Gene-modified T cells for adoptive immunotherapy of renal cell cancer maintain transgene-specific immune functions in vivo |
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Authors: | Cor H J Lamers Sabine C L Langeveld Corrien M Groot-van Ruijven Reno Debets Stefan Sleijfer Jan Willem Gratama |
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Institution: | (1) Laboratory for Clinical and Tumor Immunology, Department of Medical Oncology, Erasmus MC, Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands;(2) Department of Medical Oncology, Erasmus MC, Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands |
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Abstract: | Background We have treated three patients with carboxy-anhydrase-IX (CAIX) positive metastatic renal cell cancer (RCC) by adoptive transfer
of autologous T-cells that had been gene-transduced to express a single-chain antibody-G250 chimeric receptor scFv(G250)],
and encountered liver toxicity necessitating adaptation of the treatment protocol. Here, we investigate whether or not the
in vivo activity of the infused scFv(G250)+ T cells is reflected by changes of selected immune parameters measured in peripheral blood.
Methods ScFv(G250)-chimeric receptor-mediated functions of peripheral blood mononuclear cells (PBMC) obtained from three patients
during and after treatment were compared to the same functions of scFv(G250)+ T lymphocytes prior to infusion, and were correlated with plasma cytokine levels.
Results Prior to infusion, scFv(G250)+ T lymphocytes showed in vitro high levels of scFv(G250)-chimeric receptor-mediated functions such as killing of CAIX+ RCC cell lines and cytokine production upon exposure to these cells. High levels of IFN-γ were produced, whilst production
of TNF-α, interleukin-4 (IL-4), IL-5 and IL-10 was variable and to lower levels, and that of IL-2 virtually absent. PBMC taken
from patients during therapy showed lower levels of in vitro scFv(G250)-receptor-mediated functions as compared to pre-infusion,
whilst IFN-γ was the only detectable cytokine upon in vitro PBMC exposure to CAIX. During treatment, plasma levels of IFN-γ
increased only in the patient with the most prominent liver toxicity. IL-5 plasma levels increased transiently during treatment
in all patients, which may have been triggered by the co-administration of IL-2.
Conclusion ScFv(G250)-receptor-mediated functions of the scFv(G250)+ T lymphocytes are, by and large, preserved in vivo upon administration, and may be reflected by fluctuations in plasma IFN-γ
levels. |
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Keywords: | Immunogene therapy Human T lymphocytes Single chain chimeric receptor Renal cell cancer Clinical study |
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