© 1995 by Oxford University Press
Journal of the National Cancer Institute, Vol. 87, No. 19, 1463-1469,
October 4, 1995
© 1995 Oxford University Press
Regression of Advanced Ovarian Carcinoma by Intraperitoneal Treatment With Autologous TLymphocytes Retargeted by a Bispecific Monoclonal Antibody
Divisions of Experimental Oncology, Experimental Oncology D, Experimental Surgical Gynecology, and Immunohematology, Istituto Nazionale per lo Studio e la Cura dei Tumori Milan, Italy
Departments of Medical Oncology, Surgical Oncology, and Clinical and Tumor Immunology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) Rotterdam, The Netherlands
Departments of Medical Oncology and Gynecological Oncology, University of Milan Leiden, The Netherlands
Departments of Medical Oncology and Gynecological Oncology, University Hospital Leiden, The Netherlands
Centocor Europe, Leiden.
*Correspondence to: R. L. H. Bolhuis, Ph.D., Department of Clinical and Tumor Immunology, Rotterdam Cancer Institute, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands.
BACKGROUND:: The high frequency of relapse after induction chemotherapy of advanced ovarian carcinoma calls for new therapeutic approaches. Lysis of ovarian carcinoma cells can be achieved by retargeting of T lymphocytes using F(ab')2 fragments of the bispecific monoclonal antibody (MAb) OC/TR, which is directed to the CD3 molecule on T lymphocytes and to the folate receptor on ovarian carcinoma cells.
PURPOSE:: Our purpose was to assess in ovarian carcinoma patients the antitumor activity of in vitro-activated autologous peripheral blood T lymphocytes retargeted with OC/TR.
METHODS:: Patients with epithelial ovarian cancer (International Federation of Gynecology and Obstetrics stages III and IV) meeting specific criteria were eligible to enter a phase II immunotherapy trial. Before immunotherapy, the 28 patients who entered the trial under went laparotomy to reduce their tumor load and to allow measurement of all indicator lesions. They then received two cycles of five daily intraperitoneal infusions of autologous in vitro activated peripheral blood T lymphocytes retargeted with OC/TR plus recombinant interleukin 2 (IL-2) with (n = 11) or without (n = 17) a second daily infusion of OC/TR F(ab')2 and IL-2. Response to treatment could be assessed in 26 patients following explorative laparotomy; time to progression could be assessed in 27 patients.
RESULTS:: Seven patients had clinical evidence of progressive disease after treatment and therefore did not undergo laparotomy. Of the 19 patients evaluated by surgery and histology, three showed complete response, one showed complete intraperitoneal response with progressive disease in retroperitoneal lymph nodes, three showed partial response, seven had stable disease, and five had progressive disease. The overall intraperitoneal response rate was 27% (95% confidence interval [CI] = 10%–44%). The complete responses seen in three patients lasted 26 months in one patient, 23 months in the second, and 18 months in the third. Two patients were not assessable for response. One of these patients had bowel perforation during catheter removal, which precluded further evaluation. The second patient was positive only by cytologic examination before immunotherapy, was tumor free at laparotomy after immunotherapy, and remained so for the entire 21 months of follow-up, as determined by cytologic examination of random biopsy specimens. The median time to disease progression in the 15 assessable patients plus those who had stable disease was 11 months (95% CI = 6–18 months). Immunotherapy-related toxic effects included mild to moderate fever, nausea, emesis, and fatigue. Anti-mouse antibodies were detectable by the end of the treatment in 21 of 25 patients tested.
CONCLUSIONS:: Locoregional immunotherapy of ovarian cancer with bispecific MAb-retargeted T lymphocytes can result in tumor regression. Toxicity was mild to moderate and only transient.
IMPLICATIONS:: Improvement in systemic antitumor responses is needed before this approach can prove useful as adjunctive treatment following induction chemotherapy in patients with minimal residual disease. [J Natl Cancer Inst 1995;87:1463–69]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Hasegawa, T. Nakamura, M. Harvey, Y. Ikeda, A. Oberg, M. Figini, S. Canevari, L. C. Hartmann, and K.-W. Peng The Use of a Tropism-Modified Measles Virus in Folate Receptor-Targeted Virotherapy of Ovarian Cancer. Clin. Cancer Res., October 15, 2006; 12(20): 6170 - 6178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Morecki, H. Lindhofer, E. Yacovlev, Y. Gelfand, and S. Slavin Use of trifunctional bispecific antibodies to prevent graft versus host disease induced by allogeneic lymphocytes Blood, February 15, 2006; 107(4): 1564 - 1569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Reusch, M. Sundaram, P. A. Davol, S. D. Olson, J. B. Davis, K. Demel, J. Nissim, R. Rathore, P. Y. Liu, and L. G. Lum Anti-CD3 x Anti-Epidermal Growth Factor Receptor (EGFR) Bispecific Antibody Redirects T-Cell Cytolytic Activity to EGFR-Positive Cancers In vitro and in an Animal Model Clin. Cancer Res., January 1, 2006; 12(1): 183 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Stel, B.-J. Kroesen, S. Jacobs, H. Groen, L. F. M. H. de Leij, H. C. Kluin-Nelemans, and S. Withoff The Role of B Cell-Mediated T Cell Costimulation in the Efficacy of the T Cell Retargeting Bispecific Antibody BIS20x3 J. Immunol., November 15, 2004; 173(10): 6009 - 6016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yoshida, T. Kobayashi, H. Matsuoka, C. Seki, W. L. Gosnell, S. P. Chang, and A. Ishii T-cell activation and cytokine production via a bispecific single-chain antibody fragment targeted to blood-stage malaria parasites Blood, March 15, 2003; 101(6): 2300 - 2306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Hartmann, C. Renner, W. Jung, L. da Costa, S. Tembrink, G. Held, A. Sek, J. Konig, S. Bauer, M. Kloft, et al. Anti-CD16/CD30 Bispecific Antibody Treatment for Hodgkin's Disease: Role of Infusion Schedule and Costimulation with Cytokines Clin. Cancer Res., July 1, 2001; 7(7): 1873 - 1881. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Cochlovius, S. M. Kipriyanov, M. J. J. G. Stassar, J. Schuhmacher, A. Benner, G. Moldenhauer, and M. Little Cure of Burkitt's Lymphoma in Severe Combined Immunodeficiency Mice by T Cells, Tetravalent CD3 CD19 Tandem Diabody, and CD28 Costimulation Cancer Res., August 1, 2000; 60(16): 4336 - 4341. [Abstract] [Full Text]
|
|
|
|
|
|
B. Cochlovius, S. M. Kipriyanov, M. J. J. G. Stassar, O. Christ, J. Schuhmacher, G. Strau{beta}, G. Moldenhauer, and M. Little Treatment of Human B Cell Lymphoma Xenografts with a CD3 CD19 Diabody and T Cells J. Immunol., July 15, 2000; 165(2): 888 - 895. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Loffler, P. Kufer, R. Lutterbuse, F. Zettl, P. T. Daniel, J. M. Schwenkenbecher, G. Riethmuller, B. Dorken, and R. C. Bargou A recombinant bispecific single-chain antibody, CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes Blood, March 15, 2000; 95(6): 2098 - 2103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Holliger, O. Manzke, M. Span, R. Hawkins, B. Fleischmann, L. Qinghua, J. Wolf, V. Diehl, O. Cochet, G. Winter, et al. Carcinoembryonic Antigen (CEA)-specific T-Cell Activation in Colon Carcinoma Induced by Anti-CD3Anti-CEA Bispecific Diabodies and B7Anti-CEA Bispecific Fusion Proteins Cancer Res., June 1, 1999; 59(12): 2909 - 2916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Strau{beta}, B. Guckel, D. Wallwiener, and G. Moldenhauer Without Prior Stimulation, Tumor-associated Lymphocytes from Malignant Effusions Lyse Autologous Tumor Cells in the Presence of Bispecific Antibody HEA125xOKT3 Clin. Cancer Res., January 1, 1999; 5(1): 171 - 180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Hartmann, C. Renner, W. Jung, C. Deisting, M. Juwana, B. Eichentopf, M. Kloft, and M. Pfreundschuh Treatment of Refractory Hodgkin's Disease With an Anti-CD16/CD30 Bispecific Antibody Blood, March 15, 1997; 89(6): 2042 - 2047. [Abstract] [Full Text] [PDF]
|
|