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23-01-2018 | Bladder cancer | Article

Unwrapping the genomic characteristics of urothelial bladder cancer and successes with immune checkpoint blockade therapy

Journal: Oncogenesis

Authors: Wen Cheng, Dian Fu, Feng Xu, Zhengyu Zhang

Publisher: Nature Publishing Group UK

Abstract

Urothelial bladder cancer (UBC) is one of the most common lethal cancer worldwide and the 5-year survival rate has not improved significantly with current treatment protocols during the last decade. Intravesical immunotherapy with Bacillus Calmette-Guérin is currently the standard care for non-muscle invasive UBC. Recently, a subset of patients with locally advanced or metastatic UBC have responded to checkpoint blockade immunotherapy against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1) or the cytotoxic T-lymphocyte antigen 4 that releases the inhibition of T cells, the remarkable clinical efficacy on UBC has brought total five checkpoint inhibitors approved by the FDA in the last 2 years, and this is revolutionizing treatment of advanced UBC. We discuss the rationale for immunotherapy in bladder cancer, progress with blocking the PD-1/PD-L1 pathway for UBC treatment, and ongoing clinical trials. We highlight the complexity of the interactions between cancer cells and the immune system, the genomic basis for response to checkpoint blockade immunotherapy, and potential biomarkers for predicting immunotherapeutic response.

Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).CrossRefPubMed

Krummel, M. F. & Allison, J. P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182, 459–465 (1995).CrossRefPubMed

Freeman, G. J. 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. 192, 1027–1034 (2000).CrossRefPubMedPubMedCentral

Ott, P. A., Hodi, F. S. & Robert, C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin. Cancer Res. 19, 5300–5309 (2013).CrossRefPubMed

Burnet, M. The concept of immunologic surveillance. Prog. Exp. Tumor Res. 13, 1–27 (1970).CrossRefPubMed

Dunn, G. P., Old, L. J. & Schreiber, R. D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148 (2004).CrossRefPubMed

Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).CrossRefPubMed

Angelova, M. et al. Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol. 16, 64 (2015).CrossRefPubMedPubMedCentral

Lenis, A. T. & Chamie, K. Bladder cancer in 2014: From the genomic frontier to immunotherapeutics. Nat. Rev. Urol. 12, 74–76 (2015).CrossRefPubMed

10.

Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).CrossRefPubMedPubMedCentral

11.

Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).CrossRefPubMedPubMedCentral

12.

Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).CrossRefPubMed

13.

Rosenberg, J. E. 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 387, 1909–1920 (2016).CrossRefPubMedPubMedCentral

14.

Torre, L. A. et al. Global cancer statistics, 2012. Ca. Cancer J. Clin. 65, 87–108 (2015).CrossRefPubMed

15.

von der Maase, H. et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J. Clin. Oncol. 23, 4602–4608 (2005).CrossRefPubMed

16.

Sonpavde, G. et al. Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium. Lancet Oncol. 11, 861–870 (2010).CrossRefPubMed

17.

Balar, A. V. et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389, 67–76 (2017).CrossRefPubMed

18.

Balar, A., Bellmunt, J., & O’Donnell, P. H. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial Cancer: preliminar results from the phase 2 KEYNOTE-052 study. Ann. Oncol. 27, A32 (2016). Abstract LB. https://doi.org/10.1093/annonc/mdw435.25.

19.

Sharma, P. et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol. 17, 1590–1598 (2016).CrossRefPubMedPubMedCentral

20.

Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).CrossRefPubMedPubMedCentral

21.

Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014).

22.

Colli, L. M. et al. Burden of nonsynonymous mutations among TCGA cancers and candidate immune checkpoint inhibitor responses. Cancer Res. 76, 3767–3772 (2016).CrossRefPubMedPubMedCentral

23.

Lindgren, D. et al. Integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma. PLoS. ONE 7, e38863 (2012).CrossRefPubMedPubMedCentral

24.

Chekaluk, Y. et al. Identification of nine genomic regions of amplification in urothelial carcinoma, correlation with stage, and potential prognostic and therapeutic value. PLoS. ONE 8 (2013).

25.

Iyer, G. et al. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J. Clin. Oncol. 31, 3133–3140 (2013).CrossRefPubMedPubMedCentral

26.

Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).CrossRefPubMed

27.

Nathanson, T. et al Somatic mutations and neoepitope homology in melanomas treated with CTLA-4 blockade. Cancer Immunol. Res. 5, 84–91 (2017).CrossRefPubMed

28.

Morales, A. Treatment of carcinoma in situ of the bladder with BCG. Cancer Immunol. Immunother. 9, 69–72 (1980).CrossRef

29.

Sylvester, R. J., van der, M. A. & Lamm, D. L. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J. Urol. 168, 1964–1970 (2002).CrossRefPubMed

30.

Pichler, R. et al. Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical bacillus calmette-guerin therapy in bladder cancer. Oncotarget 7, 15 (2016).CrossRef

31.

Hadaschik, B. A. et al. [Oncolytic vesicular stomatitis viruses as intravesical agents against non-muscle-invasive bladder cancer]. Urol. A. 47, 1145–1151 (2008).CrossRef

32.

Fahmy, O., Khairul-Asri, M. G., Stenzl, A. & Gakis, G. Systemic anti-CTLA-4 and intravesical Bacille-Calmette-Guerin therapy in non-muscle invasive bladder cancer: Is there a rationale of synergism? Med. Hypotheses 92, 57–58 (2016).CrossRefPubMed

33.

Gupta, S., Gill, D., Poole, A. & Agarwal, N. Systemic immunotherapy for urothelial cancer: current trends and future directions. Cancers (Basel). 9 (2017). https://doi.org/10.3390/cancers9020015.

34.

Spiess, P. E. et al. Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 15, 1240–1267 (2017).CrossRef

35.

Balar, A. V. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 18, 1483–1492 (2017).CrossRefPubMed

36.

Massard, C. et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J. Clin. Oncol. 34, 3119–3125 (2016).CrossRefPubMedPubMedCentral

37.

Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).CrossRefPubMedPubMedCentral

38.

Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).CrossRefPubMedPubMedCentral

39.

Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).CrossRefPubMedPubMedCentral

40.

Hellmann, M. D. et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohorpt study. Lancet Oncol. 18, 31–41 (2017).CrossRefPubMed

41.

Matt, D. et al. Phase II trial of gemcitabine + cisplatin + ipilimumab in patients with metastatic urothelial cancer. J. Clin. Oncol. 34, 357 (2016).

42.

Hugo, W. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).CrossRefPubMedPubMedCentral

43.

Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).CrossRefPubMedPubMedCentral

44.

Liakou, C. I. et al. CTLA-4 blockade increases IFNgamma-producing CD4 + ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc. Natl. Acad. Sci. USA 105, 14987–14992 (2008).CrossRefPubMedPubMedCentral

45.

Ng Tang, D. et al. Increased frequency of ICOS + CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol. Res. 1, 229–234 (2013).CrossRefPubMed

46.

Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. & Allison, J. P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206, 1717–1725 (2009).CrossRefPubMedPubMedCentral

47.

Ku, G. Y. et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116, 1767–1775 (2010).CrossRefPubMedPubMedCentral

48.

Ji, R. R. et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol., Immunother. 61, 1019–1031 (2012).CrossRef

49.

Gajewski, T. F., Louahed, J. & Brichard, V. G. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 16, 399–403 (2010).CrossRefPubMed

50.

Cha, E. et al. Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients. Sci. Transl. Med. 6, 238ra70 (2014).CrossRefPubMedPubMedCentral

51.

Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).CrossRefPubMedPubMedCentral

52.

Snyder, A. et al. Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis. PLoS. Med. 14, e1002309 (2017).CrossRefPubMedPubMedCentral

53.

Giannakis, M. et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 17, 857–865 (2016).

54.

Brown, S. D. et al. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 24, 743–750 (2014).CrossRefPubMedPubMedCentral

55.

Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).CrossRefPubMedPubMedCentral

56.

Herbst, R. S. et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. J. Clin. Oncol. 31 (suppl; abstr 3000) (2013).

57.

Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).CrossRefPubMedPubMedCentral

58.

Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).CrossRefPubMedPubMedCentral

59.

McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).CrossRefPubMedPubMedCentral

60.

Johanns, T. M. et al. Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov. 6, 1230–1236 (2016).CrossRefPubMedPubMedCentral

61.

Triebel, F. et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J. Exp. Med. 171, 1393–1405 (1990).CrossRefPubMed

62.

Fourcade, J. et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8 + T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175–2186 (2010).CrossRefPubMedPubMedCentral

63.

Wang, L. et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J. Exp. Med. 208, 577–592 (2011).CrossRefPubMedPubMedCentral

64.

Fourcade, J. et al. CD8( + ) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res. 72, 887–896 (2012).CrossRefPubMed

65.

Fan, X., Quezada, S. A., Sepulveda, M. A., Sharma, P. & Allison, J. P. Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J. Exp. Med. 211, 715–725 (2014).CrossRefPubMedPubMedCentral

66.

Redmond, W. L., Linch, S. N. & Kasiewicz, M. J. Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity. Cancer Immunol. Res. 2, 142–153 (2014).CrossRefPubMed

67.

Kohrt, H. E. et al. Targeting CD137 enhances the efficacy of cetuximab. J. Clin. Invest. 124, 2668–2682 (2014).CrossRefPubMedPubMedCentral

68.

Newick, K., . & O’Brien, S. & Moon, E. & AlbeldaS. M.. CAR T Cell Therapy for Solid Tumors. Annu. Rev. Med. 68, 139–152 (2017).CrossRefPubMed

69.

Petrylak, D. P. et al. A phase Ia study of MPDL3280A (anti-PDL1): updated response and survival data in urothelial bladder cancer (UBC). J. Clin. Oncol. 33 (suppl; abstr 4501) (2015).

70.

Plimack, E. R. et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J. Clin. Oncol. 33, 4502 (2015).CrossRef

71.

Bellmunt J, et al. (eds). Keynote-045: open-label, phase III study of pembrolizumab versus investigator’s choice of paclitaxel, docetaxel, or vinflunine for previously treated advanced urothelial cancer. In Proceedings of the 2016 SITC Annual Meeting; 9–13 November 2016 (1National Harbor, MD, USA, 2016).

72.

Galsky, M. D. et al. Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have recieved previous treatment: results from the pashe II CheckMate 275 study ESMO. J. Clin. Oncol. LB, A31 (2016).

73.

Apolo, A. B. et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: Analysis of safety, clinical activity, and PD-L1 expression. J. Clin. Oncol. 34, 4514 (2016).CrossRef

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Medicine Matters Oncology

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