Advertisement

Current Urology Reports

, 20:64 | Cite as

Immunotherapy in Metastatic Castration-Resistant Prostate Cancer: Past and Future Strategies for Optimization

  • Melissa A. Reimers
  • Kathryn E. Slane
  • Russell K. PachynskiEmail author
Prostate Cancer (S Prasad, Section Editor)
  • 184 Downloads
Part of the following topical collections:
  1. Topical Collection on Prostate Cancer

Abstract

Purpose of Review

To date, prostate cancer has been poorly responsive to immunotherapy. In the current review, we summarize and discuss the current literature on the use of vaccine therapy and checkpoint inhibitor immunotherapy in metastatic castration-resistant prostate cancer (mCRPC).

Recent Findings

Sipuleucel-T currently remains the only FDA-approved immunotherapeutic agent for prostate cancer. Single-agent phase 3 vaccine trials with GVAX and PROSTVAC have failed to demonstrate survival benefit to date. Clinical trials using combination approaches, including combination PROSTVAC along with a neoantigen vaccine and checkpoint inhibitor immunotherapy, are ongoing. Checkpoint inhibitor monotherapy clinical trials have demonstrated limited efficacy in advanced prostate cancer, and combination approaches and molecular patient selection are currently under investigation.

Summary

The optimal use of vaccine therapy and checkpoint inhibitor immunotherapy in metastatic castration-resistant prostate cancer remains to be determined. Ongoing clinical trials will continue to inform future clinical practice.

Keywords

Metastatic prostate cancer Castration resistance Immunotherapy Vaccines Checkpoint inhibitors Neoantigen vaccine 

Notes

Compliance with Ethical Standards

Conflict of Interest

Melissa A. Reimers and Kathryn Slane each declares no potential conflicts of interest.

Russell K. Pachynski reports personal fees from Sanofi, EMD Serono, Pfizer, Jounce, Dendreon, Bayer, Genomic Health, Merck, Genentech/Roche, and AstraZeneca; research collaboration/support from Janssen; and institutional support from Genentech/Roche.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Kelly SP, Anderson WF, Rosenberg PS, Cook MB. Past, current, and future incidence rates and burden of metastatic prostate cancer in the United States. Eur Urol Focus. 2018;4(1):121–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Hurwitz AA, Foster BA, Kwon ED, Truong T, Choi EM, Greenberg NM, et al. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res. 2000;60(9):2444–8.PubMedGoogle Scholar
  4. 4.
    van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti- cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190(3):355–66.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    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(8):711–23.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32.CrossRefGoogle Scholar
  7. 7.
    Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040–51.PubMedCrossRefGoogle Scholar
  9. 9.
    Mehra R, Seiwert TY, Gupta S, Weiss J, Gluck I, Eder JP, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow- up in KEYNOTE-012. Br J Cancer. 2018;119(2):153–9.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, 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.PubMedCrossRefGoogle Scholar
  11. 11.
    • 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 Randomized, placebo-controlled phase III clinical trial of 598 patients with asymptomatic or minimally symptomatic chemotherapy-naïve mCRPC. Patients were randomized 2:1 to receive ipilimumab 10 mg/kg IV every 3 weeks or placebo. Primary endpoint of overall survival was not met. PubMedCrossRefGoogle Scholar
  12. 12.
    • 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 Randomized, placebo-controlled phase III clinical trial of 799 mCRPC patients with progression on docetaxel chemotherapy. Patients received 8 Gy radiation directed to an osseous metastasis followed by either ipilimumab 10 mg/kg IV every 3 weeks or placebo. Primary endpoint of overall survival was not met. PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–8.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Danaher P, Warren S, Lu R, Samayoa J, Sullivan A, Pekker I, et al. Pan-cancer adaptive immune resistance as defined by the tumor inflammation signature (TIS): results from The Cancer Genome Atlas (TCGA). J Immunother Cancer. 2018;6(1):63.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, et al. Placebo- controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24(19):3089–94.PubMedCrossRefGoogle Scholar
  16. 16.
    Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115(16):3670–9.PubMedCrossRefGoogle Scholar
  17. 17.
    •• 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 Randomized, placebo-controlled phase III clinical trial of 512 patients with asymptomatic or minimally symptomatic mCRPC. Patients were randomized 2:1 to receive sipuleucel-T or placebo. The study met its primary endpoint of overall survival, with a median survival of 25.8 months in the sipuleucel-T arm and 21.7 months in the control arm, for a benefit of 4.1 months. Sipuleucel-T was FDA approved in 2010. PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    Holl EK, McNamara MA, Healy P, Anand M, Concepcion RS, Breland CD, et al. Prolonged PSA stabilization and overall survival following sipuleucel-T monotherapy in metastatic castration-resistant prostate cancer patients. Prostate Cancer Prostatic Dis. 2019.Google Scholar
  20. 20.
    Sartor AO, Armstrong A, Ahaghotu C, McLeod D, Cooperberg M, Penson D, et al. PD24-12 overall survival analysis of African American and Caucasian patients receiving sipuleucel-T: preliminary data from the proceed registry. J Urol. 2017;197(4S):e456–e7.CrossRefGoogle Scholar
  21. 21.
    Twardowski P, Wong JYC, Pal SK, Maughan BL, Frankel PH, Franklin K, et al. Randomized phase II trial of sipuleucel-T immunotherapy preceded by sensitizing radiation therapy and sipuleucel-T alone in patients with metastatic castrate resistant prostate cancer. Cancer Treat Res Commun. 2019;19:100116.PubMedCrossRefGoogle Scholar
  22. 22.
    Fong L, Carroll P, Weinberg V, Chan S, Lewis J, Corman J, et al. Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer. J Natl Cancer Inst. 2014;106(11).Google Scholar
  23. 23.
    Caram MEV, Ross R, Lin P, Mukherjee B. Factors associated with use of sipuleucel-T to treat patients with advanced prostate cancer. JAMA Netw Open. 2019;2(4):e192589.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Simons JW, Carducci MA, Mikhak B, Lim M, Biedrzycki B, Borellini F, et al. Phase I/II trial of an allogeneic cellular immunotherapy in hormone-naive prostate cancer. Clin Cancer Res. 2006;12(11 Pt 1):3394–401.PubMedCrossRefGoogle Scholar
  25. 25.
    Madan RA, Arlen PM, Mohebtash M, Hodge JW, Gulley JL. Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs. 2009;18(7):1001–11.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28(7):1099–105.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Kantoff PWGJ, 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;35:124–5.PubMedCrossRefGoogle Scholar
  28. 28.
    • Gulley JL, Borre M, Vogelzang NJ, Ng S, Agarwal N, Parker CC, et al. Phase III Trial of PROSTVAC in asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. J Clin Oncol. 2019;37(13):1051–61 Randomized, placebo-controlled phase III clinical trial of 864 patients with mCRPC randomized to receive PROSTVAC + GM-CSF or placebo. The primary endpoint was overall survival, and the study was halted prematurely at the third interim analysis due to futility. PubMedCrossRefGoogle Scholar
  29. 29.
    Hansen AR, Massard C, Ott PA, Haas NB, Lopez JS, Ejadi S, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol. 2018;29(8):1807–13.PubMedCrossRefGoogle Scholar
  30. 30.
    Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol. 2011;11(5):330–42.PubMedCrossRefGoogle Scholar
  31. 31.
    Johnson LE, Brockstedt D, Leong M, Lauer P, Theisen E, Sauer JD, et al. Heterologous vaccination targeting prostatic acid phosphatase (PAP) using DNA and Listeria vaccines elicits superior anti-tumor immunity dependent on CD4+ T cells elicited by DNA priming. Oncoimmunology. 2018;7(8):e1456603.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Hannan R, Zhang H, Wallecha A, Singh R, Liu L, Cohen P, et al. Combined immunotherapy with Listeria monocytogenes-based PSA vaccine and radiation therapy leads to a therapeutic response in a murine model of prostate cancer. Cancer Immunol Immunother. 2012;61(12):2227–38.PubMedCrossRefGoogle Scholar
  33. 33.
    NBea H. Phase I-II study of ADXS31-142 alone and in combination with pembrolizumab in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC): the KEYNOTE- 046 trial. J Immunother Cancer. 2015;3(Suppl2):P153.Google Scholar
  34. 34.
    Mkrtichyan M, Chong N, Abu Eid R, Wallecha A, Singh R, Rothman J, et al. Anti-PD-1 antibody significantly increases therapeutic efficacy of Listeria monocytogenes (Lm)-LLO immunotherapy. J Immunother Cancer. 2013;1:15.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Rekoske BT, Smith HA, Olson BM, Maricque BB, McNeel DG. PD-1 or PD-L1 blockade restores antitumor efficacy following SSX2 epitope-modified DNA vaccine immunization. Cancer Immunol Res. 2015;3(8):946–55.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Zahm CD, Colluru VT, McNeel DG. Vaccination with high-affinity epitopes impairs antitumor efficacy by increasing PD-1 expression on CD8(+) T cells. Cancer immunology research. 2017;5(8):630–41.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    McNeel DG, Eickhoff JC, Wargowski E, Zahm C, Staab MJ, Straus J, et al. Concurrent, but not sequential, PD-1 blockade with a DNA vaccine elicits anti-tumor responses in patients with metastatic, castration-resistant prostate cancer. Oncotarget. 2018;9(39):25586–96.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Lambricht L, Lopes A, Kos S, Sersa G, Preat V, Vandermeulen G. Clinical potential of electroporation for gene therapy and DNA vaccine delivery. Expert Opin Drug Deliv. 2016;13(2):295–310.PubMedCrossRefGoogle Scholar
  39. 39.
    de Bono JS. KEYNOTE-199: Pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC). Journal of Clinical Oncology. 2018;36(15):suppl.5007.CrossRefGoogle Scholar
  40. 40.
    Padmanee S, Russel KP, Vivek N, Aude F, Gwenaelle G, Matt DG, et al. Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). Journal of Clinical Oncology. 2019;37(7):suppl.142.Google Scholar
  41. 41.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    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.PubMedCrossRefGoogle Scholar
  43. 43.
    Fong P. Keynote-365 cohort C: Pembrolizumab (pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic castrate resistant prostate cance (mCRPC). Journal of Clinical Oncology. 2019;37(7):suppl (March 1 2019)):171.CrossRefGoogle Scholar
  44. 44.
    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;22(8):1969–77.PubMedCrossRefGoogle Scholar
  45. 45.
    •• Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;162(2):454 Comprehensive analysis of the genomic landscape of 150 patients with mCRPC. Aberrations of AR , ETS genes, TP53 and PTEN were most frequent. PubMedCrossRefGoogle Scholar
  46. 46.
    Quigley DA, Dang HX, Zhao SG, Lloyd P, Aggarwal R, Alumkal JJ, et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell. 2018;175(3):889.PubMedCrossRefGoogle Scholar
  47. 47.
    Antonarakis ES, Shaukat F, Isaacsson Velho P, Kaur H, Shenderov E, Pardoll DM, et al. Clinical features and therapeutic outcomes in men with advanced prostate cancer and DNA mismatch repair gene mutations. Eur Urol. 2019;75(3):378–82.PubMedCrossRefGoogle Scholar
  48. 48.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. 2019;5(4):471-8.PubMedCrossRefGoogle Scholar
  50. 50.
    Karzai F, VanderWeele D, Madan RA, Owens H, Cordes LM, Hankin A, et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J Immunother Cancer. 2018;6(1):141.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Boudadi K, Suzman DL, Anagnostou V, Fu W, Luber B, Wang H, et al. Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer. Oncotarget. 2018;9(47):28561–71.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    • Wu YM, Cieslik M, Lonigro RJ, Vats P, Reimers MA, Cao X, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell. 2018;173(7):1770–82 e14 CDK12 loss has been identified as a novel subtype of mCRPC, characterized by focal tandem duplications and increased gene fusions. PubMedCrossRefGoogle Scholar
  53. 53.
    Massari F, Ciccarese C, Calio 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. 2016;11(3):345–51.PubMedCrossRefGoogle Scholar
  54. 54.
    Vitkin N, Nersesian S, Siemens DR, Koti M. The tumor immune contexture of prostate cancer. Front Immunol. 2019;10:603.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Melissa A. Reimers
    • 1
  • Kathryn E. Slane
    • 1
  • Russell K. Pachynski
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Internal Medicine, Division of OncologyWashington University School of MedicineSt. LouisUSA
  2. 2.Center for Human Immunology and Immunotherapy Programs (CHiiPs)Washington University School of MedicineSt. LouisUSA
  3. 3.Siteman Cancer CenterWashington University in St. LouisSt. LouisUSA

Personalised recommendations