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. 1999 Nov;81(6):1009–1016. doi: 10.1038/sj.bjc.6690800

Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma

I G H Schmidt-Wolf 1, S Finke 1, B Trojaneck 1, A Denkena 1, P Lefterova 1, N Schwella 1, H-G Heuft 1, G Prange 1, M Korte 1, M Takeya 3, T Dorbic 3, A Neubauer 2, B Wittig 3, D Huhn 1
PMCID: PMC2362953  PMID: 10576658

Abstract

Natural killer-like T lymphocytes termed cytokine-induced killer (CIK) cells have been shown to eradicate established tumours in a severe combined immune deficient (SCID) mouse/human lymphoma model. Recently, we demonstrated that CIK cells transfected with cytokine genes possess an improved proliferation rate and a significantly higher cytotoxic activity as compared to non-transfected cells. Here, in a phase I clinical protocol, autologous CIK cells were generated from peripheral blood obtained by leukapheresis in patients with metastatic renal cell carcinoma, colorectal carcinoma and lymphoma. CIK cells were transfected with a plasmid containing the interleukin-2 (IL-2) gene via electroporation. Transfected cells generated IL-2 in the range of 330–1800 pg 10−6 cells 24 h−1 with a mean of 836 pg 10−6 cells 24 h−1. Ten patients received 1–5 intravenous infusions of IL-2-transfected CIK cells; five infusions with transfected CIK cells were given. In addition, the same patients received five infusions with untransfected CIK cells for control reasons. In three patients, WHO grade 2 fever was observed. Based on polymerase chain reaction of peripheral blood transfected cells could be detected for up to 2 weeks after infusion. There was a significant increase in serum levels of interferon gamma (IFN-γ), granulocyte–macrophage colony-stimulating factor (GM-CSF) and transforming growth factor beta (TGF-β) during treatment. Interestingly, there was also an increase in CD3+ lymphocytes in the blood of patients during therapy. In accordance, a partial increase in cytotoxic activity in peripheral blood lymphocytes (PBLs) was documented when patient samples before and after therapy were compared. Concerning clinical outcome, six patients remained in progressive disease, three patients showed no change by treatment, and one patient with lymphoma developed a complete response. In conclusion, we were able to demonstrate that CIK cells transfected with the IL-2 gene can be administered without major side-effects and are promising for future therapeutic trials. © 1999 Cancer Research Campaign

Keywords: interleukin-2, gene transfer, colorectal cancer, renal cancer, lymphoma, cytokine-induced killer cells

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Footnotes

Present address: Med. Klinik und Poliklinik I, Rheinische Friedrich-Wilhelms Universitat, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Buschle M., Cotten M., Kirlappos H., Mechtler K., Schaffner G., Zauner W., Birnstiel M. L., Wagner E. Receptor-mediated gene transfer into human T lymphocytes via binding of DNA/CD3 antibody particles to the CD3 T cell receptor complex. Hum Gene Ther. 1995 Jun;6(6):753–761. doi: 10.1089/hum.1995.6.6-753. [DOI] [PubMed] [Google Scholar]
  2. Ebert O., Finke S., Salahi A., Herrmann M., Trojaneck B., Lefterova P., Wagner E., Kircheis R., Huhn D., Schriever F. Lymphocyte apoptosis: induction by gene transfer techniques. Gene Ther. 1997 Apr;4(4):296–302. doi: 10.1038/sj.gt.3300394. [DOI] [PubMed] [Google Scholar]
  3. Finke S., Trojaneck B., Lefterova P., Csipai M., Wagner E., Kircheis R., Neubauer A., Huhn D., Wittig B., Schmidt-Wolf I. G. Increase of proliferation rate and enhancement of antitumor cytotoxicity of expanded human CD3+ CD56+ immunologic effector cells by receptor-mediated transfection with the interleukin-7 gene. Gene Ther. 1998 Jan;5(1):31–39. doi: 10.1038/sj.gt.3300560. [DOI] [PubMed] [Google Scholar]
  4. Grimm E. A., Mazumder A., Zhang H. Z., Rosenberg S. A. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982 Jun 1;155(6):1823–1841. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Hickman C. J., Crim J. A., Mostowski H. S., Siegel J. P. Regulation of human cytotoxic T lymphocyte development by IL-7. J Immunol. 1990 Oct 15;145(8):2415–2420. [PubMed] [Google Scholar]
  6. Hwu P., Yannelli J., Kriegler M., Anderson W. F., Perez C., Chiang Y., Schwarz S., Cowherd R., Delgado C., Mulé J. Functional and molecular characterization of tumor-infiltrating lymphocytes transduced with tumor necrosis factor-alpha cDNA for the gene therapy of cancer in humans. J Immunol. 1993 May 1;150(9):4104–4115. [PubMed] [Google Scholar]
  7. Lotze M. T., Grimm E. A., Mazumder A., Strausser J. L., Rosenberg S. A. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Cancer Res. 1981 Nov;41(11 Pt 1):4420–4425. [PubMed] [Google Scholar]
  8. Lu P. H., Negrin R. S. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol. 1994 Aug 15;153(4):1687–1696. [PubMed] [Google Scholar]
  9. Lynch D. H., Miller R. E. Induction of murine lymphokine-activated killer cells by recombinant IL-7. J Immunol. 1990 Sep 15;145(6):1983–1990. [PubMed] [Google Scholar]
  10. Margolin K. A., Negrin R. S., Wong K. K., Chatterjee S., Wright C., Forman S. J. Cellular immunotherapy and autologous transplantation for hematologic malignancy. Immunol Rev. 1997 Jun;157:231–240. doi: 10.1111/j.1600-065x.1997.tb00986.x. [DOI] [PubMed] [Google Scholar]
  11. Markowitz S. D., Roberts A. B. Tumor suppressor activity of the TGF-beta pathway in human cancers. Cytokine Growth Factor Rev. 1996 Jun;7(1):93–102. doi: 10.1016/1359-6101(96)00001-9. [DOI] [PubMed] [Google Scholar]
  12. Mehta B. A., Schmidt-Wolf I. G., Weissman I. L., Negrin R. S. Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells. Blood. 1995 Nov 1;86(9):3493–3499. [PubMed] [Google Scholar]
  13. Ramp U., Jaquet K., Reinecke P., Nitsch T., Gabbert H. E., Gerharz C. D. Acquisition of TGF-beta 1 resistance: an important progression factor in human renal cell carcinoma. Lab Invest. 1997 May;76(5):739–749. [PubMed] [Google Scholar]
  14. Riedl E., Strobl H., Majdic O., Knapp W. TGF-beta 1 promotes in vitro generation of dendritic cells by protecting progenitor cells from apoptosis. J Immunol. 1997 Feb 15;158(4):1591–1597. [PubMed] [Google Scholar]
  15. Rosenberg S. A., Aebersold P., Cornetta K., Kasid A., Morgan R. A., Moen R., Karson E. M., Lotze M. T., Yang J. C., Topalian S. L. Gene transfer into humans--immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med. 1990 Aug 30;323(9):570–578. doi: 10.1056/NEJM199008303230904. [DOI] [PubMed] [Google Scholar]
  16. Rosenberg S. A., Spiess P., Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986 Sep 19;233(4770):1318–1321. doi: 10.1126/science.3489291. [DOI] [PubMed] [Google Scholar]
  17. Schmidt-Wolf G. D., Negrin R. S., Schmidt-Wolf I. G. Activated T cells and cytokine-induced CD3+CD56+ killer cells. Ann Hematol. 1997 Feb;74(2):51–56. doi: 10.1007/s002770050257. [DOI] [PubMed] [Google Scholar]
  18. Schmidt-Wolf G. D., Schmidt-Wolf I. G. Cancer and gene therapy. Ann Hematol. 1996 Nov;73(5):207–218. doi: 10.1007/s002770050231. [DOI] [PubMed] [Google Scholar]
  19. Schmidt-Wolf I. G., Huhn D., Neubauer A., Wittig B. Interleukin-7 gene transfer in patients with metastatic colon carcinoma, renal cell carcinoma, melanoma, or with lymphoma. Hum Gene Ther. 1994 Sep;5(9):1161–1168. doi: 10.1089/hum.1994.5.9-1161. [DOI] [PubMed] [Google Scholar]
  20. Schmidt-Wolf I. G., Lefterova P., Johnston V., Huhn D., Blume K. G., Negrin R. S. Propagation of large numbers of T cells with natural killer cell markers. Br J Haematol. 1994 Jul;87(3):453–458. doi: 10.1111/j.1365-2141.1994.tb08297.x. [DOI] [PubMed] [Google Scholar]
  21. Schmidt-Wolf I. G., Negrin R. S., Kiem H. P., Blume K. G., Weissman I. L. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med. 1991 Jul 1;174(1):139–149. doi: 10.1084/jem.174.1.139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Welch P. A., Namen A. E., Goodwin R. G., Armitage R., Cooper M. D. Human IL-7: a novel T cell growth factor. J Immunol. 1989 Dec 1;143(11):3562–3567. [PubMed] [Google Scholar]
  23. Wright J. A., Huang A. Growth factors in mechanisms of malignancy: roles for TGF-beta and FGF. Histol Histopathol. 1996 Apr;11(2):521–536. [PubMed] [Google Scholar]
  24. Zoll B., Lefterova P., Csipai M., Finke S., Trojaneck B., Ebert O., Micka B., Roigk K., Fehlinger M., Schmidt-Wolf G. D. Generation of cytokine-induced killer cells using exogenous interleukin-2, -7 or -12. Cancer Immunol Immunother. 1998 Dec;47(4):221–226. doi: 10.1007/s002620050524. [DOI] [PMC free article] [PubMed] [Google Scholar]

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