Molekulare Konzepte der Immunmodulation zur Behandlung des metastasierten Nierenzellkarzinoms: Wo stehen wir?

Zusammenfassung

Die Einführung molekularer zielgerichteter Substanzen hat einen Wandel in der Therapie des metastasierten Nierenzellkarzinoms (mNZK) eingeleitet. Die Prognose betroffener Patienten verbesserte sich dadurch signifikant. Dennoch bleibt die Behandlung des mNZK sehr anspruchsvoll, da die meisten Patienten einen Progress erleben müssen und Langzeitüberlebende immer noch eine Seltenheit darstellen. Dieses ist eine klare Grundlage für die weitere Suche nach verbesserten Therapieoptionen. In den letzten Jahren ist die Immuntherapie durch die Entwicklung neuer Substanzen und Therapieansätze mit der zielgerichteten Aktivierung und Modulation des Immunsystems wieder in den Interessensfokus gerückt. Eine bedeutende Entwicklung ist die Anwendung sogenannter Immuncheckpoint-Inhibitoren, durch die eine zielgerichtete (Re-) Aktivierung von T-Zellen erfolgt. Nachfolgend werden die derzeitigen Methoden zur Verbesserung der Standardtherapien mit den etablierten zielgerichteten Substanzen dargestellt und diese mit den neuen immun-onkologischen Ansätzen der Checkpoint-Modulation in einen aktuellen Zusammenhang für die Behandlung von Patienten mit einem mNZK diskutiert.

Abstract

The introduction of molecular targeted agents has started to transform the treatment of metastatic renal cell carcinoma (mRCC), leading to a significant improvement of the prognosis of patients affected by that disease. However, treatment of metastatic disease still remains challenging as almost all patients will experience tumour progression and long-term survivors are very rare. This clearly warrants a continued search for improved treatment options. In recent years, the development of new substances and treatment approaches involving the targeted activation and modulation of the immune system have moved immunotherapy back into the focus of interest. A major development is the use of checkpoint inhibitors, which enable a targeted (re)activation of T cells. The following article describes the current methods used to improve standard treatment with the established targeted substances and discusses them along with the new immunooncological approaches of checkpoint modulation in the context of the treatment of mRCC patients.

Schlüsselwörter

Nierenzellkarzinom - Tyrosinkinase - mTOR - VEGF - Checkpoint-Inhibitor - programmed death-1

Key words

renal cell carcinoma - tyrosine kinase - mTOR - VEGF - checkpoint inhibition - programmed death-1

• Literatur

• 1 GLOBOCAN 2012. Cancer Incidence and Mortality Worldwide: IARC Cancer Base. Lyon, France: International Agency for Research on Cancer; 2015. Im Internet http://globocan.iarc.fr Stand: 12.07.2015
• 2 Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med 2005; 353: 2477-2490
• 3 Brauch H, Pomer S, Hieronymus T et al. Genetic alterations in sporadic renal-cell carcinoma: molecular analyses of tumor suppressor gene harboring chromosomal regions 3p, 5q, and 17p. World J Urol 1994; 12: 162-168
• 4 Kruck S, Bedke J, Kuczyk MA et al. Second-line systemic therapy for the treatment of metastatic renal cell cancer. Expert Rev Anticancer Ther 2012; 12: 777-785
• 5 Ljungberg B, Bensalah K, Canfield S et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol 2015; 67: 913-924
• 6 Motzer RJ, Escudier B, Bukowski R et al. Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma. Br J Cancer 2013; 108: 2470-2477
• 7 Kavoussi LR, Levine SR, Kadmon D et al. Regression of metastatic renal cell carcinoma: a case report and literature review. J Urol 1986; 135: 1005-1007
• 8 Bedke J, Gouttefangeas C, Singh-Jasuja H et al. Targeted therapy in renal cell carcinoma: moving from molecular agents to specific immunotherapy. World J Urol 2013; 32: 31-38
• 9 Bockorny B, Dasanu CA. Intrinsic immune alterations in renal cell carcinoma and emerging immunotherapeutic approaches. Expert Opin Biol Ther 2013; 13: 911-925
• 10 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674
• 11 Bedke J, Gouttefangeas C, Kruck S et al. A vaccine in renal cell carcinoma: are we nearing reality?. Expert Rev Anticancer Ther 2012; 12: 1503-1505
• 12 Schmidinger M, Bellmunt J. Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma. Cancer Treat Rev 2010; 36: 416-424
• 13 Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma (mRCC): updated efficacy and safety results and further analysis of prognostic factors. New Engl J Med 2007; 356: 115-124
• 14 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
• 15 Sternberg CN, Davis ID, Mardiak J et al. Randomized, double-blind phase III study of Pazopanib in patients with advanced/metastatic renal cell carcinoma (MRCC): final overall survival (OS) results. ESMO 2010; Abstract LBA22
• 16 Sternberg CN, Hawkins RE, Wagstaff J et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer 2013; 49: 1287-1296
• 17 Motzer R, Hutson T, Reeves J et al. Randomized, open-label, phase III trial of Pazopanib versus sunitinib in first treatment of patients with metastatic renal cell carcinoma (mRCC): results of the COMPARZ trial. ESMO 2012; Abstract #LBA8_PR
• 18 Motzer RJ, Hutson TE, Cella D et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 369: 722-731
• 19 Escudier B, Pluzanska A, Koralewski P et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370: 2103-2111
• 20 Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cel1 carcinoma. N Engl J Med 2007; 356: 125-134
• 21 Escudier B, Eisen T, Stadler WM et al. 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
• 22 Rini B, Escudier B, Tamczak P et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXlS): A randomized phase three trial. Lancet 2011; 378: 1931-1939
• 23 Motzer RJ, Escudier B, Tomczak P et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013; 14: 552-562
• 24 Hudes G, Carducci M, Tomczyk P et al. Temsirolimus, interferon a, or both for advanced renal cell carcinoma. N Engl J Med 2007; 336: 2271-2281
• 25 Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase lll trial. Lancet 2008; 372: 449-456
• 26 Motzer RJ, Escudier B, Oudard S et al. Phase 3 trial of everolimus for metastatic renal cancer. Cancer 2010; 116: 4356-4365
• 27 Motzer RJ, Hutson TE, Olsen MR et al. Randomized phase II trial of sunitinib on an intermittend versus continous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol 2012; 30: 1371-1377
• 28 Atkinson BJ, Kalra S, Wang X et al. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol 2014; 191: 611-618
• 29 Najjar YG, Mittal K, Elson P et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer 2014; 50: 1084-1089
• 30 Feldman DR, Baum MS, Ginsberg MS et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 1432-1439
• 31 Rini BI, Garcia JA, Cooney MM et al. A phase I study of sunitinib plus bevacizumab in advanced solid tumors. Clin Cancer Res 2009; 15: 6277-6283
• 32 Sosman J, Flaherty FK, Atkins M et al. Updated results of phase I trial of sorafenib and bevacizumab in patient with metastatic renal cell cancer. J Clin Oncol 2008; 26 Abstract 5011
• 33 McDermott D, Manola J, Pins M et al. The BeST Trial (ECOG 2804): a randomized phase II study of VEGF, RAF kinase, and MTOR combination targeted therapy with bevacizumab, sorafenib, and temsirolimus in advanced renal cell carcinoma. J Clin Oncol 2013; 31 Abstract 345
• 34 Rini BI, Bellmunt J, Clancy J et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol 2014; 32: 752-759
• 35 Ravaud A, Barrios C, Anak O et al. Randomized phase II study of first-line everolimus (EVE) + Bevacizumab (BEV) versus interferonalfa-2a(IFN) + BEV inpatients (pts) with metastatic renal cell carcinoma (mRCC): RECORD-2. Ann Oncol 2012; 23: 7830
• 36 Motzer R, Hutson T, Glen H et al. Randomized phase II, three-arm trial of lenvatinib (LEN), everolimus (EVE), and LEN+EVE in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol 2015; 33 Abstract 4506
• 37 Dong H, Strome SE, Salomao DR et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8: 793-800
• 38 Freeman GJ, Long AJ, Iwai Y 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: 1027-1034
• 39 Curiel TJ, Wei S, Dong H et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 2003; 9: 562-567
• 40 Wang QJ, Hanada K, Robbins PF et al. Distinctive features of the differentiated phenotype and infiltration of tumor-reactive lymphocytes in clear cell renal cell carcinoma. Cancer Res 2012; 72: 6119-6129
• 41 Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012; 24: 207-212
• 42 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252-264
• 43 Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443-2454
• 44 Drake CG, McDermott DF, Sznol M et al. Survival, Safety, and Response Duration Results of Nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a Phase 1 Trial in Patients With Previously Treated Metastatic Renal Cell Carcinoma (mRCC): Long-term Patient Follow-up. J Clin Oncol 2013; 31 Abstract 4514
• 45 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
• 46 Plimack ER, Hammers HJ, Rini BI et al. Updated survival results from a randomized, dose-ranging phase II study of nivolumab (NIVO) in metastatic renal cell carcinoma (mRCC). J Clin Oncol 2015; 33 Abstract 4553
• 47 Brahmer JR, Tykodi SS, Chow LQ et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455-2465
• 48 Cho DC, Sosman JA, Sznol M et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PDL1 antibody in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 2013; 31 Abstract 4505
• 49 Amin A, Plimack ER, Infante JR 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). J Clin Oncol 2014; 32: 5s Abstract 5010
• 50 McDermott DF, Sznol M, Sosman JA et al. Immune correlates and long term follow up of a phase Ia study of MPDL3280A, an engineered PD-L1 antibody, in patients with metastatic renal cell carcinoma (mRCC). Ann Oncol 2014; 25 Abstract 809O
• 51 Chambers CA, Kuhns MS, Egen JG et al. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 2001; 19: 565-594
• 52 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
• 53 Yang JC, Hughes M, Kammula U et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother 2007; 30: 825-830
• 54 Hammers H, Plimarck ER, Infante JR et al. Phase I study of nivolumab in combination with Ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol 2014; 32: 5s Abstract 4504
• 55 Hammers HJ, Plimarck ER, Infante JR et al. Expanded cohort results from CheckMate 016: A phase 1 study of nivolumab in combination with ipilimumab in the metastatic renall cell carcinoma (mRCC). J Clinc Oncol 2015; 33 Abstract 4516
• 56 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. J Clin Oncol 2014; 32: 5s Abstract 5012
• 57 Choueiri TK, Fishman MN, Escudier BJ et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma (mRCC): Association of biomarkers with clinical outcomes. J Clin oncol 2015; 33 Abstract 4500
• 58 McGuire WL. Breast cancer prognostic factors: evaluation guidelines. J Natl Cancer Inst 1991; 83: 154-155
• 59 Simon R, Altman DG. Statistical aspects of prognostic factor studies in oncology. Br J Cancer 1994; 69: 979-985
• 60 Pajak TF, Clark GM, Sargent DJ et al. Statistical issues in tumor marker studies. Arch Pathol Lab Med 2000; 124: 1011-1015
• 61 Altman DG, Royston P. What do we mean by validating a prognostic model?. Stat Med 2000; 19: 453-473
• 62 Begg CB, Cramer LD, Venkatraman ES et al. Comparing tumour staging and grading systems: a case study and a review of the issues, using thymoma as a model. Stat Med 2000; 19: 1997-2014
• 63 Mallett S, Timmer A, Sauerbrei W et al. Reporting of prognostic studies of tumour markers: a review of published articles in relation to REMARK guidelines. Br J Cancer 2010; 102: 173-180
• 64 Altman DG, McShane LM, Sauerbrei W et al. Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): explanation and elaboration. PLoS Med 2012; 9: e1001216
• 65 Bedke J, Kruck S, Gakis G et al. Checkpoint modulation – A new way to direct the immune system against renal cell carcinoma. Hum Vaccin Immunother 2015; 11: 1201-1208