Targeting the Tumor Microenvironment with Immunotherapy for Genitourinary Malignancies

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1. 1.
   Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180–3.  https://doi.org/10.1016/S0022-5347(17)58737-6.CrossRefPubMedGoogle Scholar
2. 2.
   Kamat AM, Bellmunt J, Galsky MD, Konety BR, Lamm DL, Langham D, et al. Society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of bladder carcinoma. J Immunother Cancer. 2017;5(1):0.  https://doi.org/10.1186/s40425-017-0271-0.Google Scholar
3. 3.
   Ratliff TL, Gillen D, Catalona WJ. Requirement of a thymus dependent immune response for BCG-mediated antitumor activity. J Urol. 1987;137(1):155–8.  https://doi.org/10.1016/S0022-5347(17)43909-7.CrossRefPubMedGoogle Scholar
4. 4.
   Prescott S, James K, Hargreave TB, Chisholm GD, Smyth JF. Intravesical evans strain BCG therapy: quantitative immunohistochemical analysis of the immune response within the bladder wall. J Urol. 1992;147(6):1636–42.  https://doi.org/10.1016/S0022-5347(17)37668-1.CrossRefPubMedGoogle Scholar
5. 5.
   Kates M, Nirschl T, Sopko NA, Matsui H, Kochel CM, Reis LO, et al. Intravesical BCG induces CD4+ T-cell expansion in an immune competent model of bladder cancer. Cancer Immunol Res. 2017;5(7):594–603.  https://doi.org/10.1158/2326-6066.CIR-16-0267.CrossRefPubMedPubMedCentralGoogle Scholar
6. 6.
   von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068–77.  https://doi.org/10.1200/JCO.2000.18.17.3068.CrossRefPubMedGoogle Scholar
7. 7.
   Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42(1):50–4.  https://doi.org/10.1016/j.ejca.2005.08.032.CrossRefPubMedGoogle Scholar
8. 8.
   Sonpavde G, Watson D, Tourtellott M, Cowey CL, Hellerstedt B, Hutson TE, et al. Administration of cisplatin-based chemotherapy for advanced urothelial carcinoma in the community. Clin Genitourin Cancer. 2012;10(1):1–5.  https://doi.org/10.1016/j.clgc.2011.11.005.CrossRefPubMedGoogle Scholar
9. 9.
   Bellmunt J, Choueiri TK, Fougeray R, Schutz FAB, Salhi Y, Winquist E, et al. Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. J Clin Oncol. 2010;28(11):1850–5.  https://doi.org/10.1200/JCO.2009.25.4599.CrossRefPubMedGoogle Scholar
10. 10.
    Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, et al. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Oncol. 2011;29(17):2432–8.  https://doi.org/10.1200/JCO.2011.34.8433.CrossRefPubMedGoogle Scholar
11. 11.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.  https://doi.org/10.1038/nrc3239.CrossRefPubMedPubMedCentralGoogle Scholar
12. 12.
    •• 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(10031):1909–20.  https://doi.org/10.1016/S0140-6736(16)00561-4. This study along with refs. [14] and [22] demonstrate that the “T-cell inflamed” gene expression profile is associated with response to anti-PD-1/PD-L1 and may serve as a predictive biomarker in advanced urothelial carcinoma. This study also suggests that PD-L1 expression, TCGA subtype, and intratumoral mutational burden might be used in concert to select patients that may benefit from immune checkpoint inhibitionCrossRefPubMedPubMedCentralGoogle Scholar
13. 13.
    Genentech, a Member of the Roche Group. Genentech provides updates on phase III study of tecentriq (atezolizumab) in people with previously treated advanced bladder cancer. 2017. Retrieved from https://www.gene.com/media/press-releases/14665/2017-05-09/genentech-provides-update-on-phase-iii-s
14. 14.
    Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–22.  https://doi.org/10.1016/S1470-2045(17)30065-7.CrossRefPubMedGoogle Scholar
15. 15.
    Powles T, O’Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411.  https://doi.org/10.1001/jamaoncol.2017.2411.CrossRefPubMedGoogle Scholar
16. 16.
    Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, et al. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase ib study. J Clin Oncol. 2017;35(19):2117–24.  https://doi.org/10.1200/JCO.2016.71.6795.CrossRefPubMedPubMedCentralGoogle Scholar
17. 17.
    •• Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26.  https://doi.org/10.1056/NEJMoa1613683. The KEYNOTE-045 trial demonstrated a robust overall survival benefit of pembrolizumab over investigator’s choice chemotherapy. Pembrolizumab is the first and only agent to have demonstrated an OS benefit relative to chemotherapy in the second-line setting and remains the only immune checkpoint inhibitor with regular FDA approval for this indicationCrossRefPubMedPubMedCentralGoogle Scholar
18. 18.
    De Wit R, Vaughn DJ, Fradet Y, et al.. Pembrolizumab (pembro) versus paclitaxel, docetaxel, vinflunine for recurrent, advanced urothelial cancer (UC): mature results from the phase 3 KEYNOTE-045 trial [abstract]. In: European Society of Medical Oncology (ESMO) 2017 Congress; 2017 ; Madrid, Spain. ESMO; 2017 Abstract LBA37_PR.Google Scholar
19. 19.
    •• Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, 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. 2017;389(10064):67–76.IMvigor210 cohort 1 demonstrates that atezolizumab is active in first-line cisplatin ineligible urothelial cancer. In contrast to pembrolizumab (ref. [21]), PD-L1 expression does not appear to influence response to atezolizumab in the treatment-naïve setting. These results also contrast the companion IMvigor210 cohort 2 (ref. [12]) study, where responses to atezolizumab were enriched among platinum-refractory patients with increased PD-L1 expression on tumor-infiltrating immune cells.  https://doi.org/10.1016/S0140-6736(16)32455-2.CrossRefPubMedGoogle Scholar
20. 20.
    •• Balar AV, Castellano D, O’Donnell PH, et al. 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. 2017;18(11):1483–92 The use of pembrolizumab (and ref. [22]) in first-line cisplatin-ineligible advanced urothelial carcinoma demonstrated encouraging efficacy and safety leading to accelerated FDA approval. Responses appear to be enriched among patients with increased PD-L1 expression. Google Scholar
21. 21.
    O’Donnell PH, Grivas P, Balar AV, et al. Biomarker findings and mature clinical results from KEYNOTE-052: first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC) [abstract]. In: American Society of Clinical Oncology (ASCO); 2017; Chicago, IL. ASCO; 2017 Abstract 4502.Google Scholar
22. 22.
    Sonpavde G, Pond GR, Rosenberg JE, Bajorin DF, Choueiri TK, Necchi A, et al. Improved 5-factor prognostic classification of patients receiving salvage systemic therapy for advanced urothelial carcinoma. J Urol. 2016;195(2):277–82.  https://doi.org/10.1016/j.juro.2015.07.111.CrossRefPubMedGoogle Scholar
23. 23.
    Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016;16(5):275–87.  https://doi.org/10.1038/nrc.2016.36.CrossRefPubMedPubMedCentralGoogle Scholar
24. 24.
    Ghasemzadeh A, Bivalacqua TJ, Hahn NM, Drake CG. New strategies in bladder cancer: a second coming for immunotherapy. Clin Cancer Res. 2016;22(4):793–801.  https://doi.org/10.1158/1078-0432.CCR-15-1135.CrossRefPubMedGoogle Scholar
25. 25.
    Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–22.  https://doi.org/10.1038/ni.2703.CrossRefPubMedPubMedCentralGoogle Scholar
26. 26.
    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.  https://doi.org/10.1126/science.aaa1348.CrossRefPubMedPubMedCentralGoogle Scholar
27. 27.
    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315–22.  https://doi.org/10.1038/nature12965.CrossRefGoogle Scholar
28. 28.
    Smith DC, Gajewski TF, Hamid O et al.. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: preliminary phase I/II results of ECHO-202/KEYNOTE-037 [abstract]. In: American Society of Clinical Oncology (ASCO); 2017; Chicago, IL. ASCO; 2017 Abstract 4503.Google Scholar
29. 29.
    Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688–96.  https://doi.org/10.1200/JCO.1995.13.3.688.CrossRefPubMedGoogle Scholar
30. 30.
    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):55.Google Scholar
31. 31.
    •• 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(19):1803–13.  https://doi.org/10.1056/NEJMoa1510665. This randomized, open-label phase III randomized trial demonstrated an overall survival benefit associated with nivolumab over everolimus, leading to FDA approval of nivoumab for advanced RCC patients after anti-angiogenic therapy in 2015CrossRefPubMedPubMedCentralGoogle Scholar
32. 32.
    Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, 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):1599–611.  https://doi.org/10.1016/S1470-2045(16)30408-9.CrossRefPubMedGoogle Scholar
33. 33.
    Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237–51.  https://doi.org/10.1038/nrc3237.CrossRefPubMedPubMedCentralGoogle Scholar
34. 34.
    Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996;2(10):1096–103.  https://doi.org/10.1038/nm1096-1096.CrossRefPubMedGoogle Scholar
35. 35.
    Liu XD, Hoang A, Zhou L, Kalra S, Yetil A, Sun M, et al. Resistance to antiangiogenic therapy is associated with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma. Cancer Immunol Res. 2015;3(9):1017–29.  https://doi.org/10.1158/2326-6066.CIR-14-0244.CrossRefPubMedPubMedCentralGoogle Scholar
36. 36.
    Escudier B, et al.. CheckMate 214: efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. [abstract]. In: European Society of Medical Oncology (ESMO) 2017 Congress; 2017; Madrid, Spain. ESMO; 2017 Abstract LBA5.Google Scholar
37. 37.
    Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20(1):289–96.  https://doi.org/10.1200/JCO.2002.20.1.289.CrossRefPubMedGoogle Scholar
38. 38.
    Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794–9.  https://doi.org/10.1200/JCO.2008.21.4809.CrossRefPubMedGoogle Scholar
39. 39.
    Ko JJ, Xie W, Kroeger N, Lee J, Rini BI, Knox JJ, et al. The international metastatic renal cell carcinoma database consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. Lancet Oncol. 2015;16(3):293–300.  https://doi.org/10.1016/S1470-2045(14)71222-7.CrossRefPubMedGoogle Scholar
40. 40.
    McDermott D, Atkins MB, Motzer R et al.. A phase II study of Atezolizumab with or without bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma patients [abstract]. In: 2017 Genitourinary Cancer Symposium (ASCO GU); 2017; Orlando, FL. ASCO GU; 2017 Abstract 431.Google Scholar
41. 41.
    Choueiri TK, Larkin JMG, Oya M, et al.. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): results from a phase Ib trial. J Clin Oncol. 2017; 35 (suppl; abstr 4504).Google Scholar
42. 42.
    Lee C, Makker V, Rasco D, et al.. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma. Presented at ESMO 2017 Congress; 2017; Madrid, Spain. Abstract 847O.Google Scholar
43. 43.
    Choueiri TK, Hessel C, Halabi S, et al.. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; 2017; Madrid, Spain. Abstract LBA38.Google Scholar
44. 44.
    Derosa L, Rouche JA, Colomba E et al.. Efficacy of cabozantinib (C) after PD-1/PD-L1 checkpoint inhibitors in metastatic renal cell carcinoma (mRCC): The Gustave Roussy experience. In: Proceedings from the 2017 ESMO Congress; 2017; Madrid, Spain. Abstract 876P.Google Scholar
45. 45.
    • George S, Motzer RJ, Hammers HJ, Redman BG, Kuzel TM, Tykodi SS, 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):1179–86.  https://doi.org/10.1001/jamaoncol.2016.0775. Similar to ref. [48], a majority of patients treated beyond RECIST-defined progression derive clinical benefit from nivolumab suggesting the need for alternative metrics for treatment response evaluationCrossRefPubMedPubMedCentralGoogle Scholar
46. 46.
    Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20.  https://doi.org/10.1158/1078-0432.CCR-09-1624.CrossRefPubMedGoogle Scholar
47. 47.
    Nishino M, Ramaiya NH, Hatabu H, Hodi FS. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat Rev Clin Oncol. 2017;14(11):655–68.  https://doi.org/10.1038/nrclinonc.2017.88.
48. 48.
    •• Escudier B, Motzer RJ, Sharma P, Wagstaff J, Plimack ER, Hammers HJ, et al. Treatment beyond progression in patients with advanced renal cell carcinoma treated with nivolumab in CheckMate 025. Eur Urol. 2017;72(3):368–376. The use of the RECIST criteria to evaluate treatment response to immunotherapy may be suboptimal. This study demonstrated that approximately half (and 69% per ref [45]) of patients treated beyond RECIST-defined progression on nivolumab ultimately develop stabilization or reduction in disease parameters. This supports the use of treatment evaluation criteria catered specifically to immunotherapy, including the immune-related response criteria (irRC) or iRECIST.  https://doi.org/10.1016/j.eururo.2017.03.037.CrossRefPubMedGoogle Scholar
49. 49.
    Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, et al. Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res. 2001;61(13):5132–6.PubMedGoogle Scholar
50. 50.
    Giraldo NA, Becht E, Pages F, Skliris G, Verkarre V, Vano Y, et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res. 2015;21(13):3031–40.  https://doi.org/10.1158/1078-0432.CCR-14-2926.CrossRefPubMedGoogle Scholar
51. 51.
    Giraldo NA, Becht E, Vano Y, Petitprez F, Lacroix L, Validire P, et al. Tumor-infiltrating and peripheral blood T-cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma. Clin Cancer Res. 2017;23(15):4416–28.  https://doi.org/10.1158/1078-0432.CCR-16-2848.CrossRefPubMedGoogle Scholar
52. 52.
    McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase ia study. J Clin Oncol. 2016;34(8):833–42.  https://doi.org/10.1200/JCO.2015.63.7421.CrossRefPubMedGoogle Scholar
53. 53.
    Escudier B, Sharma P, McDermott DF, et al.. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017;72(6):962–71.Google Scholar
54. 54.
    McNeel DG, Bander NH, Beer TM, et al.. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of prostate carcinoma. J Immunother Cancer. 2016;4:x. eCollection 2016.  https://doi.org/10.1186/s40425-016-0198-x.
55. 55.
    Laccetti AL, Subudhi SK. Immunotherapy for metastatic prostate cancer: immuno-cold or the tip of the iceberg? Curr Opin Urol. 2017;27(6):566–71.  https://doi.org/10.1097/MOU.0000000000000433.CrossRefPubMedGoogle Scholar
56. 56.
    Bilusic M, Madan RA, Gulley JL. Immunotherapy of prostate cancer: facts and hopes. Clin Cancer Res. 2017;23(22):6764–70.  https://doi.org/10.1158/1078-0432.CCR-17-0019.CrossRefPubMedGoogle Scholar
57. 57.
    Lopez-Bujanda Z, Drake CG. Myeloid-derived cells in prostate cancer progression: phenotype and prospective therapies. J Leukoc Biol. 2017;102(2):393–406.  https://doi.org/10.1189/jlb.5VMR1116-491RR.CrossRefPubMedGoogle Scholar
58. 58.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22.  https://doi.org/10.1056/NEJMoa1001294.CrossRefPubMedGoogle Scholar
59. 59.
    Sheikh NA, Petrylak D, Kantoff PW, dela Rosa C, Stewart FP, Kuan LY, et al. Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer. Cancer Immunol Immunother. 2013;62(1):137–47.  https://doi.org/10.1007/s00262-012-1317-2.CrossRefPubMedGoogle Scholar
60. 60.
    • GuhaThakurta D, Sheikh NA, Fan LQ, Kandadi H, Meagher TC, Hall SJ, et al. Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcome. Clin Cancer Res. 2015;21(16):3619–30.  https://doi.org/10.1158/1078-0432.CCR-14-2334. A report documenting and validating the phenomenon of antigen spread in prostate cancer patients treated with sipuleucel-T in a phase III (IMPACT) and independent phase II trial (ProACT)CrossRefPubMedPubMedCentralGoogle Scholar
61. 61.
    Gulley JL, Madan RA, Pachynski R, et al.. Role of antigen spread and distinctive characteristics of immunotherapy in cancer treatment. J Natl Cancer Inst. 2017;109(4).  https://doi.org/10.1093/jnci/djw261.
62. 62.
    Schellhammer PF, Chodak G, Whitmore JB, Sims R, Frohlich MW, Kantoff PW. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the immunotherapy for prostate adenocarcinoma treatment (IMPACT) trial. Urology. 2013;81(6):1297–302.  https://doi.org/10.1016/j.urology.2013.01.061.CrossRefPubMedGoogle Scholar
63. 63.
    Gulley JL, Madan RA, Tsang KY, Jochems C, Marte JL, Farsaci B, et al. Immune impact induced by PROSTVAC (PSA-TRICOM), a therapeutic vaccine for prostate cancer. Cancer Immunol Res. 2014;2(2):133–41.  https://doi.org/10.1158/2326-6066.CIR-13-0108.CrossRefPubMedGoogle Scholar
64. 64.
    Kantoff PW, Gulley JL, Pico-Navarro C. Revised overall survival analysis of a phase II, randomized, double-blind, controlled study of PROSTVAC in men with metastatic castration-resistant prostate cancer. J Clin Oncol. 2017;35(1):124–5.  https://doi.org/10.1200/JCO.2016.69.7748.CrossRefPubMedGoogle Scholar
65. 65.
    •• Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700–12.  https://doi.org/10.1016/S1470-2045(14)70189-5. This phase III multi-center, placebo-controlled, double-blind trial enrolled metastatic castrate-resistant prostate cancer (mCRPC) patients in the post-docetaxel setting. The addition of ipilimumab to palliative radiotherapy failed to improve overall survival, the primary endpoint. However, planned post-hoc analysis demonstrates that patients with “good” prognostic features derive a significant survival benefit with ipilimumab relative to controlCrossRefPubMedPubMedCentralGoogle Scholar
66. 66.
    •• Beer TM, Kwon ED, Drake CG, Fizazi K, Logothetis C, Gravis G, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol. 2017;35(1):40–7.  https://doi.org/10.1200/JCO.2016.69.1584. While subset analysis within ref. [65] suggests that mCRPC patients with “good” prognostic features may derive benefit from ipilimumab, this phase III randomized trial failed to demonstrate an overall survival benefit with the addition of ipilimumab in a chemotherapy-naïve population with less advanced diseaseCrossRefPubMedGoogle Scholar
67. 67.
    • Gao J, Ward JF, Pettaway CA, Shi LZ, Subudhi SK, Vence LM, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med. 2017;23(5):551–5.  https://doi.org/10.1038/nm.4308. This work suggests that alternative immune checkpoints and immune evasion mechanisms may be at play in prostate cancer. Following treatment with ipilimumab, a population of intratumoral CD68+ macrophages upregulate VISTA or PD-L1, suggesting that VISTA may be an important immunoregulatory mechanism in prostate cancerCrossRefPubMedGoogle Scholar
68. 68.
    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(26):2443–54.  https://doi.org/10.1056/NEJMoa1200690.CrossRefPubMedPubMedCentralGoogle Scholar
69. 69.
    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(19):3167–75.  https://doi.org/10.1200/JCO.2009.26.7609.CrossRefPubMedPubMedCentralGoogle Scholar
70. 70.
    Hansen A, Massard C, Ott P, Haas N, Ejadi S, Wallmark J, et al. Pembrolizumab for patients with advanced prostate adenocarcinoma: preliminary results from the KEYNOTE-028 study. Ann Oncol. 2016;27(suppl 6):725PD.Google Scholar
71. 71.
    Graff JN, Alumkal JJ, Drake CG, Thomas GV, Redmond WL, Farhad M, et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget. 2016;7(33):52810–7.  https://doi.org/10.18632/oncotarget.10547.CrossRefPubMedPubMedCentralGoogle Scholar
72. 72.
    Graff JN, Alumkal JJ, Drake CG, et al.. First evidence of significant clinical activity of PD-1 inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Presented at ESMO 2016; Presentation #719O.Google Scholar
73. 73.
    Antonarakis ES, Kibel AS, Yu EY, Karsh LI, Elfiky A, Shore ND, et al. Sequencing of sipuleucel-T and androgen deprivation therapy in men with hormone-sensitive biochemically recurrent prostate cancer: a phase II randomized trial. Clin Cancer Res. 2017;23(10):2451–9.  https://doi.org/10.1158/1078-0432.CCR-16-1780.CrossRefPubMedGoogle Scholar
74. 74.
    Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028–38.  https://doi.org/10.1056/NEJMoa1315815.CrossRefPubMedPubMedCentralGoogle Scholar
75. 75.
    Drake CG, Doody AD, Mihalyo MA, et al. Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. Cancer Cell. 2005;7(3):239–49.  https://doi.org/10.1016/j.ccr.2005.01.027.CrossRefPubMedPubMedCentralGoogle Scholar
76. 76.
    Bishop JL, Sio A, Angeles A, Roberts ME, Azad AA, Chi KN, et al. PD-L1 is highly expressed in enzalutamide resistant prostate cancer. Oncotarget. 2015;6(1):234–42.  https://doi.org/10.18632/oncotarget.2703.CrossRefPubMedGoogle Scholar
77. 77.
    Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology. 2014;3(4):e28518.  https://doi.org/10.4161/onci.28518.CrossRefPubMedPubMedCentralGoogle Scholar
78. 78.
    Hodge JW, Garnett CT, Farsaci B, Palena C, Tsang KY, Ferrone S, et al. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int J Cancer. 2013;133(3):624–36.  https://doi.org/10.1002/ijc.28070.CrossRefPubMedPubMedCentralGoogle Scholar
79. 79.
    Malamas AS, Gameiro SR, Knudson KM, Hodge JW. Sublethal exposure to alpha radiation (223Ra dichloride) enhances various carcinomas’ sensitivity to lysis by antigen-specific cytotoxic T lymphocytes through calreticulin-mediated immunogenic modulation. Oncotarget. 2016;7(52):86937–47.  https://doi.org/10.18632/oncotarget.13520.CrossRefPubMedPubMedCentralGoogle Scholar
80. 80.
    Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D, et al. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res. 2006;12(4):1260–9.  https://doi.org/10.1158/1078-0432.CCR-05-2059.CrossRefPubMedPubMedCentralGoogle Scholar
81. 81.
    Heery CR, Madan RA, Stein MN, Stadler WM, Di Paola RS, Rauckhorst M, et al. Samarium-153-EDTMP (quadramet®) with or without vaccine in metastatic castration-resistant prostate cancer: a randomized phase 2 trial. Oncotarget. 2016;7(42):69014–23.  https://doi.org/10.18632/oncotarget.10883.CrossRefPubMedPubMedCentralGoogle Scholar
82. 82.
    Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–23.  https://doi.org/10.1056/NEJMoa1213755.CrossRefPubMedGoogle Scholar
83. 83.
    Pritchard CC, Mateo J, Walsh MF, de Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443–53.  https://doi.org/10.1056/NEJMoa1603144.CrossRefPubMedPubMedCentralGoogle Scholar
84. 84.
    Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487(7406):239–43.  https://doi.org/10.1038/nature11125.CrossRefPubMedPubMedCentralGoogle Scholar
85. 85.
    Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–28.  https://doi.org/10.1016/j.cell.2015.05.001.CrossRefPubMedPubMedCentralGoogle Scholar
86. 86.
    Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697–708.  https://doi.org/10.1056/NEJMoa1506859.CrossRefPubMedPubMedCentralGoogle Scholar
87. 87.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.  https://doi.org/10.1056/NEJMoa1500596.CrossRefPubMedPubMedCentralGoogle Scholar
88. 88.
    Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13.  https://doi.org/10.1126/science.aan6733.CrossRefPubMedPubMedCentralGoogle Scholar
89. 89.
    McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463–9.  https://doi.org/10.1126/science.aaf1490.CrossRefPubMedPubMedCentralGoogle Scholar
90. 90.
    Karzai F, Madan RA, Owens H et al.. Combination of PDL-1 and PARP inhibition in an unselected population with metastatic castration-resistant prostate cancer (mCRPC). In: Proceedings from 2017 ASCO; June 5, 2017; J Clin Oncol. 2017; 35 (suppl; abstr 5026).Google Scholar