A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer

作者：Michael H. Kershaw, Jennifer A. Westwood, Linda L. Parker, Gang Wang, Zelig Eshhar, Sharon A. Mavroukakis, Donald Edward White, John R. Wunderlich, Silvana Canevari, Linda J. Rogers-Freezer, Clara C. Chen, James Chih-Hsin Yang, Steven A. Rosenberg, Patrick Hwu · 发表于：Clinical Cancer Research · 年份：2006 · DOI：10.1158/1078-0432.ccr-06-1183 · 被引用次数：1257 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Virus-based gene therapy research

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...