Skip to main content
Log in

Antitumor activity of cytokine-induced killer cells in nude mouse xenograft model

  • Research Articles
  • Drug Actions
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Malignant glioma is the most common primary brain tumor in adults and the median survival for patients is less than a year. Despite aggressive treatments including surgical resection, radiotherapy, and chemotherapy, only modest improvement has been achieved in the survival of patients with glioma. In this study, the antitumor activity of cytokine-induced killer (CIK) cells against human glioma cancer was evaluated in vitro and in vivo. Human peripheral blood mononuclear cells were cultured with IL-2-containing medium in anti-CD3 antibody-coated flasks for 5 days, followed by incubation in IL-2-containing medium for 9 days. The number of cells increased more than 200-fold and the viability was >90%. The resulting populations were consisted of 96% CD3+, 2% CD3CD56+, 68% CD3+CD56+, 2% CD4+, <1% CD4+CD56+, 80% CD8+, and 49% CD8+CD56+. This heterogeneous cell population was called as CIK cells. At an effector-target cell ratio of 30:1, CIK cells destroyed 43% of U-87 MG human glioma cells, as measured by the 51Cr-release assay. In addition, CIK cells at doses of 0.3, 1, and 3 million cells per mouse inhibited 23%, 40%, and 50% of U-87 MG tumor growth in nude mouse xenograft assays, respectively. This study suggests that CIK cells may be used as an adoptive immunotherapy for glioma cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Alvarnas, J. C., Linn, Y. C., Hope, E. G., and Negrin, R. S., Expansion of cytotoxic CD3+ CD56+ cells from peripheral blood progenitor cells of patients undergoing autologous hematopoietic cell transplantation. Biol. Blood Marrow Transplant., 7, 216–222 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Dillman, R. O., Duma, C. M., Schiltz, P. M., DePriest, C., Ellis, R. A., Okamoto, K., Beutel, L. D., De Leon, C., and Chico, S., Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma. J. Immunother., 27, 398–404 (2004).

    Article  PubMed  Google Scholar 

  • Edinger, M., Cao, Y. A., Verneris, M. R., Bachmann, M. H., Contag, C. H., and Negrin, R. S., Revealing lymphoma growth and the efficacy of immune cell therapies using in vivo bioluminescence imaging. Blood, 101, 640–648 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Fenstermaker, R. A. and Ciesielski, M. J., Immunotherapeutic strategies for malignant glioma. Cancer Control, 11, 181–191 (2004).

    PubMed  Google Scholar 

  • Gomez, G. G. and Kruse, C. A., Mechanisms of malignant glioma immune resistance and sources of immunosuppression. Gene Ther. Mol. Biol., 10, 133–146 (2006).

    PubMed  Google Scholar 

  • Grabert, R. C., Cousens, L. P., Smith, J. A., Olson, S., Gall, J., Young, W. B., Davol, P. A., and Lum, L. G., Human T cells armed with Her2/neu bispecific antibodies divide, are cytotoxic, and secrete cytokines with repeated stimulation. Clin. Cancer Res., 12, 569–576 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Gupta, T. and Sarin, R., Poor-prognosis high-grade gliomas: evolving an evidence-based standard of care. Lancet Oncol., 3, 557–564 (2002).

    Article  PubMed  Google Scholar 

  • Hayes, R. L., Koslow, M., Hiesiger, E. M., Hymes, K. B., Hochster, H. S., Moore, E. J., Pierz, D. M., Chen, D. K., Budzilovich, G. N., and Ransohoff, J., Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma. Cancer, 76, 840–852 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Holladay, F. P., Heitz, T., and Wood, G. W., Antitumor activity against established intracerebral gliomas exhibited by cytotoxic T lymphocytes, but not by lymphokine-activated killer cells. J. Neurosurg., 77, 757–762 (1992).

    Article  CAS  PubMed  Google Scholar 

  • Jacobs, S. K., Wilson, D. J., Kornblith, P. L., and Grimm, E. A., In vitro killing of human glioblastoma by interleukin-2-activated autologous lymphocytes. J. Neurosurg., 64, 114–117 (1986).

    Article  CAS  PubMed  Google Scholar 

  • Kalinski, P., Nakamura, Y., Watchmaker, P., Giermasz, A., Muthuswamy, R., and Mailliard, R. B., Helper roles of NK and CD8+ T cells in the induction of tumor immunity. Polarized dendritic cells as cancer vaccines. Immunol. Res., 36, 137–146 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Kim, H. M., Kang, J. S., Lim, J., Park, S. K., Lee, K., Yoon, Y. D., Lee, C. W., Lee, K. H., Han, G., Yang, K. H., Kim, Y. J., Kim, Y., and Han, S. B., Inhibition of human ovarian tumor growth by cytokine-induced killer cells. Arch. Pharm. Res., 30, 1464–1470 (2007a).

    Article  CAS  PubMed  Google Scholar 

  • Kim, H. M., Lim, J., Park, S. K., Kang, J. S., Lee, K., Lee, C. W., Lee, K. H., Yun, M. J., Yang, K. H., Han, G., Kwon, S. W., Kim, Y., and Han, S. B., Antitumor activity of cytokine-induced killer cells against human lung cancer. Int. Immunopharmacol., 7, 1802–1807 (2007b).

    Article  CAS  PubMed  Google Scholar 

  • Kim, H. M., Lim, J., Yoon, Y. D., Ahn, J. M., Kang, J. S., Lee, K., Park, S. K., Jeong, Y. J., Kim, J. M., Han, G., Yang, K. H., Kim, Y. J., Kim, Y., and Han, S. B., Anti-tumor activity of ex vivo expanded cytokine-induced killer cells against human hepatocellular carcinoma. Int. Immunopharmacol., 7, 1793–1801 (2007c).

    Article  CAS  PubMed  Google Scholar 

  • Kornacker, M., Moldenhauer, G., Herbst, M., Weilguni, E., Tita-Nwa, F., Harter, C., Hensel, M., and Ho, A. D., Cytokine-induced killer cells against autologous CLL: direct cytotoxic effects and induction of immune accessory molecules by interferon-gamma. Int. J. Cancer, 119, 1377–1382 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Lacroix, M., Abi-Said, D., Fourney, D. R., Gokaslan, Z. L., Shi, W., DeMonte, F., Lang, F. F., McCutcheon, I. E., Hassenbusch, S. J., Holland, E., Hess, K., Michael, C., Miller, D., and Sawaya, R., A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J. Neurosurg., 95, 190–198 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Li, H., Yu, J. P., Cao, S., Wei, F., Zhang, P., An, X. M., Huang, Z. T., and Ren, X. B., CD4 +CD25 + regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J. Clin. Immunol., 27, 317–326 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Lu, P. H. and 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., 153, 1687–1696 (1994).

    CAS  PubMed  Google Scholar 

  • Prins, R. M., Graf, M. R., and Merchant, R. E., Cytotoxic T cells infiltrating a glioma express an aberrant phenotype that is associated with decreased function and apoptosis. Cancer Immunol. Immunother., 50, 285–292 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Raja Gabaglia, C., Diaz de Durana, Y., Graham, F. L., Gauldie, J., Sercarz, E. E., and Braciak, T. A., Attenuation of the glucocorticoid response during Ad5IL-12 adenovirus vector treatment enhances natural killer cell-mediated killing of MHC class I-negative LNCaP prostate tumors. Cancer Res., 67, 2290–2297 (2007).

    Article  PubMed  Google Scholar 

  • Ren, X., Yu, J., Liu, H., Zhang, P., An, X., Zhang, N., and Hao, X., Th1 bias in PBMC induced by multicycles of auto-CIKs infusion in malignant solid tumor patients. Cancer Biother. Radiopharm., 21, 22–33 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Schmidt-Wolf, I. G., Negrin, R. S., Kiem, H. P., Blume, K. G., and 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., 174, 139–149 (1991).

    Article  CAS  PubMed  Google Scholar 

  • Sun, S., Li, X. M., Li, X. D., and Yang, W. S., Studies on inducing apoptosis effects and mechanism of CIK cells for MGC-803 gastric cancer cell lines. Cancer Biother. Radiopharm., 20, 173–180 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Takashima, K., Fujiwara, H., Inada, S., Atsuji, K., Araki, Y., Kubota, T., and Yamagishi, H., Tracking of green fluorescent protein (GFP)-labeled LAK cells in mice carrying B16 melanoma metastases. Anticancer Res., 26, 3327–3332 (2006).

    CAS  PubMed  Google Scholar 

  • Takayama, T., Sekine, T., Makuuchi, M., Yamasaki, S., Kosuge, T., Yamamoto, J., Shimada, K., Sakamoto, M., Hirohashi, S., Ohashi, Y., and Kakizoe, T., Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet, 356, 802–807 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Thorne, S. H., Negrin, R. S., and Contag, C. H., Synergistic antitumor effects of immune cell-viral biotherapy. Science, 311, 1780–1784 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Verneris, M. R., Karami, M., Baker, J., Jayaswal, A., and Negrin, R. S., Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood, 103, 3065–3072 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Verneris, M. R., Kornacker, M., Mailander, V., and Negrin, R. S., Resistance of ex vivo expanded CD3+CD56+ T cells to Fas-mediated apoptosis. Cancer Immunol. Immunother., 49, 335–345 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Wang, P., Yu, J. P., Gao, S. Y., An, X. M., Ren, X. B., Wang, X. G., and Li, W. L., Experimental study on the treatment of intracerebral glioma xenograft with human cytokine-induced killer cells. Cell. Immunol., 253, 59–65 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Wang, W., Epler, J., Salazar, L. G., and Riddell, S. R., Recognition of breast cancer cells by CD8+ cytotoxic T-cell clones specific for NY-BR-1. Cancer Res., 66, 6826–6833 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Yamanaka, R., Cell- and peptide-based immunotherapeutic approaches for glioma. Trends Mol. Med., 14, 228–235 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Yang, L., Ng, K. Y., and Lillehei, K. O., Cell-mediated immunotherapy: a new approach to the treatment of malignant glioma. Cancer Control, 10, 138–147 (2003).

    PubMed  Google Scholar 

  • Yang, X. J., Huang, J. A., Lei, W., Zhu, Y. B., and Zhang, X. G., Antitumor effects of cocultured dendritic cells and cytokine-induced killer cells on lung cancer in vitro and in vivo. Ai Zheng, 25, 1329–1333 (2006).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sang-Bae Han.

Additional information

These authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, H.M., Kang, J.S., Lim, J. et al. Antitumor activity of cytokine-induced killer cells in nude mouse xenograft model. Arch. Pharm. Res. 32, 781–787 (2009). https://doi.org/10.1007/s12272-009-1518-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-009-1518-1

Key words

Navigation