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

: Tahtinen S, Gronberg-Vaha-Koskela S, Lumen D, Merisalo-Soikkeli M, Siurala M, Airaksinen AJ, Vaha-Koskela M, Hemminki A

Publisher: AMER ASSOC CANCER RESEARCH

: 2015

: Cancer Immunology Research

: CANCER IMMUNOLOGY RESEARCH

: CANCER IMMUNOL RES

: 3

: 8

: 915

: 925

: 11

: 2326-6066

DOI: https://doi.org/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.