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

• Published in: Cancer immunology research 2015-08, Vol.3 (8), p.915-925
• Main Authors: Tähtinen, Siri, Grönberg-Vähä-Koskela, Susanna, Lumen, Dave, Merisalo-Soikkeli, Maiju, Siurala, Mikko, Airaksinen, Anu J, Vähä-Koskela, Markus, Hemminki, Akseli
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-14-0220-T

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.