Clinical research of genetically modified dendritic cells in combination with cytokine-induced killer cell treatment in advanced renal cancer

Danhong Wang, Bin Zhang, Haiyan Gao, Guoliang Ding, Qiong Wu, Jinchao Zhang, Li Liao, Hu Chen, Danhong Wang, Bin Zhang, Haiyan Gao, Guoliang Ding, Qiong Wu, Jinchao Zhang, Li Liao, Hu Chen

Abstract

Background: Renal cell carcinoma (RCC) is a malignant disease that demonstrates resistance to standard chemotherapeutic agents. Yet Active immunization using genetically modified dendritic cells holds promise for the adjuvant treatment of malignancies to eradicate or control residual disease. Cytokine-induced killer (CIK) cells are a heterogeneous population of effector CD8+ T cells with diverse TCR specificities, possessing non-MHC-restricted cytolytic activities against tumor cells. Clinical studies have confirmed benefit and safety of CIK cell-based therapy for patients with malignancies. This clinical trial was conducted to evaluate efficacy and safety of genetically modified dendritic cells in combination with Cytokine-Induced Killer Cell (gmDCs-CIK) treatment of patients with RCC.

Methods: 28 patients with advanced renal cancer were admitted to Affiliated Hospital of Academy of Military Medical Sciences from December 2010 to March 2012 and treated by gmDCs-CIK. Clinical efficacy and safety between pre- and post-treatment were compared.

Results: This analysis showed an objective response rate (ORR) of 39% and a disease control rate (DCR) of as 75%. There is no significant relationship between clinical efficacy and whether metastasis occurred or not (P > 0.05). There is no significant relationship between ORR and cycles of treatment (P > 0.05), but DCR was significantly related with cycles of treatment (P < 0.05). No clinically significant side effects were observed. There were no significant changes of T cell subsets including CD3+, CD4+, CD8+, CD4+ CD25+ Treg cells except Th1 in peripheral blood between day 30 after immunotherapy and 1 day before immunotherapy in 11 patients.

Conclusion: DC-CIK is feasible and effective in treating advanced renal cancer and thus provides a new approach.

Trial registration: ClinicalTrials.gov Identifier: NCT01924156. Registration date: August 14, 2013.

Figures

Figure 1
Figure 1
The changes of Th1/Th2 after treatment for 11 patients.
Figure 2
Figure 2
Clinical response to gmDCs-CIK treatment patient with renal cancer. CT scans of patient with renal cancer showing lung metastases. (A) arrow, sites are from lung metastases before gmDCs-CIK treatment, (B) arrow, sites are from lung metastases after gmDCs-CIK treatment.

References

    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30. doi: 10.3322/caac.21166.
    1. Koul H, Huh JS, Rove KO, Crompton L, Koul S, Meacham RB, Kim FJ. Molecular aspects of renal cell carcinoma: a review. Am J Cancer Res. 2011;1:240–254.
    1. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–124. doi: 10.1056/NEJMoa065044.
    1. Escudier B. Emerging immunotherapies for renal cell carcinoma. Ann Oncol. 2012;8:35–40.
    1. Palucka K, Banchereau J, Mellman I. Designing vaccines based on biology of human dendritic cell subsets. Immunity. 2010;33:464–478. doi: 10.1016/j.immuni.2010.10.007.
    1. Schmidt-Wolf IG, Finke S, Trojaneck B, Denkena A, Lefterova P, Schwella N, Heuft HG, Prange G, Korte M, Takeya M, Dorbic T, Neubauer A, Wittig B, Huhn D. 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. Br J Cancer. 1999;81:1009–1016. doi: 10.1038/sj.bjc.6690800.
    1. Thanendrarajan S1, Nowak M, Abken H, Schmidt-Wolf IG. Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: more than one plus one? Leuk Res. 2011;35:1136–1142. doi: 10.1016/j.leukres.2011.05.005.
    1. Sun Y, Chen J, Cai P, Hu YH, Zhong GC, Feng HZ. Therapy of relapsed or refractory non-Hodgkin’s lymphoma by antigen specific dendric cells-activated lymphocytes. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010;18:219–223.
    1. Yagoda A, Bander NH. Failure of cytotoxic chemotherapy,1983-1988, and the emerging role of monoclonal antibodies for renal cancer. Urol Int. 1989;44:338–345. doi: 10.1159/000281537.
    1. Hirschowitz E, Foody T, Hidalgo G, Yannelli J. Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells. Lung Cancer. 2007;57:365–372. doi: 10.1016/j.lungcan.2007.04.002.
    1. Yang B, Lu XC, Zhu HL, Han WD, Wang Y, Fan H, Li SX, Liu Y, Dai HR, Yao SQ. Clinical study of autologous cytokine induced killer cells combined with IL-2 for therapy of elderly patients with B-cell malignant lymphoma. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010;18:1244–1249.
    1. Schwaab T, Schwarzer A, Wolf B, Crocenzi TS, Seigne JD. Clinical and immunologic effects of intranodal autologous tumor lysate-dendritic cell vaccine with ALdesleukin (Interleukin2) and IFN-α2a therapy in metastatic renal cell carcinoma patients. Clin Cancer Res. 2009;15:4986–4992. doi: 10.1158/1078-0432.CCR-08-3240.
    1. Motzer RJ, Mazumdar M, Bacik J, Russo P, Berg WJ, Metz EM. Effect of cytokine therapy on survival for patients with advanced renal cell carcinoma. J Clin Oncol. 2000;8:1928–1935.
    1. Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ. Dendritic cell immunotherapy: mappingthe way. Nat Med. 2004;10:475–480. doi: 10.1038/nm1039.
    1. Atzpodien J, Kirchner H, Jonas U, Bergmann L, Schott H, Heynemann H, Fornara P, Loening SA, Roigas J, Müller SC, Bodenstein H, Pomer S, Metzner B, Rebmann U, Oberneder R, Siebels M, Wandert T, Puchberger T, Reitz M. Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN) Interleukin-2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN) J Clin Oncol. 2004;22:1188–1194. doi: 10.1200/JCO.2004.06.155.
    1. Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, Ravaud A, Mercatello A, Peny J, Mousseau M, Philip T, Tursz T. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunothérapie. N Engl J Med. 1998;338:1272–1278. doi: 10.1056/NEJM199804303381805.
    1. Turnbull JD, Cobert J, Jaffe T, Harrison MR, George DJ, Armstrong AJ. Activity of single-agent Bevacizumab in patients with metastatic renal cell carcinoma previously treated with vascular endothelial growth factor tyrosine kinase inhibitors. Clin Genitourin Cancer. 2013;11:45–50. doi: 10.1016/j.clgc.2012.06.001.
    1. Bukowski RM, Eisen T, Szczylik C. Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: survival and biomarker analysis. J Clin Oncol. 2007;25:abstract5023.
    1. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27:3312–3318. doi: 10.1200/JCO.2008.19.5511.
    1. Maroto JP, Del Muro XG, Mellado B, Perez-Gracia JL, Andrés R, Cruz J, Gallardo E, Domenech M, Arranz JA, Meana JA. Phase II trial of sequential subcutaneous interleukin-2 plus interferon alpha followed by sorafenib in renal cell carcinoma (RCC) Clin Transl Oncol. 2013. [Epub ahead of print]
    1. Lesterhuis WJ1, Haanen JB, Punt CJ. Cancer immunotherapy--revisited. Nat Rev Drug Discov. 2011;10:591–600. doi: 10.1038/nrd3500.
    1. Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother Nat Rev Drug Discov. 2011;10:591–600.
    1. Hoos A, Eggermont AM, Janetzki S, Hodi FS, Ibrahim R, Anderson A, Humphrey R, Blumenstein B, Old L, Wolchok J. Improved endpoints for cancer immunotherapy trials. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst. 2010;18:1388–1397.
    1. Knutson KL1, Disis ML. Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother. 2005;54:721–728. doi: 10.1007/s00262-004-0653-2.
    1. Kraemer M, Hauser S, Schmidt-Wolf IG. Long-term survival of patients with metastatic renal cell carcinoma treated with pulsed dendritic cells. Anticancer Res. 2010;30:2081–2086.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться