Cancer Immunology, Immunotherapy

, Volume 61, Issue 1, pp 109–117 | Cite as

Endpoints, patient selection, and biomarkers in the design of clinical trials for cancer vaccines

Focussed Research Review


Therapeutic cancer vaccines are an emerging and potentially effective treatment modality. Cancer vaccines are usually very well tolerated, with minimal toxicity compared with chemotherapy. Unlike conventional cytotoxic therapies, immunotherapy does not result in immediate tumor shrinkage but may alter growth rate and thus prolong survival. Multiple randomized controlled trials of various immunotherapeutic agents have shown a delayed separation in Kaplan–Meier survival curves, with no evidence of clinical benefit within the first 6–12 months of vaccine treatment. Overall survival benefit is seen in patients with lower disease burden who are not expected to die within those initial 6–12 months. The concept of improved overall survival without marked initial tumor reduction represents a significant shift from the current paradigms established by standard cytotoxic therapies. Future clinical studies of therapeutic vaccines should enroll patients with either lower tumor burden, more indolent disease or both, and must seek to identify early markers of clinical benefit that may correlate with survival. Until then, improved overall survival is the only clear, discriminatory endpoint for therapeutic vaccines as monotherapies.


Cancer Immunotherapy Tumor growth kinetics Tumor volume Biomarkers CIMT 2011 



The authors thank Bonnie L. Casey for editorial assistance in the preparation of this manuscript.


  1. 1.
    Oliver RT, Nouri AM (1992) T cell immune response to cancer in humans and its relevance for immunodiagnosis and therapy. Cancer Surv 13:173–204PubMedGoogle Scholar
  2. 2.
    Hellstrom IE, Hellstrom KE, Pierce GE, Bill AH (1968) Demonstration of cell-bound and humoral immunity against neuroblastoma cells. Proc Natl Acad Sci USA 60:1231–1238PubMedCrossRefGoogle Scholar
  3. 3.
    Vose BM, Moore M (1985) Human tumor-infiltrating lymphocytes: a marker of host response. Semin Hematol 22:27–40PubMedGoogle Scholar
  4. 4.
    Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273PubMedCrossRefGoogle Scholar
  5. 5.
    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 64:4328–4337PubMedCrossRefGoogle Scholar
  6. 6.
    Gulley JL, Arlen PM, Bastian A, Morin S, Marte J, Beetham P, Tsang KY, Yokokawa J, Hodge JW, Menard C, Camphausen K, Coleman CN, Sullivan F, Steinberg SM, Schlom J, Dahut W (2005) Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res 11:3353–3362PubMedCrossRefGoogle Scholar
  7. 7.
    Matzinger P (2002) The danger model: a renewed sense of self. Science 296:301–305PubMedCrossRefGoogle Scholar
  8. 8.
    Tanaka K, Tanahashi N, Tsurumi C, Yokota KY, Shimbara N (1997) Proteasomes and antigen processing. Adv Immunol 64:1–38PubMedCrossRefGoogle Scholar
  9. 9.
    Hammer GE, Kanaseki T, Shastri N (2007) The final touches make perfect the peptide-MHC class I repertoire. Immunity 26:397–406PubMedCrossRefGoogle Scholar
  10. 10.
    Schlom J, Arlen PM, Gulley JL (2007) Cancer vaccines: moving beyond current paradigms. Clin Cancer Res 13:3776–3782PubMedCrossRefGoogle Scholar
  11. 11.
    Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM (2006) Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089–3094PubMedCrossRefGoogle Scholar
  12. 12.
    Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, Manson K, Panicali DL, Laus R, Schlom J, Dahut WL, Arlen PM, Gulley JL, Godfrey WR (2010) 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 28:1099–1105PubMedCrossRefGoogle Scholar
  13. 13.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422PubMedCrossRefGoogle Scholar
  14. 14.
    Finke L, Wentworth K, Blumenstein B, Rudolph N, Levitsky H, Hoos A (2007) Lessons from randomized phase III studies with active cancer immunotherapies—outcomes from the 2006 meeting of the Cancer Vaccine Consortium (CVC). Vaccine 25(Suppl 2):B97–B109PubMedCrossRefGoogle Scholar
  15. 15.
    Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420PubMedCrossRefGoogle Scholar
  16. 16.
    FDA (2011, Oct) Clinical considerations for therapeutic cancer vaccines: draft guidance. Available from:
  17. 17.
    Drake CG (2010) Prostate cancer as a model for tumour immunotherapy. Nat Rev Immunol 10:580–593PubMedCrossRefGoogle Scholar
  18. 18.
    FDA approves a cellular immunotherapy for men with advanced prostate cancer. Available from:
  19. 19.
    So-Rosillo R, Small EJ (2006) Sipuleucel-T (APC8015) for prostate cancer. Expert Rev Anticancer Ther 6:1163–1167PubMedCrossRefGoogle Scholar
  20. 20.
    Burch PA, Croghan GA, Gastineau DA, Jones LA, Kaur JS, Kylstra JW, Richardson RL, Valone FH, Vuk-Pavlovic S (2004) Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce durable remission of metastatic androgen-independent prostate cancer: a phase 2 trial. Prostate 60:197–204PubMedCrossRefGoogle Scholar
  21. 21.
    Beinart G, Rini BI, Weinberg V, Small EJ (2005) Antigen-presenting cells 8015 (Provenge) in patients with androgen-dependent, biochemically relapsed prostate cancer. Clin Prostate Cancer 4:55–60PubMedGoogle Scholar
  22. 22.
    Small EJ, Fratesi P, Reese DM, Strang G, Laus R, Peshwa MV, Valone FH (2000) Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol 18:3894–3903PubMedGoogle Scholar
  23. 23.
    Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP (2007) A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res 13:1810–1815PubMedCrossRefGoogle Scholar
  24. 24.
    Aguilar L, Teh B, Ayala G, Vlachaki M, Wheeler T, Kadmon D, Thompson T, Miles B, Aguilar-Cordova E, Butler E (2004) PSA nadir and 24 month biopsy interim analysis of AdV-tk/Valacyclovir gene therapy in combination with radiotherapy vs radiotherapy alone for prostate cancer [abstract]. J Clin Oncol 22(14S):4571Google Scholar
  25. 25.
    Stein WD, Figg WD, Dahut W, Stein AD, Hoshen MB, Price D, Bates SE, Fojo T (2008) Tumor growth rates derived from data for patients in a clinical trial correlate strongly with patient survival: a novel strategy for evaluation of clinical trial data. Oncologist 13:1046–1054PubMedCrossRefGoogle Scholar
  26. 26.
    Stein WD, Gulley JL, Schlom J, Madan RA, Dahut W, Figg WD, Ning YM, Arlen PM, Price D, Bates SE, Fojo T (2011) Tumor regression and growth rates determined in five intramural NCI prostate cancer trials: the growth rate constant as an indicator of therapeutic efficacy. Clin Cancer Res 17:907–917PubMedCrossRefGoogle Scholar
  27. 27.
    Gulley JL, Drake CG (2011) Immunotherapy for prostate cancer: recent advances, lessons learned, and areas for further research. Clin Cancer Res 17:3884–3891PubMedCrossRefGoogle Scholar
  28. 28.
    Gulley JL, Madan RA, Arlen PM (2007) Enhancing efficacy of therapeutic vaccinations by combination with other modalities. Vaccine 25(Suppl 2):B89–B96PubMedCrossRefGoogle Scholar
  29. 29.
    Madan RA, Gulley JL, Fojo T, Dahut WL (2010) Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression. Oncologist 15:969–975PubMedCrossRefGoogle Scholar
  30. 30.
    Ma Y, Kepp O, Ghiringhelli F, Apetoh L, Aymeric L, Locher C, Tesniere A, Martins I, Ly A, Haynes NM, Smyth MJ, Kroemer G, Zitvogel L (2010) Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol 22:113–124PubMedCrossRefGoogle Scholar
  31. 31.
    Zitvogel L, Apetoh L, Ghiringhelli F, Andre F, Tesniere A, Kroemer G (2008) The anticancer immune response: indispensable for therapeutic success? J Clin Invest 118:1991–2001PubMedCrossRefGoogle Scholar
  32. 32.
    Hoos A, Eggermont AM, Janetzki S, Hodi FS, Ibrahim R, Anderson A, Humphrey R, Blumenstein B, Old L, Wolchok J (2010) Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst 102:1388–1397PubMedCrossRefGoogle Scholar
  33. 33.
    Tang PA, Bentzen SM, Chen EX, Siu LL (2007) Surrogate end points for median overall survival in metastatic colorectal cancer: literature-based analysis from 39 randomized controlled trials of first-line chemotherapy. J Clin Oncol 25:4562–4568PubMedCrossRefGoogle Scholar
  34. 34.
    Panageas KS, Ben-Porat L, Dickler MN, Chapman PB, Schrag D (2007) When you look matters: the effect of assessment schedule on progression-free survival. J Natl Cancer Inst 99:428–432PubMedCrossRefGoogle Scholar
  35. 35.
    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 11:2416–2426PubMedCrossRefGoogle Scholar
  36. 36.
    Coulie PG, van der Bruggen P (2003) T-cell responses of vaccinated cancer patients. Curr Opin Immunol 15:131–137PubMedCrossRefGoogle Scholar
  37. 37.
    Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T Jr, Grob JJ, Chesney J, Chin K, Chen K, Hoos A, O’Day SJ, Lebbe C (2010) Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 11:155–164PubMedCrossRefGoogle Scholar
  38. 38.
    Burch PA, Breen JK, Buckner JC, Gastineau DA, Kaur JA, Laus RL, Padley DJ, Peshwa MV, Pitot HC, Richardson RL, Smits BJ, Sopapan P, Strang G, Valone FH, Vuk-Pavlovic S (2000) Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. Clin Cancer Res 6:2175–2182PubMedGoogle Scholar
  39. 39.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723PubMedCrossRefGoogle Scholar
  40. 40.
    Eaton JD, Perry MJ, Nicholson S, Guckian M, Russell N, Whelan M, Kirby RS (2002) Allogeneic whole-cell vaccine: a phase I/II study in men with hormone-refractory prostate cancer. BJU Int 89:19–26PubMedCrossRefGoogle Scholar
  41. 41.
    Ward JE, McNeel DG (2007) GVAX: an allogeneic, whole-cell, GM-CSF-secreting cellular immunotherapy for the treatment of prostate cancer. Expert Opin Biol Ther 7:1893–1902PubMedCrossRefGoogle Scholar
  42. 42.
    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 14:4526–4531PubMedCrossRefGoogle Scholar
  43. 43.
    Hsu FJ, Caspar CB, Czerwinski D, Kwak LW, Liles TM, Syrengelas A, Taidi-Laskowski B, Levy R (1997) Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma—long-term results of a clinical trial. Blood 89:3129–3135PubMedGoogle Scholar
  44. 44.
    Morton DL, Ollila DW, Hsueh EC, Essner R, Gupta RK (1999) Cytoreductive surgery and adjuvant immunotherapy: a new management paradigm for metastatic melanoma. CA Cancer J Clin 49:101–116, 165Google Scholar
  45. 45.
    Gulley J, Madan R, Schlom J (2011) Impact of tumour volume on the potential efficacy of therapeutic vaccines. Curr Oncol 18:e150–e157PubMedCrossRefGoogle Scholar
  46. 46.
    Fu T, Shen Y, Fujimoto S (2000) Tumor-specific CD4(+) suppressor T-cell clone capable of inhibiting rejection of syngeneic sarcoma in A/J mice. Int J Cancer 87:680–687PubMedCrossRefGoogle Scholar
  47. 47.
    Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, Chauffert B, Solary E, Bonnotte B, Martin F (2004) CD4+ CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 34:336–344PubMedCrossRefGoogle Scholar
  48. 48.
    Teicher BA (2007) Transforming growth factor-beta and the immune response to malignant disease. Clin Cancer Res 13:6247–6251PubMedCrossRefGoogle Scholar
  49. 49.
    Muller AJ, Prendergast GC (2007) Indoleamine 2, 3-dioxygenase in immune suppression and cancer. Curr Cancer Drug Targets 7:31–40PubMedCrossRefGoogle Scholar
  50. 50.
    von Mehren M, Arlen P, Gulley J, Rogatko A, Cooper HS, Meropol NJ, Alpaugh RK, Davey M, McLaughlin S, Beard MT, Tsang KY, Schlom J, Weiner LM (2001) The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma. Clin Cancer Res 7:1181–1191Google Scholar
  51. 51.
    Madan RA, Mohebtash M, Schlom J, Gulley JL (2010) Therapeutic vaccines in metastatic castration-resistant prostate cancer: principles in clinical trial design. Expert Opin Biol Ther 10:19–28PubMedCrossRefGoogle Scholar
  52. 52.
    Morse MA, Hobeika A, Osada T, Niedzwiecki D, Marcom PK, Blackwell KL, Anders C, Devi GR, Lyerly HK, Clay TM (2007) Long term disease-free survival and T cell and antibody responses in women with high-risk Her2 + breast cancer following vaccination against Her2. J Transl Med 5:42PubMedCrossRefGoogle Scholar
  53. 53.
    Czerniecki BJ, Koski GK, Koldovsky U, Xu S, Cohen PA, Mick R, Nisenbaum H, Pasha T, Xu M, Fox KR, Weinstein S, Orel SG, Vonderheide R, Coukos G, DeMichele A, Araujo L, Spitz FR, Rosen M, Levine BL, June C, Zhang PJ (2007) Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. Cancer Res 67:1842–1852PubMedCrossRefGoogle Scholar
  54. 54.
    Ullenhag GJ, Frodin JE, Jeddi-Tehrani M, Strigard K, Eriksson E, Samanci A, Choudhury A, Nilsson B, Rossmann ED, Mosolits S, Mellstedt H (2004) Durable carcinoembryonic antigen (CEA)-specific humoral and cellular immune responses in colorectal carcinoma patients vaccinated with recombinant CEA and granulocyte/macrophage colony-stimulating factor. Clin Cancer Res 10:3273–3281PubMedCrossRefGoogle Scholar
  55. 55.
    Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T (2001) Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:18–32PubMedCrossRefGoogle Scholar
  56. 56.
    Morse MA, Hobeika AC, Osada T, Serra D, Niedzwiecki D, Lyerly HK, Clay TM (2008) Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood 112:610–618PubMedCrossRefGoogle Scholar
  57. 57.
    Vergati M, Cereda V, Madan RA, Gulley JL, Huen NY, Rogers CJ, Hance KW, Arlen PM, Schlom J, Tsang KY (2011) Analysis of circulating regulatory T cells in patients with metastatic prostate cancer pre- versus post-vaccination. Cancer Immunol Immunother 60:197–206PubMedCrossRefGoogle Scholar
  58. 58.
    Britten CM, Meyer RG, Kreer T, Drexler I, Wolfel T, Herr W (2002) The use of HLA-A*0201-transfected K562 as standard antigen-presenting cells for CD8(+) T lymphocytes in IFN-gamma ELISPOT assays. J Immunol Methods 259:95–110PubMedCrossRefGoogle Scholar
  59. 59.
    Janetzki S, Panageas KS, Ben-Porat L, Boyer J, Britten CM, Clay TM, Kalos M, Maecker HT, Romero P, Yuan J, Kast WM, Hoos A (2008) Results and harmonization guidelines from two large-scale international Elispot proficiency panels conducted by the Cancer Vaccine Consortium (CVC/SVI). Cancer Immunol Immunother 57:303–315PubMedCrossRefGoogle Scholar
  60. 60.
    Disis ML (2011) Immunologic biomarkers as correlates of clinical response to cancer immunotherapy. Cancer Immunol Immunother 60:433–442PubMedCrossRefGoogle Scholar
  61. 61.
    Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA, Knutson KL, Schiffman K (2002) Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol 20:2624–2632PubMedCrossRefGoogle Scholar
  62. 62.
    Salazar L, Goodell V, O’Meara M, Knutson K, Dang Y, dela Rosa C, Guthrie K, Disis M (2009) Persistent immunity and survival after immunization with a HER2/neu (HER2) vaccine [abstract]. J Clin Oncol 27(15S):3010Google Scholar
  63. 63.
    May KF Jr, Gulley JL, Drake CG, Dranoff G, Kantoff PW (2011) Prostate cancer immunotherapy. Clin Cancer Res 17:5233–5238PubMedCrossRefGoogle Scholar
  64. 64.
    Phase 3 Study of Immunotherapy to Treat Advanced Prostate Cancer [October 2011]. Available from:
  65. 65.
    A trial of PROSTVAC ± GM-CSF in men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC) (Prospect) [October 2011]. Available from:
  66. 66.
    Study of immunotherapy to treat advanced prostate cancer [October 2011]. Available from:
  67. 67.
    Phase 3 Study of ProstAtak with standard radiation therapy for localized prostate cancer (PrTK03) [October 2011]. Available from:

Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  1. 1.Laboratory of Tumor Immunology and Biology and Medical Oncology Branch, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA

Personalised recommendations