Skip to main content

Advertisement

SpringerLink
Log in

Anti-tumor immunotherapy despite immunity to adenovirus using a novel adenoviral vector Ad5 [E1-, E2b-]-CEA

  • Short communication
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Adenovirus serotype 5 (Ad5) has been widely used in clinical trials because it expresses inserted transgenes robustly and augments the innate immune response. Strategies to improve Ad5 vectors that can circumvent Ad5 immunity have become a critical issue, especially for use as a cancer immunotherapeutic in which repeated immunization is required. In this study, we constructed a novel Ad5 vector with unique deletions of the viral DNA polymerase and the pre-terminal protein region (Ad5 [E1-, E2b-]). This vector contains the carcinoembryonic antigen (CEA) gene insert and is designed to induce cell-mediated immunity (CMI) against the tumor-associated target. The CEA immunogenicity and in vivo anti-tumor effects of repeated immunizations with Ad5 [E1-, E2b-]-CEA compared with those observed with current generation Ad5 [E1-]-CEA were tested in Ad5 pre-immunized mice. We report that Ad5-immune mice immunized multiple times with Ad5 [E1-, E2b-]-CEA induced CEA-specific CMI responses that were significantly increased over those detected in Ad5-immune mice immunized multiple times with a current generation Ad5 [E1-]-CEA. Ad5 immune mice bearing CEA-expressing tumors that were treated with Ad5 [E1-, E2b-]-CEA had increased anti-tumor response as compared with Ad5 [E1-]-CEA treated mice. These results demonstrate that Ad5 [E1-, E2b-]-CEA can induce CMI immune responses which result in tumor growth inhibition despite the presence of pre-existing Ad5 immunity. Multiple re-immunizations using the same vector platform are now possible with the novel Ad5 [E1-, E2b-] platform.

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

References

  1. Kirk CJ, Hartigan-O’Connor D, Mule JJ (2001) The dynamics of the T-cell antitumor response: chemokine-secreting dendritic cells can prime tumor-reactive T cells extranodally. Cancer Res 61:8794–8802

    CAS  PubMed  Google Scholar 

  2. Kirk CJ, Hartigan-O’Connor D, Nickoloff BJ, Chamberlain JS, Giedlin M, Aukerman L, Mule JJ (2001) T cell-dependant antitumor immunity mediated by secondary lymphoid tissue chemokine; augmentation of dendritic cell-based immunotherapy. Cancer Res 61:2062–2070

    CAS  PubMed  Google Scholar 

  3. Polo JM, Dubensky TW (2002) Virus-based vectors for human vaccine applications. Drug Discov Today 1:53–100

    Google Scholar 

  4. Liniger M, Zuniga A, Naim HY (2007) Use of viral vectors for the development of vaccines. Expert Rev Vaccines 6:255–266

    Article  CAS  PubMed  Google Scholar 

  5. Gaydos CA, Gaydos JC (2004) Adenovirus vaccine. In: Orenstein WA (ed) Vaccines, 4th edn. Sauders, Philadelphia, pp 863–885

    Google Scholar 

  6. Papp Z, Babiuk LA, Baca-Estrada ME (1999) The effect of pre-existing adenovirus-specific immunity on immune responses induced by recombinant adenovirus expressing glycoprotein D of bovine herpesvirus type 1. Vaccine 17:933–943

    Article  CAS  PubMed  Google Scholar 

  7. McCoy K, Tatsis N, Korioth-Schmitz B, Lasaro MO, Hensley SE, Lin SW, Li Y, Giles-Davis W, Cun A, Zhou D, Xiang Z, Letvin NL, Ertl HC (2007) Effect of preexisting immunity to adenovirus human serotype 5 antigens on the Immune responses of nonhuman primates to vaccine regimens based on human- or chimpanzee-derived adenovirus vectors. J Virol 81(12):6594–6604

    Article  CAS  PubMed  Google Scholar 

  8. Mast TC, Kierstead L, Gupta SB, Nikas AA, Kallas EG, Novitsky V, Mbewe B, Pitisuttithum P, Schechter M, Vardas E, Wolfe ND, Aste-Mezaga M, Casimiro DR, Coplan P, Straus WL, Shiver JW (2009) International epidemiology of human pre-existing adenovirus (Ad) type-5, type-6, type-26 and type-36 neutralizing antibodies: correlates of high Ad5 titers and implications for potential HIV vaccine trials. Vaccine 28:950–957

    Google Scholar 

  9. Amalfitano A, Begy CR, Chamberlain JS (1996) Improved adenovirus packaging cell lines to support the growth of replication-defective gene-delivery vectors. Proc Natl Acad Sci USA 93:3352–3356

    Article  CAS  PubMed  Google Scholar 

  10. Hodges BL, Serra D, Hu H, Begy CA, Chamberlain JS, Amalfitano A (2000) Multiply deleted [E1, polymerase-, and pTP-] adenovirus vector persists despite deletion of the preterminal protein. J Gene Med 2:250–259

    Article  CAS  PubMed  Google Scholar 

  11. Amalfitano A, Hauser MA, Hu H, Serra D, Begy CR, Chamberlain JS (1998) Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 genes deleted. J Virol 72:926–933

    CAS  PubMed  Google Scholar 

  12. Everett RS, Hodges BL, Ding EY, Xu F, Serra D, Amalfitano A (2003) Liver toxicities typically induced by first-generation adenoviral vectors can be reduced by use of E1, E2b-deleted adenoviral vectors. Hum Gene Ther 14:1715–1726

    Article  CAS  PubMed  Google Scholar 

  13. Gabitzsch ES, Xu Y, Yosida L, Balint JP, Gayle RB, Amalfitano A, Jones FR (2009) A preliminary and comparative evaluation of a novel Ad5 [E1-, E2b-] recombinant based vaccine used to induce cell mediated immune responses. Immunol Lett 122:44–51

    Article  CAS  PubMed  Google Scholar 

  14. Thompson JA, Grunert F, Zimmerman W (1991) Carcinoembryonic antigen gene family: molecular biology and clinical perspectives. J Clin Lab Anal 5:344–366

    Article  CAS  PubMed  Google Scholar 

  15. Shively JE, Beatty JD (1985) CEA-related antigens: molecular biology and clinical significance. Crit Rev Oncol Hematol 2:355–399

    Article  CAS  PubMed  Google Scholar 

  16. Schlom J (1986) Basic principle and applications of monoclonal antibodies in the management of carcinomas: the Richard and Hinda Tosenthal Foundation Award Lecture. Cancer Res 46:3225–3238

    CAS  PubMed  Google Scholar 

  17. Berinstein NL (2002) Carcinoembryonic antigen as a target for therapeutic anticancer vaccines: a review. J Clin Oncol 20:2197–2207

    Article  CAS  PubMed  Google Scholar 

  18. Marshall JL, Hoyer RJ, Toomey MA et al (2000) Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J Clin Oncol 18:3964–3973

    CAS  PubMed  Google Scholar 

  19. Marshall JL, Hawkins MJ, Tsang KY, Richmond E, Pedicano JE, Zhu MZ, Schlom J (1999) Phase I study in cancer patients of a replication- defective avipox recombinant vaccine that expresses human carcinoembryonic antigen. J Oncol 17:332–337

    CAS  Google Scholar 

  20. Tsang KY, Zaremba S, Nieroda CA, Zhu MZ, Hamilton JM, Schlom J (1995) Generation of human cytotoxic T cells specific for human carcinoembryonic antigen epitopes from patients immunized with recombinant vaccinia-CEA vaccine. J Nat Cancer Inst 87:982–990

    Article  CAS  PubMed  Google Scholar 

  21. Samanci A, Yi Q, Fagerberg J, Strigård K, Smith G, Rudén U, Wahren B, Mellstedt H (1998) Pharmacological administration of granulocyte/macrophage-colony-stimulating factor is of significant importance for the induction of a strong humoral and cellular response in patients immunized with recombinant carcinoembryonic antigen. Cancer Immunol Immunother 47:131–142

    Article  CAS  PubMed  Google Scholar 

  22. Mincheff M, Altankova I, Zoubak S, Tchakarov S, Botev C, Petrov S, Krusteva E, Kurteva G, Kurtev P, Dimitrov V, Ilieva M, Georgiev G, Lissitchkov T, Chernozemski I, Meryman HT (2001) In vivo transfection and/or cross-priming of dendritic cells following DNA and adenoviral immunizations for immunotherapy of cancer–changes in peripheral mononuclear subsets and intracellular IL-4 and IFN-gamma lymphokine profile. Crit Rev Oncol Hematol 39(1-2):125–132

    Article  CAS  PubMed  Google Scholar 

  23. Robbins PF, Kantor JA, Salgaller M, Hand PH, Fernsten PD, Schlom J (1991) Transduction and expression of the human carcinoembryonic antigen gene in a murine colon carcinoma cell line. Caner Res 51:3657–3662

    CAS  Google Scholar 

  24. Clarke P, Mann J, Simpson JF, Rickard-Dickson K, Primus FJ (1998) Mice transgenic for carcinoembryonic antigen as a model for immunotherapy. Cancer Res 58:1468–1477

    Google Scholar 

Download references

Acknowledgments

This study was funded in part by NIH-NCI grants 1R43CA134063-01 and 2R44CA134063-02. The authors thank Dr. Winston Witcomb for management and care of the animals and Ms. Carol Jones for management of the grant activities. The authors would also like to thank Dr. Jack Greiner and Dr. Jeffrey Schlom for providing the MC38-cea2 cells and ViraQuest, North Liberty, IA, USA, for virus vector production. H. Kim Lyerly is a paid consultant to the Etubics Corporation.

Author information

Authors and Affiliations

  1. Etubics Corporation, 410 West Harrison Street, Suite 100, Seattle, WA, 98119, USA

    Elizabeth S. Gabitzsch, Younong Xu, Joseph P. Balint Jr. & Frank R. Jones

  2. Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC, 27710, USA

    Zachary C. Hartman & H. Kim Lyerly

Authors
  1. Elizabeth S. Gabitzsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Younong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joseph P. Balint Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zachary C. Hartman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Kim Lyerly
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frank R. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elizabeth S. Gabitzsch.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gabitzsch, E.S., Xu, Y., Balint, J.P. et al. Anti-tumor immunotherapy despite immunity to adenovirus using a novel adenoviral vector Ad5 [E1-, E2b-]-CEA. Cancer Immunol Immunother 59, 1131–1135 (2010). https://doi.org/10.1007/s00262-010-0847-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-010-0847-8

Keywords

Search

Navigation