Metastatic renal cell carcinoma (RCC) seems to be resistant to conventional chemo- and radiotherapy and the general treatment regimen of cytokine therapy produces only modest responses while inducing severe side effects. Nowadays standard of care is the treatment with VEGF-inhibiting agents or mTOR inhibition; nevertheless, immunotherapy can induce complete remissions and long-term survival in selected patients. Among different adoptive lymphocyte therapies, cytokine-induced killer (CIK) cells have a particularly advantageous profile as these cells are easily available, have a high proliferative rate, and exhibit a high antitumor activity. Here, we reviewed clinical studies applying CIK cells, either alone or with standard therapies, for the treatment of RCC. The adverse events in all studies were mild, transient, and easily controllable. In vitro studies revealed an increased antitumor activity of peripheral lymphocytes of participants after CIK cell treatment and CIK cell therapy was able to induce complete clinical responses in RCC patients. The combination of CIK cell therapy and standard therapy was superior to standard therapy alone. These studies suggest that CIK cell immunotherapy is a safe and competent treatment strategy for RCC patients and further studies should investigate different treatment combinations and schedules for optimal application of CIK cells. 1. Biology of Renal Cell Carcinoma and Current Treatment Options Renal cell carcinoma (RCC) accounts for nearly 3% of all adult malignancies. Metastatic RCC has a particularly poor prognosis with an overall survival of 12 months and a 5-year survival of less than 10% [1, 2]. RCC can be divided into three major subtypes with clear cell RCC (70–80%) being the prominent one. Most patients with clear cell RCC carry an inactivated von Hippel Lindau (VHL) tumor suppressor gene. The inactivation of this gene causes an upregulation of several survival and proangiogenic factors such as transforming growth factor-alpha (TGF- ) and vascular endothelial growth factor (VEGF). Apart from clear cell RCC, papillary (10–15%) and chromophobe RCC (5%) are histological subtypes of RCC. These subtypes can be caused, for example, by somatic mutations activating the tyrosine kinase of the cell surface receptor c-MET. The primary treatment strategy for renal cancer is surgery [3]. Metastatic RCC seems to be resistant to other conventional therapy regimens such as chemotherapy, hormone therapy, or radiotherapy [2, 4]. Until the recent evolution of targeted therapies, interleukin-2 (IL-2) combined with interferon-
References
[1]
Surveillance Epidemiology and End Results, “SEER Stat Fact Sheets,” National Cancer Institute, http://seer.cancer.gov/statfacts/html/kidrp.html.
[2]
J. A. Garcia and B. I. Rini, “Recent progress in the management of advanced renal cell carcinoma,” CA—A Cancer Journal for Clinicians, vol. 57, no. 2, pp. 112–125, 2007.
[3]
American Cancer Society, Cancer Facts & Figures 2011, American Cancer Society, Atlanta, Ga, USA.
[4]
D. T. Harris, “Hormonal therapy and chemotherapy of renal cell carcinoma,” Seminars in Oncology, vol. 10, no. 4, pp. 422–430, 1983.
[5]
J. C. Yang, R. M. Sherry, S. M. Steinberg et al., “Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer,” Journal of Clinical Oncology, vol. 21, no. 16, pp. 3127–3132, 2003.
[6]
D. F. McDermott, M. M. Regan, J. I. Clark et al., “Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma,” Journal of Clinical Oncology, vol. 23, no. 1, pp. 133–141, 2005.
[7]
D. F. McDermott, “Immunotherapy of metastatic renal cell carcinoma,” Cancer, vol. 115, no. 10, pp. 2298–2305, 2009.
[8]
S. A. Rosenberg, “Interleukin 2 for patients with renal cancer,” Nature Clinical Practice Oncology, vol. 4, no. 9, article 497, 2007.
[9]
J. A. Gollob, J. W. Mier, K. Veenstra et al., “Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-γ induction is associated with clinical response,” Clinical Cancer Research, vol. 6, no. 5, pp. 1678–1692, 2000.
[10]
R. J. Motzer, A. Rakhit, L. H. Schwartz et al., “Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma,” Clinical Cancer Research, vol. 4, no. 5, pp. 1183–1191, 1998.
[11]
J. A. Gollob, K. G. Veenstra, R. A. Parker et al., “Phase I trial of concurrent twice-weekly recombinant human interleukin-12 plus low-dose IL-2 in patients with melanoma or renal cell carcinoma,” Journal of Clinical Oncology, vol. 21, no. 13, pp. 2564–2573, 2003.
[12]
H. Haddad and B. I. Rini, “Current treatment considerations in metastatic renal cell carcinoma,” Current Treatment Options in Oncology, vol. 13, no. 2, pp. 212–229, 2012.
[13]
L. Liu, W. Zhang, X. Qi et al., “Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma,” Clinical Cancer Research, vol. 18, no. 6, pp. 1751–1759, 2012.
[14]
I. G. H. Schmidt-Wolf, R. S. Negrin, H. P. Kiem, K. G. Blume, and I. L. Weissman, “Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity,” Journal of Experimental Medicine, vol. 174, no. 1, pp. 139–149, 1991.
[15]
R. D. Lopez, E. K. Waller, P. H. Lu, and R. S. Negrin, “CD58/LFA-3 and IL-12 provided by activated monocytes are critical in the in vitro expansion of CD56+ T cells,” Cancer Immunology, Immunotherapy, vol. 49, no. 11, pp. 629–640, 2000.
[16]
I. G. H. Schmidt-Wolf, P. Lefterova, B. A. Mehta et al., “Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells,” Experimental Hematology, vol. 21, no. 13, pp. 1673–1679, 1993.
[17]
E. Sievers, P. Albers, I. G. H. Schmidt-Wolf, and A. M？rten, “Telomerase pulsed dendritic cells for immunotherapy for renal cell carcinoma,” Journal of Urology, vol. 171, no. 1, pp. 114–119, 2004.
[18]
M. Franceschetti, A. Pievani, G. Borleri et al., “Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes,” Experimental Hematology, vol. 37, no. 5, pp. 616–628, 2009.
[19]
I. G. H. Schmidt-Wolf, P. Lefterova, V. Johnston, D. Huhn, K. G. Blume, and R. S. Negrin, “Propagation of large numbers of T cells with natural killer cell markers,” British Journal of Haematology, vol. 87, no. 3, pp. 453–458, 1994.
[20]
M. R. Verneris, M. Ito, J. Baker, A. Arshi, R. S. Negrin, and J. A. Shizuru, “Engineering hematopoietic grafts: purified allogeneic hematopoietic stem cells plus expanded CD8+ NK-T cells in the treatment of lymphoma,” Biology of Blood and Marrow Transplantation, vol. 7, no. 10, pp. 532–542, 2001.
[21]
M. R. Verneris, M. Karami, J. Baker, A. Jayaswal, and R. S. Negrin, “Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells,” Blood, vol. 103, no. 8, pp. 3065–3072, 2004.
[22]
V. Groh, R. Rhinehart, H. Secrist, S. Bauer, K. H. Grabstein, and T. Spies, “Broad tumor-associated expression and recognition by tumor-derived γδ T cells of MICA and MICB,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 12, pp. 6879–6884, 1999.
[23]
H. R. Salih, H. Antropius, F. Gieseke et al., “Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia,” Blood, vol. 102, no. 4, pp. 1389–1396, 2003.
[24]
D. Pende, P. Rivera, S. Marcenaro et al., “Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity,” Cancer Research, vol. 62, no. 21, pp. 6178–6186, 2002.
[25]
I. G. H. Schmidt-Wolf, P. Lefterova, V. Johnston et al., “Sensitivity of multidrug-resistant tumor cell lines to immunologic effector cells,” Cellular Immunology, vol. 169, no. 1, pp. 85–90, 1996.
[26]
J. J. Mulé, S. Shu, S. L. Schwarz, and S. A. Rosenberg, “Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2,” Science, vol. 225, no. 4669, pp. 1487–1489, 1984.
[27]
S. A. Rosenberg, M. T. Lotze, and L. M. Muul, “Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer,” The New England Journal of Medicine, vol. 313, no. 23, pp. 1485–1492, 1985.
[28]
R. Lafreniere and S. A. Rosenberg, “Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin 2,” Cancer Research, vol. 45, no. 8, pp. 3735–3741, 1985.
[29]
H. Takahashi, T. Nakada, and I. Puisieux, “Inhibition of human colon cancer growth by antibody-directed human LAK cells in SCID mice,” Science, vol. 259, no. 5100, pp. 1460–1463, 1993.
[30]
C. Scheffold, K. Brandt, V. Johnston et al., “Potential of autologous immunologic effector cells for bone marrow purging in patients with chronic myeloid leukemia,” Bone Marrow Transplantation, vol. 15, no. 1, pp. 33–39, 1995.
[31]
X. Ren, J. Yu, H. Liu et al., “Th1 bias in PBMC induced by multicycles of auto-CIKs infusion in malignant solid tumor patients,” Cancer Biotherapy and Radiopharmaceuticals, vol. 21, no. 1, pp. 22–33, 2006.
[32]
P. H. Lu and R. S. Negrin, “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,” Journal of Immunology, vol. 153, no. 4, pp. 1687–1696, 1994.
[33]
S. A. Rosenberg, P. Spiess, and R. Lafreniere, “A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes,” Science, vol. 233, no. 4770, pp. 1318–1321, 1986.
[34]
T. L. Whiteside, “Human tumor-infiltrating lymphocytes and their characterization,” in Interleukin-2 and Killer Cells in Cancer, E. Lotzova and R. B. Herberman, Eds., pp. 133–151, CRCPress, Boca Raton, Fla, USA, 1990.
[35]
C. Yee, S. R. Riddell, and P. D. Greenberg, “Prospects for adoptive T cell therapy,” Current Opinion in Immunology, vol. 9, no. 5, pp. 702–708, 1997.
[36]
P. Frost, R. Caliliw, A. Belldegrun, and B. Bonavida, “Immunosensitization of resistant human tumor cells to cytotoxicity by tumor infiltrating lymphocytes,” International Journal of Oncology, vol. 22, no. 2, pp. 431–437, 2003.
[37]
I. G. H. Schmidt-Wolf, S. Finke, B. Trojaneck et al., “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,” British Journal of Cancer, vol. 81, no. 6, pp. 1009–1016, 1999.
[38]
P. Olioso, R. Giancola, M. Di Riti, A. Contento, P. Accorsi, and A. Iacone, “Immunotherapy with cytokine induced killer cells in solid and hematopoietic tumours: a pilot clinical trial,” Hematological Oncology, vol. 27, no. 3, pp. 130–139, 2009.
[39]
P. Therasse, S. G. Arbuck, E. A. Eisenhauer et al., “New guidelines to evaluate the response to treatment in solid tumors,” Journal of the National Cancer Institute, vol. 92, no. 3, pp. 205–216, 2000.
[40]
X. Su, L. Zhang, L. Jin et al., “Immunotherapy with cytokine-induced killer cells in metastatic renal cell carcinoma,” Cancer Biotherapy and Radiopharmaceuticals, vol. 25, no. 4, pp. 465–470, 2010.
[41]
K. Lei, J. Wang, Y. Jia, Y. Xiong, and Z. Yuan, “The effects of CIK cells on the treatment of renal cell carcinoma,” Chinese-German Journal of Clinical Oncology, vol. 8, no. 6, pp. 346–348, 2009.
[42]
X. Li, W. Xu, J. Cui, L. Yang, J. Ai, and W. Zhao, “Effect of CIK treatment on localized renal carcinoma patients after radical operation,” China Research on Prevention and Treatment, vol. 38, no. 8, pp. 950–953, 2011.
[43]
H. Wang, F. J. Zhou, Q. J. Wang et al., “Efficacy of autologous renal tumor cell lysate-loaded dendritic cell vaccine in combination with cytokine-induced killer cells on advanced renal cell carcinoma—a report of ten cases,” Ai Zheng, vol. 25, no. 5, pp. 625–630, 2006.
[44]
H. Li, J. P. Yu, S. Cao et al., “CD4+CD25+ regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients,” Journal of Clinical Immunology, vol. 27, no. 3, pp. 317–326, 2007.
[45]
G. Lin, J. Wang, X. Lao et al., “Interleukin-6 inhibits regulatory t cells and improves the proliferation and cytotoxic activity of cytokine-induced killer cells,” Journal of Immunotherapy, vol. 35, no. 4, pp. 337–343, 2012.
[46]
C. Hontscha, Y. Borck, H. Zhou, D. Messmer, and I. G. H. Schmidt-Wolf, “Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC),” Journal of Cancer Research and Clinical Oncology, vol. 137, no. 2, pp. 305–310, 2011.
[47]
Y. An, Y. Li, H. Gao, and X. Zhang, “A Phase I/II Evaluation of Cytokine Induced Killer Cells Stimulated by DC(DCIK) Immunotherapy in Patients With Renal Cell Carcinoma,” http://clinicaltrials.gov/ct2/show/NCT01240005.
