Skip to main content

Advertisement

SpringerLink
Log in

The anti-tumor efficacy of a GM-CSF-secreting tumor cell vaccine is not inhibited by docetaxel administration

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Docetaxel has demonstrated therapeutic efficacy against breast, prostate, and ovarian cancer and other solid tumors. The tumoricidal activity of docetaxel is mainly attributed to its ability to block microtubule depolymerization, thus inducing G2-M arrest and apoptosis. Mounting evidence indicates that docetaxel also possesses immunomodulatory activity such as augmenting macrophage and lymphokine activated killer activity and inducing pro-inflammatory cytokines, suggesting that docetaxel may be a good chemotherapeutic agent to combine with cancer immunotherapies, assuming that it does not inhibit the vaccine-induced immune response. The anti-tumor activity of the combination of docetaxel and a GM-CSF-secreting B16F10 tumor cell vaccine (B16.GM) was evaluated in the murine B16 melanoma model. Dose levels of docetaxel and the B16.GM vaccine known to be ineffective when used as single agents were selected. Three iv treatments of 6 mg/kg docetaxel per injection given on days 5, 9, and 13 after tumor challenge or a single vaccination with 2–3×106 B16.GM cells on day 3 were ineffective at inhibiting tumor growth when used as single agents [median survival time (MST)=24 days in both treatment groups and in control animals]. However, combination of docetaxel and B16.GM vaccine significantly delayed tumor growth, increasing MST to 45 days. A similar improvement in anti-tumor efficacy was observed using multiple treatment cycles of the B16.GM vaccine/docetaxel combination. Administration of docetaxel every 4 days between bi-weekly B16.GM vaccinations increased the median survival of tumor-bearing mice from 31 to 52 days compared to multiple B16.GM vaccinations alone. In summary, these data demonstrate that rather than inhibiting the anti-tumor effects of a GM-CSF-secreting tumor cell vaccine, docetaxel combined with a whole cell vaccine significantly inhibits tumor growth, increases survival time and does not impede T-cell activation in the murine B16F10 melanoma tumor model. GM-secreting tumor cell vaccines in combination with docetaxel may represent a new strategy for combining chemo and immunotherapy for cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Katsumata N (2003) Docetaxel: an alternative taxane in ovarian cancer. Br J Cancer 89(Suppl 3):S9–S15

    Article  PubMed  CAS  Google Scholar 

  2. Ghersi D, Wilcken N, Simes J, Donoghue E (2003) Taxane containing regimens for metastatic breast cancer. Cochrane Database Syst Rev CD003366

  3. Davies AM, Lara PN Jr, Mack PC, Gandara DR (2003) Docetaxel in non-small cell lung cancer: a review. Expert Opin Pharmacother 4:553–565

    Article  PubMed  CAS  Google Scholar 

  4. Trump D, Lau YK (2003) Chemotherapy of prostate cancer: present and future. Curr Urol Rep 4:229–232

    Article  PubMed  Google Scholar 

  5. Obasaju C, Hudes GR (2001) Paclitaxel and docetaxel in prostate cancer. Hematol Oncol Clin North Am 15:525–545

    Article  PubMed  CAS  Google Scholar 

  6. Ringel I, Horwitz SB (1991) Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst 83:288–291

    Article  PubMed  CAS  Google Scholar 

  7. Abal M, Andreu JM, Barasoain I (2003) Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets 3:193–203

    Article  PubMed  CAS  Google Scholar 

  8. Herbst RS, Khuri FR (2003) Mode of action of docetaxel—a basis for combination with novel anticancer agents. Cancer Treat Rev 29:407–415

    Article  PubMed  CAS  Google Scholar 

  9. Lin HL, Liu TY, Chau GY, Lui WY, Chi CW (2000) Comparison of 2-methoxyestradiol-induced, docetaxel-induced, and paclitaxel-induced apoptosis in hepatoma cells and its correlation with reactive oxygen species. Cancer 89:983–994

    Article  PubMed  CAS  Google Scholar 

  10. Nabell L, Spencer S (2003) Docetaxel with concurrent radiotherapy in head and neck cancer. Semin Oncol 30:89–93

    Article  PubMed  CAS  Google Scholar 

  11. Milas L (2002) Docetaxel/radiation combinations: rationale and preclinical findings. Clin Lung Cancer 3(Suppl 2):S29–36

    Article  PubMed  Google Scholar 

  12. Mason K, Staab A, Hunter N, McBride W, Petersen S, Terry N, Milas L (2001) Enhancement of tumor radioresponse by docetaxel: involvement of immune system. Int J Oncol 18:599–606

    PubMed  CAS  Google Scholar 

  13. Mason KA, Hunter NR, Milas M, Abbruzzese JL, Milas L (1997) Docetaxel enhances tumor radioresponse in vivo. Clin Cancer Res 3:2431–2438

    PubMed  CAS  Google Scholar 

  14. Chan OT, Yang LX (2000) The immunological effects of taxanes. Cancer Immunol Immunother 49:181–185

    Article  PubMed  CAS  Google Scholar 

  15. Tsavaris N, Kosmas C, Vadiaka M, Kanelopoulos P, Boulamatsis D (2002) Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes. Br J Cancer 87:21–27

    Article  PubMed  CAS  Google Scholar 

  16. Tong AW, Seamour B, Lawson JM, Ordonez G, Vukelja S, Hyman W, Richards D, Stein L, Maples PB, Nemunaitis J (2000) Cellular immune profile of patients with advanced cancer before and after taxane treatment. Am J Clin Oncol 23:463–472

    PubMed  CAS  Google Scholar 

  17. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan RC (1993) Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 90:3539–3543

    Article  PubMed  CAS  Google Scholar 

  18. Herrlinger U, Kramm CM, Johnston KM, Louis DN, Finkelstein D, Reznikoff G, Dranoff G, Breakefield XO, Yu JS (1997) Vaccination for experimental gliomas using GM-CSF-transduced glioma cells. Cancer Gene Ther 4:345–352

    PubMed  CAS  Google Scholar 

  19. Hrouda D, Perry M, Dalgleish AG (1999) Gene therapy for prostate cancer. Semin Oncol 26:455–471

    PubMed  CAS  Google Scholar 

  20. Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, Goemann M, Coleman J, Grochow L, Donehower RC, Lillemoe KD, O’Reilly S, Abrams RA, Pardoll DM, Cameron JL, Yeo CJ (2001) Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 19:145–156

    PubMed  CAS  Google Scholar 

  21. Jaffee EM, Thomas MC, Huang AY, Hauda KM, Levitsky HI, Pardoll DM (1996) Enhanced immune priming with spatial distribution of paracrine cytokine vaccines. J Immunother Emphasis Tumor Immunol 19:176–183

    PubMed  CAS  Google Scholar 

  22. Kusumoto M, Umeda S, Ikubo A, Aoki Y, Tawfik O, Oben R, Williamson S, Jewell W, Suzuki T (2001) Phase 1 clinical trial of irradiated autologous melanoma cells adenovirally transduced with human GM-CSF gene. Cancer Immunol Immunother 50:373–381

    Article  PubMed  CAS  Google Scholar 

  23. Lim M, Simons JW (1999) Emerging concepts in GM-CSF gene-transduced tumor vaccines for human prostate cancer. Curr Opin Mol Ther 1:64–71

    PubMed  CAS  Google Scholar 

  24. Mach N, Dranoff G (2000) Cytokine-secreting tumor cell vaccines. Curr Opin Immunol 12:571–575

    Article  PubMed  CAS  Google Scholar 

  25. Fernandes DM, Vidard L, Rock KL (2000) Characterization of MHC class II-presented peptides generated from an antigen targeted to different endocytic compartments. Eur J Immunol 30:2333–2343

    Article  PubMed  CAS  Google Scholar 

  26. Miyazaki J, Takaki S, Araki K, Tashiro F, Tominaga A, Takatsu K, Yamamura K (1989) Expression vector system based on the chicken beta-actin promoter directs efficient production of interleukin-5. Gene 79:269–277

    Article  PubMed  CAS  Google Scholar 

  27. Dull T, Zufferey R, Kelly M, Mandel RJ, Nguyen M, Trono D, Naldini L (1998) A third-generation lentivirus vector with a conditional packaging system. J Virol 72:8463–8471

    PubMed  CAS  Google Scholar 

  28. Zennou V, Petit C, Guetard D, Nerhbass U, Montagnier L, Charneau P (2000) HIV-1 genome nuclear import is mediated by a central DNA flap. Cell 101:173–185

    Article  PubMed  CAS  Google Scholar 

  29. Zufferey R, Donello JE, Trono D, Hope TJ (1999) Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors. J Virol 73:2886–2892

    PubMed  CAS  Google Scholar 

  30. Zufferey R, Dull T, Mandel RJ, Bukovsky A, Quiroz D, Naldini L, Trono D (1998) Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol 72:9873–9880

    PubMed  CAS  Google Scholar 

  31. Sweeney CJ, Miller KD, Sissons SE, Nozaki S, Heilman DK, Shen J, Sledge GW Jr (2001) The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res 61:3369–3372

    PubMed  CAS  Google Scholar 

  32. Piechocki MP, Lonardo F, Ensley JF, Nguyen T, Kim H, Yoo GH (2002) Anticancer activity of docetaxel in murine salivary gland carcinoma. Clin Cancer Res 8:870–877

    PubMed  CAS  Google Scholar 

  33. Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, Okoye FI, Jaffee EM (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 61:3689–3697

    PubMed  CAS  Google Scholar 

  34. Ma J, Urba WJ, Si L, Wang Y, Fox BA, Hu HM (2003) Anti-tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution. Eur J Immunol 33:2123–2132

    Article  PubMed  CAS  Google Scholar 

  35. Dummer W, Niethammer AG, Baccala R, Lawson BR, Wagner N, Reisfeld RA, Theofilopoulos AN (2002) T cell homeostatic proliferation elicits effective antitumor autoimmunity. J Clin Invest 110:185–192

    Article  PubMed  CAS  Google Scholar 

  36. Hu HM, Poehlein CH, Urba WJ, Fox BA (2002) Development of antitumor immune responses in reconstituted lymphopenic hosts. Cancer Res 62:3914–3919

    PubMed  CAS  Google Scholar 

  37. Terando A, Mule JJ (2003) On combining antineoplastic drugs with tumor vaccines. Cancer Immunol Immunother 52:680–685

    Article  PubMed  Google Scholar 

  38. Bruno R, Hille D, Riva A, Vivier N, Bokkel Huinnink WW X, van Oosterom AT, Kaye SB, Verweij J, Fossella FV, Valero V, Rigas JR, Seidman AD, Chevallier B, Fumoleau P, Burris HA, Ravdin PM, Sheiner LB (1998) Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187–196

    PubMed  CAS  Google Scholar 

  39. van Tellingen O, Beijnen JH, Verweij J, Scherrenburg EJ, Nooijen WJ, Sparreboom A (1999) Rapid esterase-sensitive breakdown of polysorbate 80 and its impact on the plasma pharmacokinetics of docetaxel and metabolites in mice. Clin Cancer Res 5:2918–2924

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Drs. Peter Working and Natalie Sacks for their critical review of the manuscript.

Author information

Authors and Affiliations

  1. Department of Preclinical Oncology and Immunology, Cell Genesys Inc, 500 Forbes Blvd, South San Francisco, CA, 94080, USA

    Rodney A. Prell, Lisa Gearin, Andrew Simmons, Melinda VanRoey & Karin Jooss

Authors
  1. Rodney A. Prell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa Gearin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew Simmons
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Melinda VanRoey
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karin Jooss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karin Jooss.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Prell, R.A., Gearin, L., Simmons, A. et al. The anti-tumor efficacy of a GM-CSF-secreting tumor cell vaccine is not inhibited by docetaxel administration. Cancer Immunol Immunother 55, 1285–1293 (2006). https://doi.org/10.1007/s00262-005-0116-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-005-0116-4

Keywords

Search

Navigation