A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer.
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.
Kershaw
Michael H
MH
Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
Westwood
Jennifer A
JA
Parker
Linda L
LL
Wang
Gang
G
Eshhar
Zelig
Z
Mavroukakis
Sharon A
SA
White
Donald E
DE
Wunderlich
John R
JR
Canevari
Silvana
S
Rogers-Freezer
Linda
L
Chen
Clara C
CC
Yang
James C
JC
Rosenberg
Steven A
SA
Hwu
Patrick
P
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
D017931:DNA Primers