title: A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Westwood
authors.forename: Linda L
authors.initials: LL
authors.lastname: Parker
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Zelig
authors.initials: Z
authors.lastname: Eshhar
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Mavroukakis
authors.forename: Donald E
authors.initials: DE
authors.lastname: White
authors.forename: John R
authors.initials: JR
authors.lastname: Wunderlich
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.forename: Linda
authors.initials: L
authors.lastname: Rogers-Freezer
authors.forename: Clara C
authors.initials: CC
authors.lastname: Chen
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
mesh_terms: D015331:Cohort Studies; D017931:DNA Primers; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects*; D017710:Lymphocyte Transfusion / Q000009:adverse effects*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D018579:Patient Selection; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000637:transplantation*; D014184:Transplantation, Homologous
chemical_list: D017931:DNA Primers