Novel immunotherapy approaches for metastatic urothelial and renal cell carcinoma
Zhiying Shaoa, Andrew Z. Wangb, Daniel J. Georgec, Tian Zhangd
a Department of Medical Oncology, The Affiliated Hospital of Xuzhou Medical University, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; b Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA c Division of Medical Oncology, Department of Medicine, Division of Urology, Department of Surgery, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA; d Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
Abstract The treatment of metastatic renal cell carcinoma (RCC) and urothelial carcinoma (UC) remains a major challenge. Past research has implicated the immune system in tumor surveillance of both malignancies, leading to the application of immunotherapy agents for both cancers. Among them, the most promising agents are the checkpoint blockade drugs, such as antibodies targeting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death receptor 1 (PD-1), and PD-1 ligand (PD-L1). In normal physiology, these immune checkpoints act as inhibitory signals to fine-tune the duration and strength of immune reactions, which is pivotal for maintaining self-tolerance. However, tumor cells also utilize immune checkpoint pathways to evade anti-tumor immune response, leading to disease progression and metastasis. Thus, there has been intense preclinical and clinical effort focused on the application of checkpoint inhibitors in metastatic RCC and UC. To date, nivolumab (anti-PD-1) and atezolizumab (anti-PD-L1) have been approved for the treatment of metastatic RCC and UC, respectively. Despite these successes, challenges remain in how to further improve response rates to immunotherapy and how to select patients that will benefit from this approach. In this report, we review existing data and research on immunotherapy in metastatic RCC and UC.
Zhiying Shao,Andrew Z. Wang,Daniel J. George, et al. Novel immunotherapy approaches for metastatic urothelial and renal cell carcinoma[J]. Asian Journal of Urology,
2016, 3(4): 268-277.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide:sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.
[2]
Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin 2015;2015:5-29.
[3]
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515:558-62.
[4]
Patil S, Manola J, Elson P, Negrier S, Escudier B, Eiken T, et al. Improvement in overall survival of patients with advanced renal cell carcinoma:prognostic factor trend analysis from an international data set of clinical trials. J Urol 2012;188:2095-100.
[5]
Raman R, Vaena D. Immunotherapy in metastatic renal cell carcinoma:a comprehensive review. Biomed Res Int 2015; 2015:367354.
[6]
Massari F, Santoni M, Ciccarese C, Santini D, Alfieri S, Martignoni G, et al. PD-1 blockade therapy in renal cell carcinoma:current studies and future promises. Cancer Treat Rev 2015;41:114-21.
[7]
McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005;23:133-41.
[8]
Dutcher JP, Fisher RI, Weiss G, Aronson F, Margolin K, Louie A, et al. Outpatient subcutaneous interleukin-2 and interferonalpha for metastatic renal cell cancer:five-year follow-up of the cytokine working group study. Cancer J Sci Am 1997;3:157-62.
[9]
Vogelzang NJ, Lipton A, Figlin RA. Subcutaneous interleukin-2 plus interferon alfa-2a in metastatic renal cancer:an outpatient multicenter trial. J Clin Oncol 1993;11:1809-16.
[10]
Dutcher JP, Atkins M, Fisher R, Weiss G, Margolin K, Aronson F, et al. Interleukin-2-based therapy for metastatic renal cell cancer:the Cytokine Working Group experience, 1989-1997. Cancer J Sci Am 1997;3(Suppl. 1):S73-8.
[11]
Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie. N Engl J Med 1998;338:1272-8.
Tsujihashi H, Matsuda H, Uejima S, Akiyama T, Kurita T. Immunoresponse of tissue infiltrating lymphocytes in bladder tumors. J Urol 1989;141:1467-70.
[15]
Tsujihashi H, Matsuda H, Uejima S, Akiyama T, Kurita T. Immunocompetence of tissue infiltrating lymphocytes in bladder tumors. J Urol 1988;140:890-4.
[16]
Patard J, Saint F, Velotti F, Abbou C, Chopin D. Immune response following intravesical bacillus Calmette-Guerin instillations in superficial bladder cancer:a review. Urol Res 1998;26:155-9.
[17]
Carosella ED, Ploussard G, LeMaoult J, Desgrandchamps F. A systematic review of immunotherapy in urologic cancer:evolving roles for targeting of CTLA-4, PD-1/PD-L1, and HLAG. Eur Urol 2015;68:267-79.
[18]
Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015;348:56-61.
[19]
Noessner E, Brech D, Mendler AN, Masouris I, Schlenker R, Prinz PU. Intratumoral alterations of dendritic-cell differentiation and CD8+ T-cell anergy are immune escape mechanisms of clear cell renal cell carcinoma. Oncoimmunology 2012;1:1451-3.
[20]
Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasetti C, et al. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 1992; 176:1595-604.
[21]
Walunas TL, Lenschow DJ, Bakker CY, Bakker CY, Linsley PS, Freeman GJ, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994;1:405-13.
[22]
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-64.
[23]
Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995;3:541-7.
[24]
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:22.
[25]
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23.
[26]
McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S; MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol 2013;24:2694-8.
[27]
Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, et al. Ipilimumab (Anti-CTLA4 antibody) causes regression of metastatic renal cell Cancer associated with enteritis and hypophysitis. J Immunother 2007;30:825-30.
[28]
Rini BI, Stein M, Shannon P, Eddy S, Tyler A, Stephenson Jr JJ, et al. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer 2011;117:758-67.
[29]
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24.
[30]
Carthon BC, Wolchok JD, Yuan J, Kamat A, Ng Tang DS, Sun J, et al. Preoperative CTLA-4 blockade:tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res 2010;16:2861-71.
[31]
Liakou CI, Kamat A, Tang DN, Chen H, Sun J, Troncoso P, et al. CTLA-4 blockade increases IFNg-producing CD4+ ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci 2008;105:14987-92.
[32]
Powderly JD, Gutierrez M, Wang D, Chae YK, Mahadevan D, Braiteh FS, et al. A phase 1b/2, open-label study to evaluate the safety and tolerability of MEDI6469 in combination with immune therapeutic agents or therapeutic mAbs in patients with selected advanced solid tumors or aggressive B-cell lymphomas. ASCO Meet Abstr 2015. TPS3091.
[33]
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027-34.
[34]
Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001;193:839-46.
[35]
Dong H, Strome SE, Salomao DR, Tamua H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis:a potential mechanism of immune evasion. Nat Med 2002;8:793-800.
[36]
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 2002;99:12293-7.
[37]
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1(MDX-1106) in refractory solid tumors:safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28:3167-75.
[38]
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54.
[39]
McDermott DF, Drake CG, Sznol M, Choueiri TK, Powderly JD, Smith DC, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol 2015;33:2013-20.
[40]
Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, et al. Nivolumab for metastatic renal cell carcinoma:results of a randomized phase II trial. J Clin Oncol 2015;33:1430-7.
[41]
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-13.
[42]
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-33.
[43]
Patnaik A, Kang SP, Rasco D, Papadopoulos KP, ElassaissSchaap J, Beeram M, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 2015;21:4286-93.
[44]
Inman BA, Sebo TJ, Frigola X, Dong H, Bergstralh EJ, Frank I, et al. PD-L1(B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata:associations with localized stage progression. Cancer 2007;109:1499-505.
[45]
Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S. Overexpression of B7-H1(PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 2007;56:1173-82.
[46]
Plimack ER, Bellmunt J, Gupta S, Berger R, Montgomery RB, Heath K, et al. Pembrolizumab (MK-3475) for advanced urothelial cancer:updated results and biomarker analysis from KEYNOTE-012. ASCO Meet Abstr 2015:4502.
[47]
Powderly JD, Koeppen H, Hodi FS, Sosman JA, Gettinger SN, Desai R, et al. Biomarkers and associations with the clinical activity of PD-L1 blockade in a MPDL3280A study. ASCO Meet Abstr 2013:3001.
[48]
McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, et al. Atezolizumab, an antieprogrammed deathligand 1 antibody, in metastatic renal cell carcinoma:longterm safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol 2016;34:833-42.
[49]
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455-65.
[50]
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy:a single-arm, multicentre, phase 2 trial. Lancet 2016;387:1909-20.
[51]
Ibrahim R, Stewart R, Shalabi A. PD-L1 blockade for cancer treatment:MEDI4736. Semin Oncol 2015;42:474-83.
[52]
Heery CR, O'Sullivan Coyne GH, Madan RA, Schlom J, von Heydebreck A, Cuillerot J, et al. Phase I open-label, multiple ascending dose trial of MSB0010718C, an anti-PD-L1 monoclonal antibody, in advanced solid malignancies. ASCO Meet Abstr 2014:3064.
[53]
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 2012; 4. 127ra37.
[54]
Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 2006;66:3381-5.
[55]
Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320-30.
[56]
Paz-Ares L, Horn L, Borghaei H, Spigel DR, Steins M, Ready N, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced nonsquamous cell (non-SQ) non-small cell lung cancer (NSCLC). ASCO Meet Abstr 2015. LBA109.
[57]
Herbst RS, Gordon MS, Fine GD, Sosman JA, Soria J, Hamid O, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. ASCO Meet Abstr 2013:3000.
[58]
Callea M, Genega EM, Gupta M, Fay AP, Song J, Carvo I, et al. PD-L1 expression in primary clear cell renal cell carcinomas (ccRCCs) and their metastases. ASCO Meet Abstr 2014:467.
[59]
Powles T, Nickles D, Van Allen E, Chappey C, Zou W, Kowanetz M, et al. Immune biomarkers associated with clinical benefit from atezolizumab (MPDL3280a; anti-PD-L1) in advanced urothelial bladder cancer (UBC). J Immunother Cancer 2015;3(Suppl. 2):83.
[60]
Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the antiPD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515:563-7.
[61]
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010;107:4275-80.
[62]
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005;25:9543-53.
[63]
Selby M, Engelhardt J, Lu LS, Quigley M, Wang C, Chen B, et al. Antitumor activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical models. ASCO Meet Abstr 2013:3061.
[64]
Hammers H, Plimack ER, Infante JR, Emstoff M, Rini BI, McDermott DF, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (MRCC). Ann Onc 2014;25(Suppl. 4):iv361-72.
[65]
Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2(VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol 2013;172:500-6.
[66]
Amin A, Plimack ER, Infante JR, Ernstoff MS, Rini BI, McDermott DF, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). ASCO Meet Abstr 2014:5010.
[67]
Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest 2007;117:3383-92.
[68]
Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, et al. Role of LAG-3 in regulatory T cells. Immunity 2004;21:503-13.
[69]
Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 2012;72:917-27.
[70]
Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 2005;23:23-68.
[71]
French RR, Taraban VY, Crowther GR, Rowley TF, Gray JC, Johnson PW, et al. Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation. Blood 2007;109:4810-5.
[72]
He LZ, Prostak N, Thomas LJ, Vitale L, Weidlick J, Crocker A, et al. Agonist anti-human CD27 monoclonal antibody induces T cell activation and tumor immunity in human CD27-transgenic mice. J Immunol 2013;191:4174-83.
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