Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

Cancer Immunol Res. 2015 Aug;3(8):915-25. doi: 10.1158/2326-6066.CIR-14-0220-T. Epub 2015 May 14.


Despite the rapid progress in the development of novel adoptive T-cell therapies, the clinical benefits in treatment of established tumors have remained modest. Several immune evasion mechanisms hinder T-cell entry into tumors and their activity within the tumor. Of note, oncolytic adenoviruses are intrinsically immunogenic due to inherent pathogen-associated molecular patterns. Here, we studied the capacity of adenovirus to overcome resistance of chicken ovalbumin-expressing B16.OVA murine melanoma tumors to adoptive ovalbumin-specific CD8(+) T-cell (OT-I) therapy. Following intraperitoneal transfer of polyclonally activated OT-I lymphocytes, control of tumor growth was superior in mice given intratumoral adenovirus compared with control mice, even in the absence of oncolytic virus replication. Preexisting antiviral immunity against serotype 5 did not hinder the therapeutic efficacy of the combination treatment. Intratumoral adenovirus injection was associated with an increase in proinflammatory cytokines, CD45(+) leukocytes, CD8(+) lymphocytes, and F4/80(+) macrophages, suggesting enhanced tumor immunogenicity. The proinflammatory effects of adenovirus on the tumor microenvironment led to expression of costimulatory signals on CD11c(+) antigen-presenting cells and subsequent activation of T cells, thus breaking the tumor-induced peripheral tolerance. An increased number of CD8(+) T cells specific for endogenous tumor antigens TRP-2 and gp100 was detected in combination-treated mice, indicating epitope spreading. Moreover, the majority of virus/T-cell-treated mice rejected the challenge of parental B16.F10 tumors, suggesting that systemic antitumor immunity was induced. In summary, we provide proof-of-mechanism data on combining adoptive T-cell therapy and adenovirotherapy for the treatment of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / immunology*
  • Adenoviridae Infections / immunology
  • Adoptive Transfer*
  • Animals
  • Antigen Presentation / immunology
  • Antigens, Neoplasm / immunology
  • Biomarkers
  • Clonal Anergy
  • Cross-Priming / immunology
  • Disease Models, Animal
  • Humans
  • Immunomodulation
  • Lymphocyte Activation / immunology
  • Melanoma, Experimental
  • Mice
  • Neoplasms / immunology*
  • Neoplasms / therapy*
  • Oncolytic Viruses / immunology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism


  • Antigens, Neoplasm
  • Biomarkers