Borne AEGK, Roos D, Tetteroo PAT. The PI-linked receptor FcRIII is released on stimulation of neutrophils. Nature. 1988;333:667. doi: 10.1038/333667a0. [DOI] [PubMed] [Google Scholar]
  • 22.Kurane I, Innis BL, Nimmannitya S, Nisalak A, Meager A, Janus J, Ennis FA. Activation of T lymphocytes in Dengue virus infections. J Clin Invest. 1991;88:1473. doi: 10.1172/JCI115457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Sawada S, Sugai A, Lyma S, Takei M, Paredas E, Hayama T, Nishinarita S, Hosokawa Y, Horie T, Obara T. Increased soluble CD4 and decreased soluble CD8 molecules in patients with Sjögren's syndrome. Am J Med. 1992;92:134. doi: 10.1016/0002-9343(92)90103-i. [DOI] [PubMed] [Google Scholar]
  • 24.Symons JA, McCulloch JF, Wood NC, Duff GW. Soluble CD4 in patients with rheumatoid arthritis and osteoarthritis. Clin Immunol Immunopathol. 1991;60:72. doi: 10.1016/0090-1229(91)90113-o. [DOI] [PubMed] [Google Scholar]
  • 25.Beguin Y, Lapertz S, De Groote D, Igot D, Malaise M, Fillet G. Soluble CD23 and other receptors (CD4, CD8, CD25, CD71) in serum of patients with chronic lymphocytic leukemia. Leukemia. 1993;7:2019. [PubMed] [Google Scholar]
  • 26.Krutmann J, Kirnbauer R, Köck A, Schwarz T, Schöpf E, May LT, Sehgal PB, Luger TA. Cross-linking Fc receptors on monocytes triggers IL-6 production: role in anti-CD3-induced T cell activation. J Immunol. 1990;145:1337. [PubMed] [Google Scholar]
  • 27.Yoshimura TY, Matsushima K, Tanaka S, Robinson EA, Appella E, Oppenheim JJ, Leonard EJ. Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines. Proc Natl Acad Sci USA. 1987;84:9233. doi: 10.1073/pnas.84.24.9233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Peters PM, Ortaldo JR, Shalaby MR, Svedersky LP, Nedwin GE, Bringman TS, Hass PE, Aggarwal BB, Herberman RB, Goeddel DV, Palladino MA. Natural killer-sensitive targets stimulate production of TNF-α but not TNF-β (lymphotoxin) by highly purified human peripheral blood large granular lymphocytes. J Immunol. 1986;137:2592. [PubMed] [Google Scholar]
  • 29.Haagen I-A, Geerars AJG, De Lau WBM, Bast EJEG, de Gast GC (1995) The efficacy of CD3×CD19 bsAb in a clonogenic assay; the effect of repeated addition of bispecific antibody and IL-2. Blood (in press) [PubMed]
  • 30.Mueller DL, Jenkins MK, Schwartz RH. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  • 31.Guinan EC, Gribben JG, Boussiotis VA, Freeman GJ, Nadler LM. Pivotal role of the B7:CD28 pathway in transplantation tolerance and tumor immunity. Blood. 1994;84:3261. [PubMed] [Google Scholar]
  • 32.June CH, Ledbetter JA, Linsley PS, Thompson CB. Role of the CD28 receptor in T-cell activation. Immunol Today. 1990;11:211. doi: 10.1016/0167-5699(90)90085-n. [DOI] [PubMed] [Google Scholar]
  • 33.Bohlen H, Hopff T, Manzke O, Engert A, Kube D, Wickramanayake PD, Diehl V, Tesch H. Lysis of malignant B cells from patients with B-chronic lymphocytic leukemia by autologous T cells activated with CD3×CD19 bispecific antibodies in combination with bivalent CD28 antibodies. Blood. 1993;82:1803. [PubMed] [Google Scholar]
  • 34.Bohlen H, Manzke O, Patel B, Moldenhauer G, Dörken B, von Fliedner V, Diehl V, Tesch Cytolysis of leukemic B-cells by T-cells activated via two bispecific antibodies. Cancer Res. 1993;53:4310. [PubMed] [Google Scholar]
  • 35.Weiner GJ. Bispecific IgG and IL-2 therapy of a syngenic B-cell lymphoma in immunocompetent mice. Int J Cancer. 1992;7:63. [PubMed] [Google Scholar]
  • 36.Nakajima F, Khanna A, Xu G, Lagman M, Haschemeyer R, Mouradian J, Wang JC, Stenzel KH, Rubin AL, Suthanthiran M. Immunotherapy with anti-CD3 monoclonal antibodies and recombinant interleukin 2: stimulation of molecular programs of cytotoxic killer cells and induction of tumor regression. Proc Natl Acad Sci USA. 1994;91:7889. doi: 10.1073/pnas.91.17.7889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Kroesen BJ, Buter J, Sleijfer DTh, Jansen RAJ, van der Graaf WTA, The TH, de Leij L, Mulder NH. Phase I study of intravenously applied bispecific antibody in renal cell cancer patients receiving subcutaneous interleukin 2. Br J Caner. 1994;70:652. doi: 10.1038/bjc.1994.366. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES