Advertisement

Cancer Immunology, Immunotherapy

, Volume 59, Issue 5, pp 663–674 | Cite as

Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer

  • James L. Gulley
  • Philip M. Arlen
  • Ravi A. Madan
  • Kwong-Yok Tsang
  • Mary P. Pazdur
  • Lisa Skarupa
  • Jacquin L. Jones
  • Diane J. Poole
  • Jack P. Higgins
  • James W. Hodge
  • Vittore Cereda
  • Matteo Vergati
  • Seth M. Steinberg
  • Susan Halabi
  • Elizabeth Jones
  • Clara Chen
  • Howard Parnes
  • John J. Wright
  • William L. Dahut
  • Jeffrey SchlomEmail author
Original Article

Abstract

A concurrent multicenter, randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of enhanced median overall survival (OS) (p = 0.0061) in patients with metastatic castrate-resistant prostate cancer (mCRPC). The study reported here employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. Thirty-two patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three costimulatory molecules. Patients received boosters with recombinant fowlpox containing the same four transgenes. Twelve of 32 patients showed declines in serum PSA post-vaccination and 2/12 showed decreases in index lesions. Median OS was 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). Patients with greater PSA-specific T-cell responses showed a trend (p = 0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF versus no GM-CSF. Patients with a Halabi predicted survival of <18 months (median predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of ≥18 months (median predicted survival 20.9 months) will meet or exceed 37.3 months, with 12/15 patients living longer than predicted (p = 0.035). Treg suppressive function was shown to decrease following vaccine in patients surviving longer than predicted, and increase in patients surviving less than predicted. This hypothesis-generating study provides evidence that patients with more indolent mCRPC (Halabi predicted survival ≥18 months) may best benefit from vaccine therapy.

Keywords

Cancer vaccine Immunotherapy Prostate cancer Overall survival PSA–TRICOM PROSTVAC 

Notes

Acknowledgments

Grant support: Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. The authors thank Bonnie L. Casey and Debra Weingarten for their editorial assistance in the preparation of the manuscript.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Supplementary material

262_2009_782_MOESM1_ESM.tif (106 kb)
Supplementary figure (TIF 106 kb)

References

  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin l59:225–249CrossRefGoogle Scholar
  2. 2.
    Halabi S, Small EJ, Kantoff PW, Kattan MW, Kaplan EB, Dawson NA, Levine EG, Blumenstein BA, Vogelzang NJ (2003) Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol l21:1232–1237CrossRefGoogle Scholar
  3. 3.
    Corman JSE, Smith D et al (2006) Immunotherapy with GVAX® vaccine for prostate cancer improves predicted survival in metastatic hormone refractory prostate cancer: results from two phase 2 studies [abstract 976]. In: Proceedings of the American Urological Association Annual Meeting, Atlanta, GAGoogle Scholar
  4. 4.
    Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med l351:1502–1512CrossRefGoogle Scholar
  5. 5.
    Schellhammer PF, Higano C, Berger ER, Shore N, Small E, Penson D, Ferrari A, Sims R, Yuh L, Frohlich M, Kantoff P, for the IMPACT Study Investigators (2009) A randomized, double-blind, placebo-controlled multi-center, phase III trial of sipuleucel-T in men with metastatic, androgen independent prostatic adenocarcinoma (AIPC) [abstract]. In: American Urological Association Annual Meeting. 25–30 April 2009, Chicago, ILGoogle Scholar
  6. 6.
    Grosenbach DW, Barrientos JC, Schlom J, Hodge JW (2001) Synergy of vaccine strategies to amplify antigen-specific immune responses and antitumor effects. Cancer Res l61:4497–4505Google Scholar
  7. 7.
    Hodge JW, Sabzevari H, Yafal AG, Gritz L, Lorenz MG, Schlom J (1999) A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res l59:5800–5807Google Scholar
  8. 8.
    Hodge JW, Chakraborty M, Kudo-Saito C, Garnett CT, Schlom J (2005) Multiple costimulatory modalities enhance CTL avidity. J Immunol l174:5994–6004Google Scholar
  9. 9.
    Kass E, Panicali DL, Mazzara G, Schlom J, Greiner JW (2001) Granulocyte/macrophage-colony stimulating factor produced by recombinant avian poxviruses enriches the regional lymph nodes with antigen-presenting cells and acts as an immunoadjuvant. Cancer Res l61:206–214Google Scholar
  10. 10.
    Eder JP, Kantoff PW, Roper K, Xu GX, Bubley GJ, Boyden J, Gritz L, Mazzara G, Oh WK, Arlen P, Tsang KY, Panicali D, Schlom J, Kufe DW (2000) A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clin Cancer Res l6:1632–1638Google Scholar
  11. 11.
    Kaufman HL, Wang W, Manola J, DiPaola RS, Ko YJ, Sweeney C, Whiteside TL, Schlom J, Wilding G, Weiner LM (2004) Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol l22:2122–2132CrossRefGoogle Scholar
  12. 12.
    Kaufman H, Wang W, Manola J, Do D, Re R, Mi M, Fa F (2005) Phase II prime/boost vaccination using poxviruses expressing PSA in hormone dependent prostate cancer: follow-up clinical results from ECOG 7897 [abstract]. ASCO Meeting Abstracts l23(16S):4501Google Scholar
  13. 13.
    Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D, Beetham P, Tsang KY, Grosenbach DW, Feldman J, Steinberg SM, Jones E, Chen C, Marte J, Schlom J, Dahut W (2006) A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res l12:1260–1269CrossRefGoogle Scholar
  14. 14.
    Arlen PM, Gulley JL, Todd N, Lieberman R, Steinberg SM, Morin S, Bastian A, Marte J, Tsang KY, Beetham P, Grosenbach DW, Schlom J, Dahut W (2005) Antiandrogen, vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate cancer. J Urol l174:539–546CrossRefGoogle Scholar
  15. 15.
    Madan RA, Gulley JL, Schlom J, Steinberg SM, Liewehr DJ, Dahut WL, Arlen PM (2008) Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy. Clin Cancer Res l14:4526–4531CrossRefGoogle Scholar
  16. 16.
    Aarts WM, Schlom J, Hodge JW (2002) Vector-based vaccine/cytokine combination therapy to enhance induction of immune responses to a self-antigen and antitumor activity. Cancer Res l62:5770–5777Google Scholar
  17. 17.
    Hodge JW, Grosenbach DW, Aarts WM, Poole DJ, Schlom J (2003) Vaccine therapy of established tumors in the absence of autoimmunity. Clin Cancer Res l9:1837–1849Google Scholar
  18. 18.
    Yang S, Hodge JW, Grosenbach DW, Schlom J (2005) Vaccines with enhanced costimulation maintain high avidity memory CTL. J Immunol l175:3715–3723Google Scholar
  19. 19.
    Arlen PM, Skarupa L, Pazdur M, Seetharam M, Tsang KY, Grosenbach DW, Feldman J, Poole DJ, Litzinger M, Steinberg SM, Jones E, Chen C, Marte J, Parnes H, Wright J, Dahut W, Schlom J, Gulley JL (2007) Clinical safety of a viral vector based prostate cancer vaccine strategy. J Urol l178:1515–1520CrossRefGoogle Scholar
  20. 20.
    Kantoff P, Glode L, Tannenbaum S, Bilhartz D, Pittman W, Schuetz T (2006) Randomized, double-blind, vector-controlled study of targeted immunotherapy in patients (pts) with hormone-refractory prostate cancer (HRPC) [abstract]. J Clin Oncol l 24(18S):A2501Google Scholar
  21. 21.
    Kantoff PW, Schuetz T, Blumenstein BA, Glode MM, Bilhartz D, Gulley J, Schlom J, Laus R, Godfrey W (2009) Overall survival (OS) analysis of a Phase II randomized controlled trial (RCT) of a poxviral-based PSA targeted immunotherapy in metastatic castration-resistant prostate cancer (mCRPC) [abstract 5013]. In: 2009 ASCO Annual Meeting, 29 May–2 June 2009 Orlando, FLGoogle Scholar
  22. 22.
    Kantoff PW, Schuetz T, Blumenstein BA, Glode LM, Bilhartz D, Wyand M, Manson K, Panicali DL, Laus R, Schlom J, Dahut WL, Arlen PM, Gulley JL, Godfrey WR (2009) Overall survival (OS) analysis of a Phase II randomized controlled trial (RCT) of a poxviral-based PSA targeted immunotherapy in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol (in press)Google Scholar
  23. 23.
    Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, Freidlin B, Halabi S, Hudes G, Hussain M, Kaplan R, Myers C, Oh W, Petrylak DP, Reed E, Roth B, Sartor O, Scher H, Simons J, Sinibaldi V, Small EJ, Smith MR, Trump DL, Wilding G et al (1999) Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol l17:3461–3467Google Scholar
  24. 24.
    Terasawa H, Tsang KY, Gulley J, Arlen P, Schlom J (2002) Identification and characterization of a human agonist cytotoxic T-lymphocyte epitope of human prostate-specific antigen. Clin Cancer Res l8:41–53Google Scholar
  25. 25.
    Marshall JL, Gulley JL, Arlen PM, Beetham PK, Tsang KY, Slack R, Hodge JW, Doren S, Grosenbach DW, Hwang J, Fox E, Odogwu L, Park S, Panicali D, Schlom J (2005) Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas. J Clin Oncol l23:720–731CrossRefGoogle Scholar
  26. 26.
    Gulley J, Chen AP, Dahut W, Arlen PM, Bastian A, Steinberg SM, Tsang K, Panicali D, Poole D, Schlom J, Michael Hamilton J (2002) Phase I study of a vaccine using recombinant vaccinia virus expressing PSA (rV-PSA) in patients with metastatic androgen-independent prostate cancer. Prostate l53:109–117CrossRefGoogle Scholar
  27. 27.
    Hodge JW, Rad AN, Grosenbach DW, Sabzevari H, Yafal AG, Gritz L, Schlom J (2000) Enhanced activation of T cells by dendritic cells engineered to hyperexpress a triad of costimulatory molecules. J Natl Cancer Inst l92:1228–1239CrossRefGoogle Scholar
  28. 28.
    Yokokawa J, Cereda V, Remondo C, Gulley JL, Arlen PM, Schlom J, Tsang KY (2008) Enhanced functionality of CD4 + CD25(high)FoxP3 + regulatory T cells in the peripheral blood of patients with prostate cancer. Clin Cancer Res l14:1032–1040CrossRefGoogle Scholar
  29. 29.
    Dahut WL, Gulley JL, Arlen PM, Liu Y, Fedenko KM, Steinberg SM, Wright JJ, Parnes H, Chen CC, Jones E, Parker CE, Linehan WM, Figg WD (2004) Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. J Clin Oncol l22:2532–2539CrossRefGoogle Scholar
  30. 30.
    Figg WD, Retter A, Steinberg SM, Dahut W (2005) Inhibition of angiogenesis: thalidomide or low-molecular-weight heparin?: authors’ reply. J Clin Oncol l23:2112–2113Google Scholar
  31. 31.
    Smaletz O, Scher HI, Small EJ, Verbel DA, McMillan A, Regan K, Kelly WK, Kattan MW (2002) Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration. J Clin Oncol l20:3972–3982CrossRefGoogle Scholar
  32. 32.
    Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW (2004) External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res l64:4328–4337CrossRefGoogle Scholar
  33. 33.
    Kudo-Saito C, Schlom J, Hodge JW (2005) Induction of an antigen cascade by diversified subcutaneous/intratumoral vaccination is associated with antitumor responses. Clin Cancer Res l11:2416–2426CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • James L. Gulley
    • 1
    • 2
  • Philip M. Arlen
    • 1
    • 2
  • Ravi A. Madan
    • 1
    • 2
  • Kwong-Yok Tsang
    • 1
  • Mary P. Pazdur
    • 1
  • Lisa Skarupa
    • 1
  • Jacquin L. Jones
    • 2
  • Diane J. Poole
    • 1
  • Jack P. Higgins
    • 1
  • James W. Hodge
    • 1
  • Vittore Cereda
    • 1
  • Matteo Vergati
    • 1
  • Seth M. Steinberg
    • 3
  • Susan Halabi
    • 4
  • Elizabeth Jones
    • 5
  • Clara Chen
    • 6
  • Howard Parnes
    • 7
  • John J. Wright
    • 8
  • William L. Dahut
    • 2
  • Jeffrey Schlom
    • 1
    Email author
  1. 1.Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Medical Oncology Branch, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  3. 3.Biostatistics and Data Management Section, National Cancer InstituteNational Institutes of HealthRockvilleUSA
  4. 4.Department of Biostatistics and BioinformaticsDuke University School of MedicineDurhamUSA
  5. 5.Department of Diagnostic Radiology, Clinical CenterNational Institutes of HealthBethesdaUSA
  6. 6.Department of Nuclear Medicine, Clinical CenterNational Institutes of HealthBethesdaUSA
  7. 7.Division of Cancer Prevention, National Cancer InstituteNational Institutes of HealthRockvilleUSA
  8. 8.Investigational Drug Branch, Cancer Therapy and Evaluation Program, National Cancer InstituteNational Institutes of HealthRockvilleUSA

Personalised recommendations