A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer

Michael H. Kershaw, Jennifer A. Westwood, Linda L. Parker, Gang Wang, Zelig Eshhar, Sharon A. Mavroukakis, Donald E. White, John R. Wunderlich, Silvana Canevari, Linda Rogers-Freezer, Clara C. Chen, James C. Yang, Steven A. Rosenberg, Patrick Hwu

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Abstract

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 α-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 γ 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-specificTcells (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 Tcells 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.

Original languageEnglish
Pages (from-to)6106-6115
Number of pages10
JournalClinical Cancer Research
Volume12
Issue number20 PART 1
DOIs
Publication statusPublished - Oct 15 2006

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kershaw, M. H., Westwood, J. A., Parker, L. L., Wang, G., Eshhar, Z., Mavroukakis, S. A., White, D. E., Wunderlich, J. R., Canevari, S., Rogers-Freezer, L., Chen, C. C., Yang, J. C., Rosenberg, S. A., & Hwu, P. (2006). A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clinical Cancer Research, 12(20 PART 1), 6106-6115. https://doi.org/10.1158/1078-0432.CCR-06-1183