Abstract
In this study, we identified murine breast cancer cell lines that support DNA replication of E1-deleted adenovirus vectors and which can be killed by an oncolytic adenovirus expressing adenovirus E1A and tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) in a replication-dependent manner (Ad.IR-E1A/TRAIL). We showed that systemic or intratumoral (i.t.) injection of adenovirus vectors into mice increases plasma levels of proinflammatory cytokines and chemokines, including TNF-alpha, INF-gamma, and MCP-1, which are potent inducers of dendritic cell maturation. Furthermore, we showed that in vivo expression of Flt3L from an adenovirus vector increases the number of CD11b+ and CD11c+ cells (populations that include dendritic cells) in the blood circulation. Based on these findings, we tested whether Ad.IR-E1A/TRAIL induced killing of tumor cells in combination with dendritic cell mobilization by Ad.Flt3L or, for comparison, Ad.GM-CSF would have an additive antitumor effect. As a model, we used immunocompetent C3H mice with syngeneic s.c. tumors derived from C3L5 cells. We found that vaccination of mice with C3L5 cells that underwent viral oncolysis in combination with Flt3L or granulocyte-macrophage colony-stimulating factor (GM-CSF) expression induces a systemic antitumor immune response. I.t. injection of the oncolytic and Flt3L expressing vectors into established tumors delayed tumor growth but did not cause efficient tumor elimination. This study shows the effectiveness of a combined oncolytic/immunostimulatory tumor therapy approach.
Highlights
Adenoviruses are known to elicit expression of proinflammatory cytokines as well as cell-mediated immune responses upon in vivo administration
High sensitivity to Ad.inverted homology regions (IR)-E1A/ TRAIL implies that the cell line is readily infectible by adenovirus vectors, supports DNA replication of E1-deleted adenoviruses and formation of rearranged genomes, and is susceptible to TRAILmediated apoptosis
We showed that the combination of an oncolytic vector and an immunostimulatory vector expressing FMS-related tyrosine kinase 3 ligand (Flt3L) or granulocyte-macrophage colony-stimulating factor (GM-CSF) has an additive antitumor effect
Summary
Adenoviruses are known to elicit expression of proinflammatory cytokines as well as cell-mediated immune responses upon in vivo administration. Adenovirus infections have been associated with transient autoimmune features [1] and graft versus host disease after allogeneic bone marrow transplantation [2, 3]. These clinical observations suggest that adenovirus can break, or help break, tolerance, and for this reason, adenoviruses have been extensively studied as delivery vectors and adjuvant for vaccination. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). In the largest nonhuman primate study of HIV vaccines to date (using an SIV-HIV hybrid model), adenovirus vectors expressing the SIV gag protein were most efficient in providing true clinical protection when compared with various vaccine approaches [4]
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