Gene-modified T cells for adoptive immunotherapy of renal cell cancer maintain transgene-specific immune functions in vivo
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-gamma were produced, whilst production of TNF-alpha, 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-gamma was the only detectable cytokine upon in vitro PBMC exposure to CAIX. During treatment, plasma levels of IFN-gamma 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-gamma levels.
|Keywords||Carcinoma, Renal Cell/ metabolism, Cytokines/metabolism, Humans, Immune System, Immunotherapy, Adoptive/ methods, Immunotherapy/methods, Interferon-gamma/metabolism, Kidney Neoplasms/ metabolism, Kinetics, Leukocytes, Mononuclear/metabolism, Liver/metabolism, Retroviridae/metabolism, T-Lymphocytes/ cytology/metabolism, Transgenes, Tumor Necrosis Factor-alpha/metabolism|
|Persistent URL||dx.doi.org/10.1007/s00262-007-0330-3, hdl.handle.net/1765/21708|
Lamers, C.H.J., Langeveld, S.C.L., Groot-van Ruijven, C.M., Debets, J.E.M.A., Sleijfer, S., & Gratama, J.W.. (2007). Gene-modified T cells for adoptive immunotherapy of renal cell cancer maintain transgene-specific immune functions in vivo. Cancer Immunology, Immunotherapy: other biological response modifications, 56(12), 1875–1883. doi:10.1007/s00262-007-0330-3