Immunotherapeutic strategies for the treatment of renal cell carcinoma: Where will we go?

References

• Ferlay J, Shin H-R, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–2917.
   PubMed Web of Science ®Google Scholar
• Chow W-H, Devesa SS. Contemporary epidemiology of renal cell cancer. Cancer J. 2008;14:288–301.
   PubMed Web of Science ®Google Scholar
• Ehrlich P. Über den jetzigen stand der karzinomforschung. Ned. Tijdschr. Geneeskd.. 1909;5:273–290.
   Google Scholar
• Burnet M. Cancer; a biological approach. I. The processes of control. Br Med J. 1957;1:779–786.
   PubMed Web of Science ®Google Scholar
• Burnet M. Immunological surveillance in neoplasia. Transplant Rev. 1971;7:3–25.
   Google Scholar
• Klein G, Sjogren HO, Klein E, et al. Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res. 1960;20(1):561–1572.
   Google Scholar
• Coppin C, Porzsolt F, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD001425.
   Google Scholar
• Klapper JA, Downey SG, Smith FO, et al. High‐dose interleukin‐2 for the treatment of metastatic renal cell carcinoma. Cancer. 2008;113:293–301.
   PubMed Web of Science ®Google Scholar
• Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. New England J Med. 1985;313:1485–1492.
   PubMed Web of Science ®Google Scholar
• Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med. 1987;316:889–897.
   PubMed Web of Science ®Google Scholar
• Kammula US, White DE, Rosenberg SA. Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer. Cancer. 1998;83:797–805.
   PubMed Web of Science ®Google Scholar
• Pizzocaro G, Piva L, Colavita M, et al. Interferon adjuvant to radical nephrectomy in robson stages II and III renal cell carcinoma: a multicentric randomized study. J Clin Oncol. 2001;19:425–431.
   PubMed Web of Science ®Google Scholar
• Messing EM, Manola J, Wilding G et al. Phase III study of interferon alfa-nl as adjuvant treatment for resectable renal cell carcinoma: an eastern cooperative oncology group/intergroup trial. J Clin Oncol. 2003;21:1214–1222.
   PubMed Web of Science ®Google Scholar
• Clark JI, Atkins MB, Urba WJ, et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: A Cytokine working group randomized trial. J Clin Oncol. 2003;21:3133–3140.
   PubMed Web of Science ®Google Scholar
• Passalacqua R, Caminiti C, Buti S, et al. Adjuvant low-dose interleukin-2 (IL-2) plus interferon-α (IFN-α) in operable renal cell carcinoma (RCC). J Immunotherapy. 2014;37:440–447.
   PubMed Web of Science ®Google Scholar
• Albiges L, Choueiri T, Escudier B, et al. A systematic review of sequencing and combinations of systemic therapy in metastatic renal cancer. Eur Urol. 2015;67:100–110.
   PubMed Web of Science ®Google Scholar
• Camillo Porta CP, Alessandra M. Targeting PI3K/Akt/mTOR Signaling in Cancer. Frontiers in Oncology. 2014;4:64.
   Google Scholar
• Dodd KM, Yang J, Shen MH, et al. mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene. 2015;34:2239–2250.
   PubMed Web of Science ®Google Scholar
• Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 2011;4:51.
   PubMed Web of Science ®Google Scholar
• Mihaly Z, Sztupinszki Z, Surowiak P, et al. A comprehensive overview of targeted therapy in metastatic renal cell carcinoma. Current Cancer Drug Targets. 2012;12:857–872.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. Jama. 2006;295:2516.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. New England J Med. 2007;356:115–124.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584–3590.
   PubMed Web of Science ®Google Scholar
• Ljungberg B, Bensalah K, Bex A, et al. Guidelines on renal cell carcinoma. Guidelines on Renal Cell Carcinoma B. Ljungberg (Chair)Patient Advocate). 2015;67(5):913–924.
   Google Scholar
• Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. New England J Med. 2015;373:1814–1823.
   PubMed Web of Science ®Google Scholar
• Cabozantinib (CABOMETYX) FDA Approval. (2016).
   Google Scholar
• Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet. Oncol. 2016;17:917–927.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473–1482.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol. 2016. Available from: http://ascopubs.org/doi/abs/10.1200/JCO.2016.70.7398.
   Google Scholar
• Bedke J, Stenzl A. Immunotherapeutic strategies for the treatment of renal cell carcinoma: where are we now? Expert Rev Anticancer Ther. 2013;13:1399–1408.
   PubMed Web of Science ®Google Scholar
• Jocham D, Richter A, Hoffmann L, et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet (London, England). 2004;363:594–599.
   PubMed Web of Science ®Google Scholar
• Wood C, Srivastava P, Bukowski R, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet (London, England). 2008;372:145–154.
   PubMed Web of Science ®Google Scholar
• Amin A, Dudek AZ, Logan TF, et al. Survival with AGS-003, an autologous dendritic cell–based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): phase 2 study results. J Immunother. 2015;3:14.
   Web of Science ®Google Scholar
• Kirner A, Mayer-Mokler A, Reinhardt C. IMA901: a multi-peptide cancer vaccine for treatment of renal cell cancer. Human Vaccines & Immunotherapeutics. 2014;10:3179–3189.
   PubMed Web of Science ®Google Scholar
• Bedke J, Stenzl A. IMA901: a peptide vaccine in renal cell carcinoma. Expert Opin Investig Drugs. 2013;22:1329–1336.
   PubMed Web of Science ®Google Scholar
• Rausch S, Kruck S, Stenzl A, et al. IMA901 for metastatic renal cell carcinoma in the context of new approaches to immunotherapy. Future Oncol. 2014;10:937–948.
   PubMed Web of Science ®Google Scholar
• Walter S, Weinschenk T, Reinhardt C, et al. Single-dose cyclophosphamide synergizes with immune responses to the renal cell cancer vaccine IMA901. Oncoimmunology. 2013;2:e22246.
   PubMed Web of Science ®Google Scholar
• Rini BI, Stenzl A, Zdrojowy R, et al. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. Oncol. 2016;17(11):1599–1611.
   PubMed Web of Science ®Google Scholar
• Rosenberg SA, Restifo NP, Delorme EJ, et al. Adoptive cell transfer as personalized immunotherapy for human cancer. Science (New York, N.Y.). 2015;348:62–68.
   PubMed Web of Science ®Google Scholar
• Kalos M, June Carl H, Aleksic M, et al. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity. 2013;39:49–60.
   PubMed Web of Science ®Google Scholar
• Chinnasamy D, Yu Z, Theoret MR, et al. Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice. J Clin Invest. 2010;120:3953–3968.
   PubMed Web of Science ®Google Scholar
• Lamers CH, Sleijfer S, Van Steenbergen S. et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Therap. 2013;21:904–912.
   PubMed Web of Science ®Google Scholar
• Kobayashi H, Tanaka Y, Yagi J, et al. Phase I/II study of adoptive transfer of γδ T cells in combination with zoledronic acid and IL-2 to patients with advanced renal cell carcinoma. Cancer Immunol Immunother. 2011;60:1075–1084.
   PubMed Web of Science ®Google Scholar
• Bennouna J, Bompas E, Neidhardt EM, et al. Phase-I study of Innacell gammadelta, an autologous cell-therapy product highly enriched in gamma9delta2 T lymphocytes, in combination with IL-2, in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother. 2008;57:1599–1609.
   PubMed Web of Science ®Google Scholar
• Phan GQ, Rosenberg SA. Adoptive cell transfer for patients with metastatic melanoma: the potential and promise of cancer immunotherapy. Cancer Control. 2013;20:289–297.
   PubMed Web of Science ®Google Scholar
• Garber HR, Mirza A, Mittendorf EA, et al. Adoptive T-cell therapy for Leukemia. Mol Cell Ther. 2014;2:25.
   PubMedGoogle Scholar
• Brody J, Levy R. Lymphoma immunotherapy: vaccines Adoptive Cell Transfer and Immunotransplant.Immunotherapy. 2009;1:809–824.
   PubMed Web of Science ®Google Scholar
• Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13:688–696.
   PubMed Web of Science ®Google Scholar
• Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. 2000;6(Suppl 1):S55–57.
   PubMed Web of Science ®Google Scholar
• Levin AM, Bates DL, Ring AM et al. Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature. 2012;484:529–533.
   PubMed Web of Science ®Google Scholar
• Shablak A, Sikand K, Shanks JH, et al. High-dose interleukin-2 can produce a high rate of response and durable remissions in appropriately selected patients with metastatic renal cancer. J Immunother. 2011;34:107–112.
   PubMed Web of Science ®Google Scholar
• Amin A, White RL. Interleukin-2 in renal cell carcinoma: a has-been or a still-viable option? J Kid Cancer VHL. 2014;1:74–83.
   PubMedGoogle Scholar
• Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192:5451–5458.
   PubMed Web of Science ®Google Scholar
• Atkins M, Regan M, McDermott D, et al. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res. 2005;11:3714–3721.
   PubMed Web of Science ®Google Scholar
• Sabatino M, Kim-Schulze S, Panelli MC, et al. Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol. 2009;27:2645–2652.
   PubMed Web of Science ®Google Scholar
• Charych DH, Hoch U, Langowski JL, et al. NKTR-214, an engineered cytokine with biased il2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res. 2016;22:680–690.
   PubMed Web of Science ®Google Scholar
• Herndon TM, Demko SG, Jiang X, et al. U.S. food and drug administration approval: peginterferon-alfa-2b for the adjuvant treatment of patients with melanoma. Oncologist. 2012;17:1323–1328.
   PubMed Web of Science ®Google Scholar
• Hughes T, Klairmont M, Broucek J, et al. The prognostic significance of stable disease following high-dose interleukin-2 (IL-2) treatment in patients with metastatic melanoma and renal cell carcinoma. Cancer Immunol Immunother. 2015;64:459–465.
   PubMed Web of Science ®Google Scholar
• Makkouk A, Weiner GJ. Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. Cancer Res. 2015;75:5–10.
   PubMed Web of Science ®Google Scholar
• Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33:1889–1894.
   PubMed Web of Science ®Google Scholar
• Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267–296.
   PubMed Web of Science ®Google Scholar
• Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): A multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883–895.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II Trial. J Clin Oncol. 2015;33:1430–1437.
   PubMed Web of Science ®Google Scholar
• Hodi FS, O’Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723.
   PubMed Web of Science ®Google Scholar
• Chambers CA, Cado D, Truong T, et al. Thymocyte development is normal in CTLA-4-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 94, 9296–9301 (1997).
   Google Scholar
• Khattri R, Auger JA, Griffin MD, et al. Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses. J Immunol. 1999;162:5784–5791.
   PubMed Web of Science ®Google Scholar
• Nivolumab. FDA approval. U.S.: Food and Drug Administration; 2015.
   Google Scholar
• Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. New England J Med. 2015;373:1803–1813.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II Trial. J Clin Oncol. 2015;33:1430–1437.
   PubMed Web of Science ®Google Scholar
• McDermott DF, Drake CG, Sznol M, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol. 2015;33:2013–2020.
   PubMed Web of Science ®Google Scholar
• McDermott DF, Motzer RJ, Atkins MB, et al. Long-term overall survival (OS) with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies. J Clin Oncol. 2016;34(suppl):abstr 4507.
   Google Scholar
• Iacovelli R, Nolè F, Verri E, et al. Prognostic role of PD-L1 expression in renal cell carcinoma. a systematic review and meta-analysis. Target Oncol. 2016;11:143–148.
   PubMed Web of Science ®Google Scholar
• Gandini S, Massi D, Mandalà M. PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2016;100:88–98.
   PubMed Web of Science ®Google Scholar
• Scarpace SL. Metastatic squamous cell non-small-cell lung cancer (NSCLC): disrupting the drug treatment paradigm with immunotherapies. Drugs in Context. 2015;4:212289.
   PubMedGoogle Scholar
• Redman JM, Gibney GT, Atkins MB, et al. Advances in immunotherapy for melanoma. BMC Med. 2016;14:20.
   PubMed Web of Science ®Google Scholar
• Atrash S, Makhoul I, Mizell JS, et al. Response of metastatic mucosal melanoma to immunotherapy: it can get worse before it gets better. J Oncol Pharm Pract. 2016.  pii: 1078155215627503. Available from: http://journals.sagepub.com/doi/abs/10.1177/1078155215627503
   Google Scholar
• Chiou VL, Burotto M. Pseudoprogression and immune-related response in solid tumors. J Clin Oncol. 2015;33:3541–3543.
   PubMed Web of Science ®Google Scholar
• Wolchok JD, Hoos A, O’Day S et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–7420.
   PubMed Web of Science ®Google Scholar
• Bedke J, Kruck S, Gakis G, et al. Checkpoint modulation–A new way to direct the immune system against renal cell carcinoma. Hum Vac Immunother. 2015;11:1201–1208.
   PubMed Web of Science ®Google Scholar
• Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3 — potential mechanisms of action. Nat Rev Immunol. 2014;15:45–56.
   Web of Science ®Google Scholar
• Brignone C, Escudier B, Grygar C, et al. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res. 2009;15:6225–6231.
   PubMed Web of Science ®Google Scholar
• Atkins MB, Plimack ER, Puzanov I, et al. Axitinib in combination with pembrolizumab in patients (pts) with advanced renal cell carcinoma (aRCC): preliminary safety and efficacy results. Ann Oncol. 2016;27:773PD.
   Web of Science ®Google Scholar
• Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247.
   PubMed Web of Science ®Google Scholar
• George S, Motzer RJ, Hammers HJ, et al. Safety and `efficacy of nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical trial. JAMA Oncol. 2016;2(9):1179–1186.
   PubMed Web of Science ®Google Scholar
• Donnem T, Kilvaer TK, Andersen S, et al. Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer. Ann Oncol. 2016;27:225–232.
   PubMed Web of Science ®Google Scholar
• Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an international TILs working group 2014. Ann Oncol. 2015;26:259–271.
   PubMed Web of Science ®Google Scholar
• Galon J, Mlecnik B, Bindea G, et al. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol. 2014;232:199–209.
   PubMed Web of Science ®Google Scholar
• Taube JM. Emerging immunologic biomarkers: setting the (TNM-immune) stage. Clin Cancer Res. 2014;20:2023–2025.
   PubMed Web of Science ®Google Scholar
• Kirilovsky A, Marliot F, El Sissy C, et al. Rational bases for the use of the Immunoscore in routine clinical settings as a prognostic and predictive biomarker in cancer patients. International Immunology, Dxw021. 2016;28(8):376–382.
   Web of Science ®Google Scholar
• Leite KRM, Reis ST, Junior JP, et al. PD-L1 expression in renal cell carcinoma clear cell type is related to unfavorable prognosis. Diagn Pathol. 2015;10:189.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Figueroa DJ, Fay AP, et al. Correlation of PD-l1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ A Randomized Controlled Trial.Clin Can Res. 2015;21:1071–1077.
   PubMed Web of Science ®Google Scholar
• May M, Kendel F, Hoschke B, et al. [Adjuvant autologous tumour cell vaccination in patients with renal cell carcinoma. overall survival analysis with a follow-up period in excess of more than 10 years]. Der Urologe. Ausg. A. 2009;48:1075–1083.
   PubMedGoogle Scholar
• Amato RJ, Hawkins RE, Kaufman HL, et al. Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study. Clin Cancer Res. 2010;16:5539–5547.
   PubMed Web of Science ®Google Scholar
• Sekar RR, DiMarco MA, Dattatraya P, et al. PD-1 expression and its impact on survival in localized clear cell renal cell carcinoma. J Clin Oncol. 2016;34(suppl 2S):abstr 568.
   Google Scholar
• Choueiri TK, Fay AP, Gray KP, et al. PD-L1 expression in nonclear-cell renal cell carcinoma. Ann Oncol. 2014;25:2178–2184.
   PubMed Web of Science ®Google Scholar
• Erlmeier F, Hartmann A, Autenrieth M, et al. PD-1/PD-L1 expression in chromophobe renal cell carcinoma: an immunological exception? Med Oncol. 2016;33:120.
   PubMed Web of Science ®Google Scholar
• Brunot A, Bernhard J-C, Yacoub M, et al. PDL-1 and PDL1 expressions in clear cell renal cell carcinoma (ccRCC) of metastatic patients with sunitinib first-line treatment. 2015 ASCO Ann Meet. 2015;33(suppl):abstr e14002.
   Google Scholar
• Shin S-J, Jeon YK, P-J K, et al. Clinicopathologic analysis of PD-L1 and PD-L2 expression in renal cell carcinoma: association with oncogenic proteins status. Ann Surg Oncol. 2016;23:694–702.
   PubMed Web of Science ®Google Scholar
• Abbas M, Steffens S, Bellut M, et al. Intratumoral expression of programmed death ligand 1 (PD-L1) in patients with clear cell renal cell carcinoma (ccRCC). Med Oncol. 2016;33:80.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Fishman MN, Escudier BJ, et al. Immunomodulatory activity of nivolumab in previously treated and untreated metastatic renal cell carcinoma (mRCC): biomarker-based results from a randomized clinical trial. In: 2014 ASCO Annual Meeting. (J Clin Oncol 32:5s, 2014 (suppl; abstr 5012), 2014)
   Google Scholar
• Choueiri TK, Fishman MN, Escudier B, et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma (mRCC): association of biomarkers with clinical outcomes. J Clin Oncol. 2015;33(suppl): abstr 4500.
   Google Scholar