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E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models
Yaohe Wang1, Gunnel Hallden, Richard Hill
1Viral and Genetic Therapy Program, Cancer Research UK and Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Abstract:
Oncolytic replication-selective adenoviruses constitute a rapidly growing therapeutic platform for cancer. However, the role of the host immune response and the E3 immunoregulatory genes of the human adenovirus were unknown until now. We identified four mouse carcinoma lines of variable permissivity for adenoviral gene expression, cytopathic effects and/or burst size. To determine E3 gene effects in immunocompetent tumor-bearing hosts, we injected tumors with one of three adenoviruses: Ad5 (E3 wild type), dl309 (del. E3 10.4/14.5, 14.7 kDa) or dl704 (del. E3 gp19 kDa). Compared with Ad5 and dl704, dl309 was cleared much more rapidly and/or its activity was lower in all four models. Intratumoral injection with dl309 resulted in markedly greater macrophage infiltration and expression of both tumor necrosis factor and interferon-gamma. Adenovirus replication, CD8(+) lymphocyte infiltration and efficacy were similar upon intratumoral injection with either dl704 or Ad5. E3-dependent differences were not evident in athymic mice. These findings have important implications for the design of oncolytic adenoviruses and may explain the rapid clearance of E3-10.4/14.5,14.7-deleted adenoviruses in patients.
Insights
The E3 immunoregulatory genes of human adenovirus impact the host immune response. Deleting E3 genes 10.4/14.5 and 14.7 kDa in oncolytic adenoviruses leads to rapid clearance and increased immune cell infiltration.
Area of Science:
- Oncolytic virotherapy
- Immunology
- Virology
Background:
- Oncolytic adenoviruses are a promising cancer therapy.
- The role of adenovirus E3 immunoregulatory genes and host immune response in oncolytic virotherapy is not fully understood.
Purpose of the Study:
- To investigate the impact of specific E3 gene deletions on adenovirus activity and host immune response in immunocompetent tumor-bearing mice.
Main Methods:
- Utilized four mouse carcinoma lines with varying permissivity to adenoviral infection.
- Administered wild-type Ad5, dl309 (E3 10.4/14.5, 14.7 kDa deleted), or dl704 (E3 gp19 kDa deleted) adenoviruses intratumorally.
- Assessed viral clearance, replication, immune cell infiltration (macrophages, CD8+ lymphocytes), and cytokine expression (TNF, IFN-γ).
- Compared outcomes in immunocompetent and athymic (T-cell deficient) mice.
Main Results:
- The dl309 adenovirus (lacking E3 10.4/14.5, 14.7 kDa genes) showed significantly faster clearance and reduced activity compared to Ad5 and dl704.
- Intratumoral dl309 administration led to increased macrophage infiltration and elevated levels of tumor necrosis factor and interferon-gamma.
- Adenovirus replication, CD8+ T-cell infiltration, and therapeutic efficacy were comparable between dl704 and Ad5 groups.
- E3-dependent immune responses were not observed in athymic mice, indicating a role for T-cells.
Conclusions:
- Adenovirus E3 gene deletions, particularly E3 10.4/14.5 and 14.7 kDa, significantly influence the host immune response and viral clearance.
- These findings suggest that E3 gene deletion strategies require careful consideration to optimize oncolytic adenovirus therapy.
- The rapid clearance of E3-deleted adenoviruses in patients may be attributed to the evoked immune response, as observed in this study.