Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody

Silvana Canevari, Gerrit Stoter, Flavio Arienti, Giorgio Bolis, Maria I. Colnaghi, Emanuela M. Di Re, Alexander M M Eggermont, S. Hoo Goey, Jan W. Gratama, Cor H J Lamers, Marianne A. Nooy, Giorgio Parmiani, Francesco Raspagliesi, Ferdinando Ravagnani, Giovanna Scarfone, J. Baptist Trimbos, Sven O. Warnaar, Reinder L H Bolhuis

Research output: Contribution to journalArticle

Abstract

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 underwent 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.

Original languageEnglish
Pages (from-to)1463-1469
Number of pages7
JournalJournal of the National Cancer Institute
Volume87
Issue number19
Publication statusPublished - Oct 4 1995

Fingerprint

Bispecific Antibodies
T Lymphocytes
Monoclonal antibodies
Monoclonal Antibody
T-cells
Immunotherapy
Regression
Carcinoma
T-Lymphocytes
Tumors
Chemotherapy
Ovarian Cancer
Tumor
Interleukin
Therapeutics
Laparotomy
Progression
Blood
Gynecology
Confidence interval

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging

Cite this

Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody. / Canevari, Silvana; Stoter, Gerrit; Arienti, Flavio; Bolis, Giorgio; Colnaghi, Maria I.; Di Re, Emanuela M.; Eggermont, Alexander M M; Goey, S. Hoo; Gratama, Jan W.; Lamers, Cor H J; Nooy, Marianne A.; Parmiani, Giorgio; Raspagliesi, Francesco; Ravagnani, Ferdinando; Scarfone, Giovanna; Trimbos, J. Baptist; Warnaar, Sven O.; Bolhuis, Reinder L H.

In: Journal of the National Cancer Institute, Vol. 87, No. 19, 04.10.1995, p. 1463-1469.

Research output: Contribution to journalArticle

Canevari, S, Stoter, G, Arienti, F, Bolis, G, Colnaghi, MI, Di Re, EM, Eggermont, AMM, Goey, SH, Gratama, JW, Lamers, CHJ, Nooy, MA, Parmiani, G, Raspagliesi, F, Ravagnani, F, Scarfone, G, Trimbos, JB, Warnaar, SO & Bolhuis, RLH 1995, 'Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody', Journal of the National Cancer Institute, vol. 87, no. 19, pp. 1463-1469.
Canevari, Silvana ; Stoter, Gerrit ; Arienti, Flavio ; Bolis, Giorgio ; Colnaghi, Maria I. ; Di Re, Emanuela M. ; Eggermont, Alexander M M ; Goey, S. Hoo ; Gratama, Jan W. ; Lamers, Cor H J ; Nooy, Marianne A. ; Parmiani, Giorgio ; Raspagliesi, Francesco ; Ravagnani, Ferdinando ; Scarfone, Giovanna ; Trimbos, J. Baptist ; Warnaar, Sven O. ; Bolhuis, Reinder L H. / Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody. In: Journal of the National Cancer Institute. 1995 ; Vol. 87, No. 19. pp. 1463-1469.
@article{fc2997061bdf4dcea4c3d77fed8d6a5f,
title = "Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody",
abstract = "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 underwent 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.",
author = "Silvana Canevari and Gerrit Stoter and Flavio Arienti and Giorgio Bolis and Colnaghi, {Maria I.} and {Di Re}, {Emanuela M.} and Eggermont, {Alexander M M} and Goey, {S. Hoo} and Gratama, {Jan W.} and Lamers, {Cor H J} and Nooy, {Marianne A.} and Giorgio Parmiani and Francesco Raspagliesi and Ferdinando Ravagnani and Giovanna Scarfone and Trimbos, {J. Baptist} and Warnaar, {Sven O.} and Bolhuis, {Reinder L H}",
year = "1995",
month = "10",
day = "4",
language = "English",
volume = "87",
pages = "1463--1469",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "19",

}

TY - JOUR

T1 - Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody

AU - Canevari, Silvana

AU - Stoter, Gerrit

AU - Arienti, Flavio

AU - Bolis, Giorgio

AU - Colnaghi, Maria I.

AU - Di Re, Emanuela M.

AU - Eggermont, Alexander M M

AU - Goey, S. Hoo

AU - Gratama, Jan W.

AU - Lamers, Cor H J

AU - Nooy, Marianne A.

AU - Parmiani, Giorgio

AU - Raspagliesi, Francesco

AU - Ravagnani, Ferdinando

AU - Scarfone, Giovanna

AU - Trimbos, J. Baptist

AU - Warnaar, Sven O.

AU - Bolhuis, Reinder L H

PY - 1995/10/4

Y1 - 1995/10/4

N2 - 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 underwent 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.

AB - 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 underwent 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.

UR - http://www.scopus.com/inward/record.url?scp=0029117559&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029117559&partnerID=8YFLogxK

M3 - Article

C2 - 7674333

AN - SCOPUS:0029117559

VL - 87

SP - 1463

EP - 1469

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 19

ER -