Article thumbnail

Toward Maximizing Immunotherapy in Metastatic Castration-Resistant Prostate Cancer – Rationale for Combinatorial Approaches Using Chemotherapy

By Susan R. Slovin


Prostate cancer is particularly suited for active immunotherapy because of the expression of a distinctive number of antigens which are overexpressed on prostate cancer cells and cell lines. There is evidence in this disease that tumors promote immune tolerance starting early in the disease course. As such, chemotherapy, by suppressing tumors and activating immune system homeostatic mechanisms, may help overcome this tumor-induced immune tolerance. Sipuleucel-T which has recently been approved in the US, is an autologous cellular product immunotherapy that induces immune activity likely through activation of dendritic cells. This was associated with a survival benefit in the absence of significant toxicity. However, a post hoc analysis of phase III trial participants found a substantial survival benefit to receiving docetaxel some months after sipuleucel-T. However, another phase III immunotherapy trial combining a prostate cancer therapeutic vaccine GVAX plus docetaxel versus standard docetaxel therapy in advanced prostate cancer, observed a lower overall survival with the vaccine regimen. These trials highlight major unresolved questions concerning the optimum choice, dosing, and timing of chemotherapy relative to active immunotherapy and the overall merits of considering this approach. The ideal treatment approach remains unclear; advances in biomarker validation and trial design may likely improve our ability to assess biologic benefit irrespective of the development of true antitumor immunity

Topics: Oncology
Publisher: Frontiers Research Foundation
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (2011). A phase I study of personalized peptide vaccination using 14 kinds of vaccine in combination with low-dose estramustine in HLA-A24-positive patients with castration-resistant prostate cancer.
  2. (2009). A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxelversusdocetaxelplusprednisone in symptomatic, castrationresistantprostatecancer(CRPC),”in
  3. (2006). A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone inmetastaticandrogen-independent prostate cancer.
  4. (2007). and Cancer Vaccine Clinical Trial Working Group.
  5. and Djeu,J.Y.(2010).Anovelchemoimmunomodulating property of docetaxel: suppression of myeloidderived suppressor cells in tumor bearers.
  6. and National Cancer Institute, Bethesda,MD(2009).PhaseItrialof targetedtherapywithPSA-TRICOM vaccine (V) and ipilimumab (ipi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
  7. (2007). Androgen independent prostate cancer (AIPC) patients who receive sipuleucel-T followed by docetaxel have prolonged survival,” in American Urology Association Meeting Abstracts,
  8. C.,and Dranoff, G.(2008).Immunologicandclinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen4inpreviouslyvaccinatedcancer patients.
  9. (2011). Camouflage andsabotage:tumorescapefromthe immune system.
  10. (2010). Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice.
  11. (2006). Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (Provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitivelocaltherapy.Cancer 107,68–74.
  12. (2010). Combination of CTL-associated antigen-4 blockade and depletion of CD25 regulatory T cells enhance tumour immunity of dendritic cellbased vaccine in a mouse model of colon cancer.
  13. (2008). Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity: effects of docetaxel on immune enhancement.
  14. (2011). Contribution of the immune system to the chemotherapeutic response.
  15. (2008). CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit.
  16. (2009). Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model.
  17. (2011). Defining the optimal role of immunotherapy and chemotherapy,” in Chemotherapy Foundation Symposium XXIV2006. Available at: player.php?id=111006ada_petrylak. [accessed
  18. Drake,C.G.(2010).Prostatecancerasa model for tumour immunotherapy.
  19. (2008). Expanded phase I combination trial of GVAX immunotherapy for prostate cancer and ipilimumab in patients with metastatic hormone-refractory prostate cancer (mHPRC).
  20. (2011). Exploitation of differential homeostatic proliferation of T-cell
  21. (2011). Extended dose ipilimumab with a peptide vaccine: immune correlates associated with clinical benefit in patientswithresectedhigh-riskstage IIIc/IV melanoma.
  22. (2009). Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.
  23. H.,Schrijvers,D.,and Sacks,N. (2009).“A phase III trial of GVAX immunotherapy for porstate cancer versus docetaxel plus prednisone in asymptomatic, castrationresistant prostate cancer (CRPC),”
  24. (2009). Highdose chemotherapy augments the efficacy of recombinant adenovirus vaccinesandimprovesthetherapeutic outcome. Cancer Gene Ther.
  25. (2011). How to improve the immunogenicity of chemotherapy and radiotherapy.
  26. (2010). Immunity, inflammation, and cancer.
  27. (2011). Immunologic biomarkers as correlates of clinical response to cancer immunotherapy.
  28. (2004). Immunological monitoring during combination of patientoriented peptide vaccination and estramustine phosphate in patients with metastatic hormone refractory prostate cancer.
  29. (2011). Immunomodulatory effects of cyclophosphamide and implementations for vaccine design.
  30. (2010). Improved endpoints for cancer immunotherapy trials.
  31. (2010). Improved survival with ipilimumab in patients with metastatic melanoma.
  32. (2009). Inflammation:adrivingforcespeeds cancer metastasis.
  33. (2010). Metronomic chemotherapy enhances antitumor effects of cancer vaccine by depleting regulatory T lymphocytes and inhibiting tumor angiogenesis.
  34. (2011). Natural innate and adaptive immunity to cancer.
  35. (2010). Overall survival (OS) analysis of a phaseltrialofavector-basedvaccine (PSA-TRICOM) and ipilimumab (Ipi) in the treatment of metastatic castration-resistant prostate cancer (mCRPC).
  36. (2009). Paclitaxel and immune system.
  37. (2009). Paclitaxel reduces regulatory T cell numbers and inhibitory function and enhances the anti-tumor effects of the TLR9 agonist PF-3512676 in the mouse.
  38. (2008). Phase I trial of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with metastatic castration resistant prostate cancer (mCRPC).
  39. (2008). Phenotypicanalysisof prostate-infiltrating lymphocytes reveals TH17 and Treg skewing.
  40. (2003). Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer
  41. (2010). Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
  42. (2012). Statement: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
  43. (2007). Synergistic antitumor effect of chemotacticprostate tumor-associated antigen gene-modified tumor cell vaccine and anti-CTLA-4 mAb in murine tumor model.
  44. (2008). The anticancer immune response: indispensable for therapeutic success?
  45. (2007). The combined activation of positive costimulatory signals with modulation of a negative costimulatory signal for the enhancement of vaccine-mediated T-cell responses.
  46. (2008). The essential role of the in situ immune reaction in human colorectal cancer.
  47. (2010). Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression.
  48. (2012). Toward maximizing immunotherapy in metastatic castration-resistant prostate cancer – rationale for combinatorial approaches using chemotherapy.
  49. (2009). Transforming growth factor-beta-mediated signaling in T lymphocytes impacts on prostatespecificimmunityandearlyprostate tumor progression.
  50. (2012). Tribulations or triumphs in prostate cancer immunotherpy: on the road to victory? Expert Rev. Anticancer Ther.
  51. (2011). Tumor immunosurveillance in human cancers.
  52. (2011). Tumors that acquire resistance to low-dose metronomic cyclophosphamide retain sensitivity to maximum tolerated dose cyclophosphamide.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.