PURPOSE: A phase I study was conducted to assess the safety of adoptive immunotherapy using gene-modified autologous T cells for the treatment of metastatic ovarian cancer. EXPERIMENTAL DESIGN: T cells with reactivity against the ovarian cancer-associated antigen alpha-folate receptor (FR) were generated by genetic modification of autologous T cells with a chimeric gene incorporating an anti-FR single-chain antibody linked to the signaling domain of the Fc receptor gamma chain. Patients were assigned to one of two cohorts in the study. Eight patients in cohort 1 received a dose escalation of T cells in combination with high-dose interleukin-2, and six patients in cohort 2 received dual-specific T cells (reactive with both FR and allogeneic cells) followed by immunization with allogeneic peripheral blood mononuclear cells. RESULTS: Five patients in cohort 1 experienced some grade 3 to 4 treatment-related toxicity that was probably due to interleukin-2 administration, which could be managed using standard measures. Patients in cohort 2 experienced relatively mild side effects with grade 1 to 2 symptoms. No reduction in tumor burden was seen in any patient. Tracking 111In-labeled adoptively transferred T cells in cohort 1 revealed a lack of specific localization of T cells to tumor except in one patient where some signal was detected in a peritoneal deposit. PCR analysis showed that gene-modified T cells were present in the circulation in large numbers for the first 2 days after transfer, but these quickly declined to be barely detectable 1 month later in most patients. An inhibitory factor developed in the serum of three of six patients tested over the period of treatment, which significantly reduced the ability of gene-modified T cells to respond against FR+ tumor cells. CONCLUSIONS: Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in large numbers long term. Future studies need to employ strategies to extend T cell persistence. This report is the first to document the use of genetically redirected T cells for the treatment of ovarian cancer.
PURPOSE: A phase I study was conducted to assess the safety of adoptive immunotherapy using gene-modified autologous T cells for the treatment of metastatic ovarian cancer. EXPERIMENTAL DESIGN: T cells with reactivity against the ovarian cancer-associated antigen alpha-folate receptor (FR) were generated by genetic modification of autologous T cells with a chimeric gene incorporating an anti-FR single-chain antibody linked to the signaling domain of the Fc receptor gamma chain. Patients were assigned to one of two cohorts in the study. Eight patients in cohort 1 received a dose escalation of T cells in combination with high-dose interleukin-2, and six patients in cohort 2 received dual-specific T cells (reactive with both FR and allogeneic cells) followed by immunization with allogeneic peripheral blood mononuclear cells. RESULTS: Five patients in cohort 1 experienced some grade 3 to 4 treatment-related toxicity that was probably due to interleukin-2 administration, which could be managed using standard measures. Patients in cohort 2 experienced relatively mild side effects with grade 1 to 2 symptoms. No reduction in tumor burden was seen in any patient. Tracking 111In-labeled adoptively transferred T cells in cohort 1 revealed a lack of specific localization of T cells to tumor except in one patient where some signal was detected in a peritoneal deposit. PCR analysis showed that gene-modified T cells were present in the circulation in large numbers for the first 2 days after transfer, but these quickly declined to be barely detectable 1 month later in most patients. An inhibitory factor developed in the serum of three of six patients tested over the period of treatment, which significantly reduced the ability of gene-modified T cells to respond against FR+ tumor cells. CONCLUSIONS: Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in large numbers long term. Future studies need to employ strategies to extend T cell persistence. This report is the first to document the use of genetically redirected T cells for the treatment of ovarian cancer.
Authors: L L Parker; M T Do; J A Westwood; J R Wunderlich; M E Dudley; S A Rosenberg; P Hwu Journal: Hum Gene Ther Date: 2000-11-20 Impact factor: 5.695
Authors: Terence P F Gade; Waleed Hassen; Elmer Santos; Gertrude Gunset; Aurore Saudemont; Michael C Gong; Renier Brentjens; Xiao-Song Zhong; Matthias Stephan; Jolanta Stefanski; Clay Lyddane; Joseph R Osborne; Ian M Buchanan; Simon J Hall; Warren D Heston; Isabelle Rivière; Steven M Larson; Jason A Koutcher; Michel Sadelain Journal: Cancer Res Date: 2005-10-01 Impact factor: 12.701
Authors: Mark E Dudley; John R Wunderlich; James C Yang; Richard M Sherry; Suzanne L Topalian; Nicholas P Restifo; Richard E Royal; Udai Kammula; Don E White; Sharon A Mavroukakis; Linda J Rogers; Gerald J Gracia; Stephanie A Jones; David P Mangiameli; Michelle M Pelletier; Juan Gea-Banacloche; Michael R Robinson; David M Berman; Armando C Filie; Andrea Abati; Steven A Rosenberg Journal: J Clin Oncol Date: 2005-04-01 Impact factor: 44.544
Authors: Luca Gattinoni; Christopher A Klebanoff; Douglas C Palmer; Claudia Wrzesinski; Keith Kerstann; Zhiya Yu; Steven E Finkelstein; Marc R Theoret; Steven A Rosenberg; Nicholas P Restifo Journal: J Clin Invest Date: 2005-06 Impact factor: 14.808
Authors: Kanwarpal S Kahlon; Christine Brown; Laurence J N Cooper; Andrew Raubitschek; Stephen J Forman; Michael C Jensen Journal: Cancer Res Date: 2004-12-15 Impact factor: 12.701
Authors: S Miotti; D R Negri; O Valota; M Calabrese; R L Bolhuis; J W Gratama; M I Colnaghi; S Canevari Journal: Int J Cancer Date: 1999-02-19 Impact factor: 7.396
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Authors: Donald M O'Rourke; MacLean P Nasrallah; Arati Desai; Jan J Melenhorst; Keith Mansfield; Jennifer J D Morrissette; Maria Martinez-Lage; Steven Brem; Eileen Maloney; Angela Shen; Randi Isaacs; Suyash Mohan; Gabriela Plesa; Simon F Lacey; Jean-Marc Navenot; Zhaohui Zheng; Bruce L Levine; Hideho Okada; Carl H June; Jennifer L Brogdon; Marcela V Maus Journal: Sci Transl Med Date: 2017-07-19 Impact factor: 17.956
Authors: Shigui Zhu; Benoit J Van den Eynde; Pierre G Coulie; Yong F Li; Mona El-Gamil; Steven A Rosenberg; Paul F Robbins Journal: J Immunother Date: 2012 Nov-Dec Impact factor: 4.456