• DOI:10.1158/2326-6066.CIR-14-0220-T
• Corpus ID: 14050300

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

@article{Thtinen2015AdenovirusIT,
  title={Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor},
  author={Siri T{\"a}htinen and Susanna Gr{\"o}nberg-V{\"a}h{\"a}-Koskela and Dave Lum{\'e}n and Maiju Merisalo-Soikkeli and Mikko Siurala and Anu J. Airaksinen and Markus V{\"a}h{\"a}-Koskela and Akseli Hemminki},
  journal={Cancer Immunology Research},
  year={2015},
  volume={3},
  pages={915 - 925}
}

• S. Tähtinen, Susanna Grönberg-Vähä-Koskela, +5 authors A. Hemminki
• Published 14 May 2015
• Biology, Medicine
• Cancer Immunology Research

Tähtinen and colleagues report that intratumoral injection of nonreplicating adenovirus can overcome immune tolerance and resistance of B16.OVA murine melanomas to T-cell therapy by recruitment and stimulation of tumor-infiltrating immune cells, thus improving the efficacy of adoptive T-cell therapy in solid tumors. 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. Cancer Immunol Res; 3(8); 915–25. ©2015 AACR.