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

Authors' Affiliations: ¹ Surgery Branch, Center for Cancer Research, National Cancer Institute; ² Department of Nuclear Medicine, Clinical Center, NIH, Bethesda, Maryland; ³ Cancer Immunology Research Program, Peter MacCallum Cancer Centre; ⁴ Department of Pathology, University of Melbourne, Melbourne, Australia; ⁵ Department of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; ⁶ Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; and ⁷ Istituto Nazionale Tumori, Milan, Italy

Requests for reprints: Patrick Hwu, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 430, Houston, TX 77030. Phone: 713-792-2921; Fax: 713-745-1046; E-mail: phwu{at}mdanderson.org.

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 -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 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.

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