A pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma

Journal for ImmunoTherapy of Cancer

Kazuhiro Kakimi²  Yukio Homma¹  Tetsuya Fujimura¹  Motofumi Suzuki¹  Hiroshi Fukuhara¹  Tohru Nakagawa¹  Haruki Kume¹  Yutaka Enomoto³  Hirokazu Matsushita² 

[1] Department of Urology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;Department of Immunotherapeutics, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;Department of Urology, Mitsui Memorial Hospital, Izumicho 1, Kanda, Chiyoda-Ku, Tokyo 101-8643, Japan

关键词: Lysate;    Dendritic cell;    Sunitinib;    RCC;   

Others  :  1139873
DOI  :  10.1186/s40425-014-0030-4

 received in 2014-05-13, accepted in 2014-07-30,  发布年份 2014

【 摘 要 】

Background

Sunitinib, a tyrosine kinase inhibitor currently in use for the treatment of metastatic renal cell carcinoma (mRCC), has been reported to modulate immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in addition to exerting anti-angiogenic effects. We conducted a clinical trial of dendritic cell (DC)-based immunotherapy together with sunitinib in mRCC patients in an effort to enhance immunotherapeutic efficacy by inhibiting immunosuppressive cells.

Methods

Patients aged ≥20 years with advanced or recurrent mRCC who underwent nephrectomy were eligible for this study. Autologous tumor samples were obtained by surgery under aseptic conditions and used for preparing autologous tumor lysate. About 4 weeks after surgery, leukapheresis was performed to isolate peripheral blood mononuclear cells (PBMCs). DCs were generated from adherent PBMCs in the presence of recombinant human granulocyte macrophage colony-stimulating factor (GM-CSF) (500 IU/ml) and recombinant human IL-4 (500 IU/ml). Autologous tumor lysate was loaded into mature DC by electroporation. Eight patients were enrolled in the study and received sunitinib at a dose of 50 mg p.o. daily for 28 days followed by 14 days of rest. Tumor lysate-loaded DCs were administered subcutaneously every two weeks, with concomitant sunitinib.

Results

No severe adverse events related to vaccination were observed. Sunitinib decreased the frequencies of MDSCs in peripheral blood of 5 patients and of Tregs in 3. Tumor lysate-reactive CD4 or CD8 T cell responses were observed in 5 patients, 4 of whom showed decreased frequencies of Tregs and/or MDSCs. The remaining 3 patients who failed to develop tumor-reactive T cell responses had high levels of IL-8 in their sera and did not show consistent reductions in MDSCs and Tregs.

Conclusions

DC-based immunotherapy combined with sunitinib is safe and feasible for patients with mRCC.

Trial registration

UMIN000002136 webcite

【 授权许可】

   
2014 Matsushita et al.; licensee BioMed Central

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Med 1996, 335:865-875.
• [2]Cohen HT, McGovern FJ: Renal-cell carcinoma. N Engl J Med 2005, 353:2477-2490.
• [3]Abe H, Kamai T: Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol 2013, 20:944-955.
• [4]Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, Sherry RM, Royal RE, Steinberg SM, Rosenberg S: High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma. Cancer 2008, 113:293-301.
• [5]Negrier S, Escudier B, Lasset C, Douillard J-Y, 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. N Engl J Med 1998, 338:1272-1278.
• [6]Fujioka T, Obara W: Evidence-based clinical practice guideline for renal cell carcinoma: the Japanese urological association 2011 update. Int J Urol 2012, 19:496-503.
• [7]Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED: Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 2004, 171:1071-1076.
• [8]Biswas S, Kelly J, Eisen T: Cytoreductive nephrectomy in metastatic clear-cell renal cell carcinoma: perspectives in the tyrosine kinase inhibitor Era. Oncologist 2009, 14:52-59.
• [9]May M, Brookman-May S, Hoschke B, Gilfrich C, Kendel F, Baxmann S, Wittke S, Kiessig S, Miller K, Johannsen M: Ten-year survival analysis for renal carcinoma patients treated with an autologous tumour lysate vaccine in an adjuvant setting. Cancer Immunol Immunother 2010, 59:687-695.
• [10]Azuma T, Horie S, Tomita K, Takahashi T, Tanaka Y, Kashiwase K, Nieda M, Takeuchi T, Ohta N, Shibata Y, Hirai H, Kitamura T: Dendritic cell immunotherapy for patients with metastatic renal cell carcinoma: University of Tokyo experience. Int J Urol 2002, 9:340-346.
• [11]Matsumoto A, Haraguchi K, Takahashi T, Azuma T, Kanda Y, Tomita K, Kurokawa M, Ogawa S, Takahashi K, Chiba S, Kitamura T: Immunotherapy against metastatic renal cell carcinoma with mature dendritic cells. Int J Urol 2007, 14:277-283.
• [12]Berntsen A, Trepiakas R, Wenandy L, Geertsen PF, thor Straten P, Andersen MH, Pedersen AE, Claesson MH, Lorentzen T, Johansen JS, Svane IM: Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial. J Immunother 2008, 31:771-780.
• [13]Gitlitz BJ, Belldegrun AS, Zisman A, Chao DH, Pantuck AJ, Hinkel A, Mulders P, Moldawer N, Tso C-L, Figlin RA: A pilot trial of tumor lysate-loaded dendritic cells for the treatment of metastatic renal cell carcinoma. J Immunother 2003, 26:412-419.
• [14]Höltl L, Zelle-Rieser C, Gander H, Papesh C, Ramoner R, Bartsch G, Rogatsch H, Barsoum AL, Coggin JH, Thurnher M: Immunotherapy of metastatic renal cell carcinoma with tumor lysate-pulsed autologous dendritic cells. Clin Cancer Res 2002, 8:3369-3376.
• [15]Soleimani A, Berntsen A, Svane IM, Pedersen AE: Immune responses in patients with metastatic renal cell carcinoma treated with dendritic cells pulsed with tumor lysate. Scand J Immunol 2009, 70:481-489.
• [16]Rabinovich GA, Gabrilovich D, Sotomayor EM: Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 2007, 25:267-296.
• [17]Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012, 12:252-264.
• [18]Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, Suri KB, Levy C, Allen T, Mavroukakis S, Lowy I, White DE, Rosenberg SA: Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother 2007, 30:825-830.
• [19]Lipson EJ, Sharfman WH, Drake CG, Wollner I, Taube JM, Anders RA, Xu H, Yao S, Pons A, Chen L, Pardoll DM, Brahmer JR, Topalian SL: Durable cancer regression Off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 2013, 19:462-468.
• [20]Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M: Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med 2012, 366:2443-2454.
• [21]Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM: Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012, 366:2455-2465.
• [22]Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, McDermott D, Quiceno D, Youmans A, O'Neill A, Mier J, Ochoa AC: Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 2005, 65:3044-3048.
• [23]Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ, Lush RM, Antonia S, Gabrilovich DI: All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 2006, 66:9299-9307.
• [24]Hiles JJ, Kolesar JM: Role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma. Am J Health Syst Pharm 2008, 65:123-131.
• [25]Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA: Sunitinib versus interferon Alfa in metastatic renal-cell carcinoma. N Engl J Med 2007, 356:115-124.
• [26]Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356:125-134.
• [27]Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH: Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 2009, 15:2148-2157.
• [28]Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, Schwartz M, Divino CM, Pan P-Y, Chen S-H: The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 2009, 69:2514-2522.
• [29]Finke JH, Rini B, Ireland J, Rayman P, Richmond A, Golshayan A, Wood L, Elson P, Garcia J, Dreicer R, Bukowski R: Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res 2008, 14:6674-6682.
• [30]Hipp MM, Hilf N, Walter S, Werth D, Brauer KM, Radsak MP, Weinschenk T, Singh-Jasuja H, Brossart P: Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood 2008, 111:5610-5620.
• [31]Xin H, Zhang C, Herrmann A, Du Y, Figlin R, Yu H: Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res 2009, 69:2506-2513.
• [32]Kujawski M, Kortylewski M, Lee H, Herrmann A, Kay H, Yu H: Stat3 mediates myeloid cell–dependent tumor angiogenesis in mice. J Clin Invest 2008, 118:3367-3377.
• [33]Ko JS, Rayman P, Ireland J, Swaidani S, Li G, Bunting KD, Rini B, Finke JH, Cohen PA: Direct and differential suppression of myeloid-derived suppressor cell subsets by Sunitinib is compartmentally constrained. Cancer Res 2010, 70:3526-3536.
• [34]Waugh DJJ, Wilson C: The interleukin-8 pathway in cancer. Clin Cancer Res 2008, 14:6735-6741.
• [35]Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian C-N, Kahnoski R, Futreal PA, Furge KA, Teh BT: Interleukin-8 mediates resistance to antiangiogenic agent Sunitinib in renal cell carcinoma. Cancer Res 2010, 70:1063-1071.
• [36]Eikawa S, Ohue Y, Kitaoka K, Aji T, Uenaka A, Oka M, Nakayama E: Enrichment of Foxp3+ CD4 regulatory T cells in migrated T cells to IL-6– and IL-8–expressing tumors through predominant induction of CXCR1 by IL-6. J Immunol 2010, 185:6734-6740.
• [37]Chen DS, Mellman I: Oncology meets immunology: the cancer-immunity cycle. Immunity 2013, 39:1-10.
• [38]Vanneman M, Dranoff G: Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer 2012, 12:237-251.
• [39]Takahara M, Miyai M, Tomiyama M, Mutou M, Nicol AJ, Nieda M: Copulsing tumor antigen-pulsed dendritic cells with zoledronate efficiently enhance the expansion of tumor antigen-specific CD8+ T cells via Vγ9γδ T cell activation. J Leukoc Biol 2008, 83:742-754.
• [40]Weiss JM, Allen C, Shivakumar R, Feller S, Li L-H, Liu LN: Efficient responses in a murine renal tumor model by electroloading dendritic cells with whole-tumor lysate. J Immunother 2005, 28:542-550.
• [41]Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45:228-247.
• [42]Desombere I, Meuleman P, Rigole H, Willems A, Irsch J, Leroux-Roels G: The interferon gamma secretion assay: a reliable tool to study interferon gamma production at the single cell level. J Immunol Methods 2004, 286:167-185.