Cancer Immunology, Immunotherapy

, 60:1309

Tumor immunotherapy using adenovirus vaccines in combination with intratumoral doses of CpG ODN

Authors

  • S. M. Geary
    • Division of Pharmaceutics, College of PharmacyUniversity of Iowa
  • C. D. Lemke
    • Division of Pharmaceutics, College of PharmacyUniversity of Iowa
  • D. M. Lubaroff
    • Departments of Urology & Microbiology, Holden Comprehensive Cancer CenterUniversity of Iowa
    • Division of Pharmaceutics, College of PharmacyUniversity of Iowa
Original article

DOI: 10.1007/s00262-011-1038-y

Cite this article as:
Geary, S.M., Lemke, C.D., Lubaroff, D.M. et al. Cancer Immunol Immunother (2011) 60: 1309. doi:10.1007/s00262-011-1038-y

Abstract

The combination of viral vaccination with intratumoral (IT) administration of CpG ODNs is yet to be investigated as an immunotherapeutic treatment for solid tumors. Here, we show that such a treatment regime can benefit survival of tumor-challenged mice. C57BL/6 mice bearing ovalbumin (OVA)-expressing EG.7 thymoma tumors were therapeutically vaccinated with adenovirus type 5 encoding OVA (Ad5-OVA), and the tumors subsequently injected with the immunostimulatory TLR9 agonist, CpG-B ODN 1826 (CpG), 4, 7, 10, and 13 days later. This therapeutic combination resulted in enhanced mean survival times that were more than 3.5× longer than naïve mice, and greater than 40% of mice were cured and capable of resisting subsequent tumor challenge. This suggests that an adaptive immune response was generated. Both Ad5-OVA and Ad5-OVA + CpG IT treatments led to significantly increased levels of H-2 Kb-OVA-specific CD8+ lymphocytes in the peripheral blood and intratumorally. Lymphocyte depletion studies performed in vivo implicated both NK cells and CD8+ lymphocytes as co-contributors to the therapeutic effect. Analysis of tumor infiltrating lymphocytes (TILs) on day 12 post-tumor challenge revealed that mice treated with Ad5-OVA + CpG IT possessed a significantly reduced percentage of regulatory T lymphocytes (Tregs) within the CD4+ lymphocyte population, compared with TILs isolated from mice treated with Ad5-OVA only. In addition, the proportion of CD8+ TILs that were OVA-specific was reproducibly higher in the mice treated with Ad5-OVA + CpG IT compared with other treatment groups. These findings highlight the therapeutic potential of combining intratumoral CpG and vaccination with virus encoding tumor antigen.

Keywords

Toll-like receptor Adenovirus Intratumoral therapy Immunotherapy Tumor immunology CpG ODN

Supplementary material

262_2011_1038_MOESM1_ESM.pdf (63 kb)
Supplementary material 1 (PDF 34 kb)

Copyright information

© Springer-Verlag 2011