Cancer Immunology, Immunotherapy

, Volume 60, Issue 5, pp 715–730 | Cite as

Low-dose paclitaxel enhances the anti-tumor efficacy of GM-CSF surface-modified whole-tumor-cell vaccine in mouse model of prostate cancer

  • Qiushan He
  • Jinlong Li
  • Weihua Yin
  • Zhichun Song
  • Zhen Zhang
  • Tienan Yi
  • Jia Tang
  • Demin Wu
  • Yue Lu
  • Zhen Wang
  • Dan Liu
  • Xiaoren Zhang
  • Zhiming Hu
  • Jimin Gao
Original article


Chemotherapy combined with a tumor vaccine is an attractive approach in cancer therapy. This study was designed to investigate the optimal schedule and mechanisms of action of a novel GM-CSF (granulocyte–macrophage colony-stimulating factor) surface-modified tumor-cell vaccine in combination with paclitaxel in the treatment of mouse RM-1 prostate cancer. First, the anti-tumor efficiencies of various dosage of paclitaxel (4, 20, 40 mg/kg) in combination with the vaccine in different administration sequences were examined in the mouse RM-1 prostate cancer model. Then, the in vivo and in vitro effects of various dosage of paclitaxel on RM-1 cells, T cells, and DCs (dendritic cells) were evaluated. The results showed that: (a) the GM-CSF-surface-modified tumor-cell vaccine was more potent at inducing the uptake of tumor antigens by DCs than irradiated tumor cells plus free GM-CSF; (b) 4 mg/kg paclitaxel combined with the GM-CSF-surface-modified tumor-cell vaccine was the most effective at enhancing tumor regression in RM-1 prostate cancer mice when the vaccine was administrated 2 days after paclitaxel; and (c) administration of 4 mg/kg paclitaxel followed by the vaccine induced the highest degree of CD8+ T-cell infiltration in tumor tissue, suggesting that the induction of tumor-specific immune response had occurred. These findings suggested that the GM-CSF-surface-modified tumor-cell vaccine may have potential clinical benefit for patients with prostate cancer when it is combined with paclitaxel. Furthermore, the effect of immunochemotherapy depends on careful selection of paclitaxel dosage and the sequence of paclitaxel/vaccine administration.


Cancer immunochemotherapy Granulocyte–macrophage colony-stimulating factor Vaccine Paclitaxel 



This work was supported in part by grants from Chinese National 863 plan (2006AA02Z4C4), the Natural Science Foundation of China (30928023 and 30971516), Zhejiang Provincial Major Research Program (2007C13020 and 2008C14082), the Natural Science Foundation of Zhejiang Province (R2080407 and Y2100925), Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents, Science & Technology Innovation Program for College/University Students in Zhejiang Province (2009R413042 and 2010R413047) and Wenzhou Municipal Research Program (G20090142).


  1. 1.
    Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRefGoogle Scholar
  2. 2.
    Coen JJ, Zietman AL, Thakral H et al (2002) Radical radiation for localized prostate cancer: local persistence of disease results in a late wave of metastases. J Clin Oncol 20:3199–3205PubMedCrossRefGoogle Scholar
  3. 3.
    Roehl KA, Han M, Ramos CG et al (2004) Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3, 478 consecutive patients:long-term results. J Urol 172:910–914PubMedCrossRefGoogle Scholar
  4. 4.
    Stamey TA, Yemoto CM, McNeal JE et al (2000) Prostate cancer is highly predictable: a prognostic equation based on all morphological variables in radical prostatectomy specimens. J Urol 163:1155–1160PubMedCrossRefGoogle Scholar
  5. 5.
    Calabro F, Sternberg CN (2007) Current indications for chemotherapy in prostate cancer patients. Eur Urol 51:17–26PubMedCrossRefGoogle Scholar
  6. 6.
    Tannock IF, de Wit R, Berry WR (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512PubMedCrossRefGoogle Scholar
  7. 7.
    Petrylak DP, Tangen CM, Hussain MH et al (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513–1520PubMedCrossRefGoogle Scholar
  8. 8.
    Jeske S, Tagawa ST, Olowokure O et al (2010) Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer. Urol Oncol [Epub ahead of print]Google Scholar
  9. 9.
    Sella A, Yarom N, Zisman A et al (2009) Paclitaxel, estramustine and carboplatin combination chemotherapy after initial docetaxel-based chemotherapy in castration-resistant prostate cancer. Oncology-Basel 76:442–446Google Scholar
  10. 10.
    Pandha H, Eaton J, Greenhalgh R et al (2005) Immunotherapy of murine prostate cancer using whole tumor cells killed ex vivo by herpes simplex viral thymidine kinase/ganciclovir suicide gene therapy. Cancer Gene Ther 12:572–578PubMedCrossRefGoogle Scholar
  11. 11.
    Suckow MA, Wolter WR, Pollard M (2005) Prevention of de novo prostate cancer by immunization with tumor-derived vaccines. Cancer Immunol Immunother 54:571–576PubMedCrossRefGoogle Scholar
  12. 12.
    Moody DB, Robinson JC, Ewing CM et al (1994) Interleukin-2 transfected prostate cancer cells generate a local antitumor effect in vivo. Prostate 24:244–251PubMedCrossRefGoogle Scholar
  13. 13.
    Eager R, Nemunaitis J (2005) GM-CSF gene-transduced tumor vaccines. Mol Ther 12:18–27PubMedCrossRefGoogle Scholar
  14. 14.
    Simons JW, Mikhak B, Chang JF et al (1999) Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer. Cancer Res 59:5160–5168PubMedGoogle Scholar
  15. 15.
    Higano CS, Corman JM, Smith DC et al (2008) Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer. Cancer 113:975–984PubMedCrossRefGoogle Scholar
  16. 16.
    Small EJ, Sacks N, Nemunaitis J et al (2007) Granulocyte macrophage colony-stimulating factor–secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer. Clin Cancer Res 13:3883–3891PubMedCrossRefGoogle Scholar
  17. 17.
    Simons JW, Carducci MA, Mikhak B et al (2006) Phase I/II trial of an allogeneic cellular immunotherapy in hormone-naive prostate cancer. Clin Cancer Res 12:3394–3401PubMedCrossRefGoogle Scholar
  18. 18.
    Moon C, Park JC, Chae YK et al (2008) Current status of experimental therapeutics for prostate cancer. Cancer Lett 266:116–134PubMedCrossRefGoogle Scholar
  19. 19.
    Gao J, Huang S, Li M et al (2006) GM-CSF-surface-modified B16.F10 melanoma cell vaccine. Vaccine 24:5265–5268PubMedCrossRefGoogle Scholar
  20. 20.
    Hu Z, Tan W, Zhang L et al (2010) A novel immunotherapyfor superficial bladder cancer by intravesical immobilization of GM-CSF. J Cell Mol Med 14:1836–1844PubMedCrossRefGoogle Scholar
  21. 21.
    Prell RA, Gearin L, Simmons A et al (2006) The anti-tumor efficacy of a GM-CSF-secreting tumor cell vaccine is not inhibited by docetaxel administration. Cancer Immunol Immunother 55:1285–1293PubMedCrossRefGoogle Scholar
  22. 22.
    Eralp Y, Wang X, Wang JP et al (2004) Doxorubicin and paclitaxel enhance the antitumor efficacy of vaccines directed against HER 2/neu in a murine mammary carcinoma model. Breast Cancer Res 6:R275–R283PubMedCrossRefGoogle Scholar
  23. 23.
    Machiels JP, Duck L, Honhon B et al (2005) Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study. Ann Oncol 16:1898–1905PubMedCrossRefGoogle Scholar
  24. 24.
    Chopra A, Kim TS, O-Sullivan I et al (2006) Combined therapy of an established, highly aggressive breast cancer in mice with paclitaxel and a unique DNA-based cell vaccine. Int J Cancer 118:2888–2898PubMedCrossRefGoogle Scholar
  25. 25.
    Garnett CT, Schlom J, Hodge JW (2008) Combination of docetaxel and recombinant vaccine enhances T cell responses and antitumor activity: effects of docetaxel on immune enhancement. Clin Cancer Res 14:3536–3544PubMedCrossRefGoogle Scholar
  26. 26.
    Noguchi M, Kakuma T, Uemura H et al (2010) A randomized phase II trial of personalized peptide vaccine plus low dose estramustine phosphate (EMP) versus standard dose EMP in patients with castration resistant prostate cancer. Cancer Immunol Immunother 59:1001–1009PubMedCrossRefGoogle Scholar
  27. 27.
    Arlen PM, Gulley JL, Parker C et al (2006) A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res 12:1260–1269PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang AL, Russell PJ (2006) Paclitaxel suppresses the growth of primary prostate tumours (RM-1) and metastases in the lung in C57BL/6 mice. Cancer Lett 233:185–191PubMedCrossRefGoogle Scholar
  29. 29.
    Lutz MB, Kukutsch N, Ogilvie AL et al (1999) An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 223:77–92PubMedCrossRefGoogle Scholar
  30. 30.
    El HN, Rubio N, Blanco J (2005) Different effect of paclitaxel on primary tumor mass, tumor cell contents, and metastases for four experimental human prostate tumors expressing luciferase. Clin Cancer Res 11:1253–1258Google Scholar
  31. 31.
    Sato E, Olson SH, Ahn J et al (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8 +/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102:18538–18543PubMedCrossRefGoogle Scholar
  32. 32.
    Huang GS, Lopez-Barcons L, Freeze BS et al (2006) Potentiation of taxol efficacy and by discodermolide in ovarian carcinoma xenograft-bearing mice. Clin Cancer Res 12:298–304PubMedCrossRefGoogle Scholar
  33. 33.
    Machiels JP, Reilly RT, Emens LA et al (2001) Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 61:3689–3697PubMedGoogle Scholar
  34. 34.
    Conti L, Gessani S (2008) GM-CSF in the generation of dendritic cells from human blood monocyte precursors: recent advances. Immunobiology 213:859–870PubMedCrossRefGoogle Scholar
  35. 35.
    Bodey B Jr, Bodey B, Siegel SE et al (2000) Failure of cancer vaccines: the significant limitations of this approach to immunotherapy. Anticancer Res 20:2665–2676PubMedGoogle Scholar
  36. 36.
    Vicari AP, Luu R, Zhang NR et al (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. Cancer Immunol Immunother 58:615–628PubMedCrossRefGoogle Scholar
  37. 37.
    Galsky MD, Vogelzang NJ (2010) Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann Oncol 21:2135–2144PubMedCrossRefGoogle Scholar
  38. 38.
    Chan OT, Yang LX (2001) The immunological effects of taxanes. Cancer Immunol Immunother 49:181–185CrossRefGoogle Scholar
  39. 39.
    Zagozdzon R, Golab J (2001) Immunomodulation by anticancer chemotherapy: more is not always better. Int J Oncol 18:417–424PubMedGoogle Scholar
  40. 40.
    Yu B, Kusmartsev S, Cheng F et al (2003) Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced-stage experimental breast cancer. Clin Cancer Res 9:285–294PubMedGoogle Scholar
  41. 41.
    Zhong H, Han B, Tourkova IL et al (2007) Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. Clin Cancer Res 13:5455–5462PubMedCrossRefGoogle Scholar
  42. 42.
    Zhang L, Dermawan K, Jin M et al (2008) Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy. Clin Immunol 129:219–229PubMedCrossRefGoogle Scholar
  43. 43.
    Shurin GV, Tourkova IL, Shurin MR (2008) Low-dose chemotherapeutic agents regulate small Rho GTPase activity in dendritic cells. J Immunother 31:491–499PubMedCrossRefGoogle Scholar
  44. 44.
    Song CK, Han HD, Noh KH et al (2007) Chemotherapy enhances CD8+ T cell-mediated antitumor immunity induced by vaccination with vaccinia virus. Mol Ther 15:1558–1563PubMedCrossRefGoogle Scholar
  45. 45.
    Wada S, Yoshimura K, Hipkiss EL et al (2009) Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model. Cancer Res 69:4309–4318PubMedCrossRefGoogle Scholar
  46. 46.
    Chu Y, Wang LX, Yang G et al (2006) Efficacy of GM-CSF-producing tumor vaccine after docetaxel chemotherapy in mice bearing established Lewis lung carcinoma. J Immunother 29:367–380PubMedCrossRefGoogle Scholar
  47. 47.
    Antonarakis ES, Drake CG (2010) Current status of immunological therapies for prostate cancer. Curr Opin Urol 20:241–246PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Qiushan He
    • 1
    • 3
  • Jinlong Li
    • 2
  • Weihua Yin
    • 2
  • Zhichun Song
    • 1
  • Zhen Zhang
    • 2
  • Tienan Yi
    • 3
  • Jia Tang
    • 1
  • Demin Wu
    • 1
  • Yue Lu
    • 1
  • Zhen Wang
    • 1
  • Dan Liu
    • 1
  • Xiaoren Zhang
    • 1
  • Zhiming Hu
    • 2
    • 4
  • Jimin Gao
    • 1
  1. 1.Zhejiang Provincial Key Lab for Technology and Application of Model OrganismsSchool of Life Sciences, Wenzhou Medical CollegeWenzhouChina
  2. 2.Institute of Biotherapy, School of BiotechnologySouthern Medical UniversityGuangzhouChina
  3. 3.Department of Oncology, Affiliated Xiangfan HospitalTongji Medical College, Huazhong Scientific and Technical UniversityXiangfanChina
  4. 4.GuangzhouChina

Personalised recommendations