The role of immune checkpoint inhibitors in prostate cancer
More details
Hide details
Department of Urology and Urological Onkology, The name of John of the God Hospital, Lublin, Poland
Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Poland
Department of Dermatology, Venerology and Paediatric Dermatology, Medical University of Lublin, Poland
Prostate cancer (PC) is the most commonly diagnosed malignant tumour and the third cause of cancer deaths among men in Europe. The treatment of early-stage PC is very effective and in many cases allows achievement of a complete cure, whereas the treatment of metastatic prostate cancer (mPC) is still a huge challenge for clinicians. New therapeutic strategies for mPC are urgently needded. One of the most promising methods of treatment is anticancer immunotherapy including the monoclonal antibodies against immune checkpoint inhibitors.

To present the potential possibilities of using checkpoint inhibitors blockage in the treatment of mPC, and to overview the results of recent research on immune checkpoint inhibitors in patients with PC.

State of knowledge:
Recent studies suggest that monoclonal antibodies directed against immune checkpoint inhibitors in combination with traditional therapy may become a breakthrough in the treatment of mPC in the near future.

The immunotherapy using monoclonal antibodies against immune checkpoint inhibitors seems to be a new opportunity for patients with advanced PC. The key to achieve the maximum anti-tumour response is to choose the best candidates for this therapy and determine the optimal sequence and combination of drugs. The introduction of immunotherapy as the standard treatment of patients with advanced PC requires further studies.

Gabriel Surdacki   
Department of Urology and Urological Onkology, The name of John of the God Hospital, Lublin, Poland
1. Ferlay J, et al. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010; 46: 765–781.
2. Horwich A, Hugosson J, de Reijke T, Wiegel T, Fizazi K, Kataja V, et al. Prostate cancer: ESMO Consensus Conference Guidelines 2012. Ann Oncol Off J Eur Soc Med Oncol. 2013; 24: 1141–62.
3. McNeel DG, Smith HA, Eickhoff JC, Lang JM, Staab MJ, Wilding G, et al. Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. Cancer Immunol Immunother. 2012 Jul; 61(7): 1137–47.
4. Schweizer MT, Drake CG. Immunotherapy for prostate cancer: recent developments and future challenges. Cancer Metastasis Rev. 2014 Sep; 33(2–3): 641–55.
5. Barach YS, Lee JS, Zang X. T cell coinhibition in prostate cancer: new immune evasion pathways and emerging therapeutics. Trends Mol Med. 2011; 17(1): 47–55.
6. Boikos SA, Antonarakis ES. Immunotherapy for prostate cancer enters its golden age. Clin Med Insights Oncol. 2012; 6: 263–73.
7. Alberti C. Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance. G Chir. 2017 Sep-Oct; 37(5): 225–235.
8. McNeel DG, Bander NH, Beer TM, Drake CG, Fong L, Harrelson S, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma. J Immunother Cancer. 2016 Dec 20; 4: 92.
9. Edler von Eyben F, Roviello G, Kiljunen T, Uprimny Ch, Virgolini I, Kairemo K, et al. Third-line treatment and 177 Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review. Eur J Nucl Med Mol Imaging. 2018; 45(3): 496–508.
10. Rahbar K, Schmidt M, Heinzel A, Eppard E, Bode A, Yordanova A, et al. Response and Tolerability of a Single Dose of 177 Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer: A Multicenter Retrospective Analysis. J Nucl Med. 2016 Sep; 57(9): 1334–8.
11. Afshar-Oromieh A, U Haberkorn, Zechmann Ch, Armor T, Mier W, Spohn F, et al. Repeated PSMA-targeting radioligand therapy of metastatic prostate cancer with 131I-MIP-1095. Eur J Nucl Med Mol Imaging. 2017; 44(6): 950–959.
12. 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.
13. Kwek SS, Cha E, Fong L. Unmasking the immune recognition of prostate cancer with CTLA4 blockade. Nat Rev Cancer. 2012; 12: 289–97.
14. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJM, 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: 700–12.
15. 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. 2016; JCO691584.
16. Modena A, Ciccarese C, Iacovelli R, Brunelli M, Montironi R, Fiorentino M, et al. Immune Checkpoint Inhibitors and Prostate Cancer: A New Frontier? Oncol Rev. 2016; 10(1): 293.
17. Krawczyk P, Wojas-Krawczyk K. Przeciwciała monoklonalne przeciw immunologicznym punktom kontroli w leczeniu chorych na nowotwory. Onkol Prakt Klin. 2015; 11(2): 76–86.
18. Grzywnowicz M, Giannopoulos K. Znaczenie receptora programowanej śmierci 1 oraz jego ligandów w układzie immunologicznym oraz nowotworach. Acta Haematol Pol. 2012; 43(2).
19. Gevensleben H, Dietrich D, Golletz C, Steiner S, Jung M, Thiesler T, et al. The Immune Checkpoint Regulator PD-L1 Is Highly Expressed in Aggressive Primary Prostate Cancer. Clin Cancer Res. 2016; 23: 1969–77.
20. Martin AM, Nirschl TR, Nirschl CJ, Francica BJ, Kochel CM, van Bokhoven A, et al. Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance. Prostate Cancer Prostatic Dis. 2015; 18(4): 325–32.
21. Sfanos KS, Bruno TC, Meeker AK, De Marzo AM, Isaacs WB, Drake CG. Human prostateinfiltrating CD8+ T lymphocytes are oligoclonal and PD-1+ Prostate. 2009; 69(15): 1694–1703. 10.1002/pros.21020.
22. Baas W, Gershburg S, Dynda D, Delfino K, Robinson K, Nie D, et al. Immune Characterization of the Programmed Death Receptor Pathway in High Risk Prostate Cancer. Clin Genitourin Cancer. 2017 Oct; 15(5): 577–581.
23. 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.
24. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 Ligands, and Other Features of the Tumour Immune Microenvironment with Response to Anti- PD-1 Therapy. Clin Cancer Res. 2014; 20: 5064–74.
25. Ness N, Andersen S, Khanehkenari MR, Nordbakken CV, Valkov A, Paulsen EE, et al. The prognostic role of immune checkpoint markers programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) in a large, multicenter prostate cancer cohort. Oncotarget. 2017 Apr 18; 8(16): 26789–26801.
26. Massari F, Ciccarese C, Caliò A, Munari E, Cima L, Porcaro AB, et al. Magnitude of PD-1, PD-L1 and T Lymphocyte Expression on Tissue from Castration-Resistant Prostate Adenocarcinoma: An Exploratory Analysis. Target Oncol. 2015.
27. Ebelt K, Babaryka G, Frankenberger B, Stief CG, Eisenmenger W, Kirchner T, et al. Prostate cancer lesions are surrounded by FOXP3+, PD-1+ and B7-H1+ lymphocyte clusters. Eur J Cancer. 2009; 45: 1664–72.
28. Cappuccini F, Stribbling S, Pollock E, Hill AV, Redchenko I. Immunogenicity and efficacy of the novel cancer vaccine based on simian adenovirus and MVA vectors alone and in combination withPD-1 mAb in a mouse model of prostate cancer. Cancer Immunol Immunother. 2016; 65(6): 701–13.
29. Rekoske BT, Olson BM, McNeel DG. Antitumour vaccination of prostate cancer patients elicits PD-1/PD-L1 regulated antigen-specific immune responses. Oncoimmunology. 2016 Mar 28; 5(6).
30. Cabel L, Loir E, Gravis G, Lavaud P, Massard Ch, Albiges L, et al. Long-term complete remission with Ipilimumab in metastatic castrate-resistant prostate cancer: case report of two patients. Cabel et al. J ImmunoTher Cancer 2017; 5: 31.
31. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 201310.1093/annonc/mdt107.
32. 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 tumours: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010; 28: 3167–75.
33. Lin H, Wei S, Hurt EM, Green MD, Zhao L, Vatan L, et al. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumour regression. J Clin Invest. 2018 Apr 2; 128(4): 1708.
34. Tang H, Liang Y, Anders RA, Taube JM, Qiu X, Mulgaonkar A, et al. PD-L1 on host cells is essential for PD-L1 blockade-mediated tumour regression. J Clin Invest. 2018 Feb 1; 128(2): 580–588.
35. Mercader M, Bodner BK, Moser MT, Kwon PS, Park ES, Manecke RG, et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc Natl Acad Sci U S A. 2001 Dec 4; 98(25): 14565–70.
36. Drake CG, Doody AD, Mihalyo MA, Huang CT, Kelleher E, Ravi S, et al. Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. Cancer Cell. 2005 March; 7(3): 239–249.
37. Arlen PM, Gulley JL, Todd N, Lieberman R, Steinberg SM, Morin S, et al. Antiandrogen, vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate cancer. J Urol. 2005; 174: 539–546.
38. Madan RA, Gulley JL, Schlom J, Steinberg SM, Liewehr DJ, Dahut WL, et al. Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy. Clin Cancer Res. 2008; 14: 4526–4531.
39. Graff JN, Alumkal JJ, Drake CG. First evidence of significant clinical activity of PD-1 inhibitors in metastatic, castration resistant prostate cancer (mCRPC). Ann Oncol 2016; 27(suppl. 6).
40. 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): 52810–52817. doi: 10.18632/oncotarget.10547.
41. Popovic LS, Matovina-Brko G, Popovic M. Checkpoint inhibitors in the treatment of urological malignancies. ESMO Open. 2017 Jun 23; 2(2).
42. Hansen A, Massard C, Ott PA, Haas N, Lopez J, Ejadi S, et al. Pembrolizumab for patients with advanced prostate adenocarcinoma: preliminary results from the KEYNOTE-028 study. Ann Oncol. 2016; 27 suppl 6: 725PD.