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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 12/2007

Open Access 01-12-2007 | Original Article

Gene-modified T cells for adoptive immunotherapy of renal cell cancer maintain transgene-specific immune functions in vivo

Authors: Cor H. J. Lamers, Sabine C. L. Langeveld, Corrien M. Groot-van Ruijven, Reno Debets, Stefan Sleijfer, Jan Willem Gratama

Published in: Cancer Immunology, Immunotherapy | Issue 12/2007

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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.
Literature
1.
Eshhar Z (1997) Tumor-specific T-bodies: towards clinical application. Cancer Immunol Immunother 45:131–136PubMedCrossRef
2.
Clay TM, Custer MC, Sachs J, Hwu P, Rosenberg SA, Nishimura MI (1999) Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J Immunol 163:507–513PubMed
3.
Lamers CHJ, Sleijfer S, Willemsen RA, Debets R, Kruit WHJ, Gratama JW, et al (2004) Adoptive immuno-gene therapy of cancer with single chain antibody [scFv(Ig)] gene modified T lymphocytes. J Biol Regul Homeost Agents 18:134–140PubMed
4.
Willemsen RA, Weijtens ME, Ronteltap C, Eshhar Z, Gratama JW, Chames P, et al (2000) Grafting primary human T lymphocytes with cancer-specific chimeric single chain and two chain TCR. Gene Ther 7:1369–1377PubMedCrossRef
5.
Weijtens ME, Willemsen RA, Valerio D, Stam K, Bolhuis RL (1996) Single chain Ig/gamma gene-redirected human T lymphocytes produce cytokines, specifically lyse tumor cells, and recycle lytic capacity. J Immunol 157:836–843PubMed
6.
Bolhuis RL, Willemsen RA, Lamers CH, Stam K, Gratama JW, Weijtens ME (1998) Preparation for a phase I/II study using autologous gene modified T lymphocytes for treatment of metastatic renal cancer patients. Adv Exp Med Biol 451:547–555PubMed
7.
Lamers CH, Sleijfer S, Vulto AG, Kruit WH, Kliffen M, Debets R, et al (2006) Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 24:e20–e22PubMedCrossRef
8.
Oosterwijk E, Ruiter DJ, Hoedemaeker PJ, Pauwels EK, Jonas U, Zwartendijk J, et al (1986) Monoclonal antibody G 250 recognizes a determinant present in renal-cell carcinoma and absent from normal kidney. Int J Cancer 38:489–494PubMedCrossRef
9.
Grabmaier K, Vissers JL, De Weijert MC, Oosterwijk-Wakka JC, Van Bokhoven A, Brakenhoff RH, et al (2000) Molecular cloning and immunogenicity of renal cell carcinoma-associated antigen G250. Int J Cancer 85:865–870PubMedCrossRef
10.
Lamers CH, Willemsen RA, Luider BA, Debets R, Bolhuis RL (2002) Protocol for gene transduction and expansion of human T lymphocytes for clinical immunogene therapy of cancer. Cancer Gene Ther 9:613–623PubMedCrossRef
11.
Lamers CH, Willemsen RA, van Elzakker P, van Krimpen BA, Gratama JW, Debets R (2006) Phoenix-ampho outperforms PG13 as retroviral packaging cells to transduce human T cells with tumor-specific receptors: implications for clinical immunogene therapy of cancer. Cancer Gene Ther 13:503–509PubMedCrossRef
12.
Lamers C, van Elzakker P, Langeveld S, Sleijfer S, Gratama J (2006) Process validation and clinical evaluation of a protocol to generate gene-modified T lymphocytes for imunogene therapy for metastatic renal cell carcinoma: GMP-controlled transduction and expansion of patient’s T lymphocytes using a carboxy anhydrase IX-specific scFv transgene. Cytotherapy 8:542–553PubMedCrossRef
13.
Uemura H, Okajima E, Debruyne FMJ, Oosterwijk E (1994) Internal image antiidiotype antibodies related to renal-cell carcinoma-associated antigen G250. Int J Cancer 56:609–614PubMedCrossRef
14.
Lamers CH, Gratama JW, Pouw NM, Langeveld SC, Krimpen BA, Kraan J, et al (2005) Parallel detection of transduced T lymphocytes after immunogene therapy of renal cell cancer by flow cytometry and real-time polymerase chain reaction: implications for loss of transgene expression. Hum Gene Ther 16:1452–1462PubMedCrossRef
15.
Pross HF, Baines MG, Rubin P, Shragge P, Patterson MS (1981) Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity. J Clin Immunol 1:51–63PubMedCrossRef
16.
Vandenbroeck K, Goris A (2003) Cytokine gene polymorphisms in multifactorial diseases: gateways to novel targets for immunotherapy? Trends Pharmacol Sci 24:284–289PubMedCrossRef
17.
Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, et al (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99:16168–16173PubMedCrossRef
18.
Dudley ME, Rosenberg SA (2003) Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 3:666–675PubMedCrossRef
19.
Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6:383–393PubMedCrossRef
20.
Cragun WC, Yamshchikov GV, Bissonette EA, Smolkin ME, Eastham S, Petroni GR, et al (2005) Low-dose IL-2 induces cytokine cascade, eosinophilia, and a transient Th2 shift in melanoma patients. Cancer Immunol Immunother 54:1095–1105PubMedCrossRef
21.
Jin P, Wang E, Provenzano M, Deola S, Selleri S, Ren J, et al (2006) Molecular signatures induced by interleukin-2 on peripheral blood mononuclear cells and T cell subsets. J Transl Med 4:26. doi:10.1186/1479-5876-4-26
22.
Panelli MC, Wang E, Phan G, Puhlmann M, Miller L, Ohnmacht GA, et al (2002) Gene-expression profiling of the response of peripheral blood mononuclear cells and melanoma metastases to systemic IL-2 administration. Genome Biol 3:research 0035.1–0035.17
23.
Panelli MC, White R, Foster M, Martin B, Wang E, Smith K, et al (2004) Forecasting the cytokine storm following systemic interleukin (IL)-2 administration. J Transl Med 2:17. doi:10.1186/1479-5876-2-17
24.
Umland SP, Razac S, Shah H, Nahrebne DK, Egan RW, Billah MM (1998) Interleukin-5 mRNA stability in human T cells is regulated differently than interleukin-2, interleukin-3, interleukin-4, granulocyte/macrophage colony-stimulating factor, and interferon-gamma. Am J Respir Cell Mol Biol 18:631–642PubMed
25.
Rolfe FG, Sewell WA (1997) Analysis of human interleukin-5 gene transcription by a novel nuclear run on method based on the polymerase chain reaction. J Immunol Methods 202:143–151PubMedCrossRef
Metadata
Title
Gene-modified T cells for adoptive immunotherapy of renal cell cancer maintain transgene-specific immune functions in vivo
Authors
Cor H. J. Lamers
Sabine C. L. Langeveld
Corrien M. Groot-van Ruijven
Reno Debets
Stefan Sleijfer
Jan Willem Gratama
Publication date
01-12-2007
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 12/2007
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-007-0330-3

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