Combination effect of oncolytic adenovirotherapy and TRAIL gene therapy in syngeneic murine breast cancer models

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy and oncolytic adenovirotherapy have been investigated extensively in xenografic human tumor models established in immunocompromised nude mice. However, the effects of these therapies on syngeneic murine tumors in immunocompetent settings were not well documented. We hypothesized that TRAIL gene therapy used with an oncolytic adenovirus would overcome the weaknesses of the two therapies used individually. In this study, we evaluated the antitumor effects of an oncolytic adenovirus, Delta24, in both human and murine breast cancer cell lines. We also analyzed the effects of TRAIL gene therapy combined with oncolytic virotherapy in these cancer cells. Our results showed that Delta24 can replicate and help the E1-deleted adenovector replicate in murine cancer cells. We also found that these two therapies combined had greater antitumor activity than either one alone in both human and murine breast cancer cells lines and in the syngeneic breast cancer models established in immunocompetent mice. Moreover, Delta24 virotherapy alone and combined with TRAIL gene therapy dramatically reduced the spontaneous liver metastasis that originated in the subcutaneous 4T1 tumor established in Balb/c mice. These findings provide important considerations in the development and preclinical assessments of oncolytic virotherapy.

Targeted Cancer Gene Therapy Using a Hypoxia Inducible Factor–Dependent Oncolytic Adenovirus Armed with Interleukin-4

“…It is certainly possible that HYPR-AdmIL4 will exhibit improved antitumor potency compared with dl309-Ad in an immunocompetent animal tumor model or metastatic cancer model where IL-4 antitumor activity mediated by an induced T-and B-cell response can be evaluated. Recently, several rodent tumor cell lines that support human Ad replication have been identified (28)(29)(30)(31), including a syngeneic metastatic breast cancer model (32). Now that this paper has shown proof of principle, a next useful study would be to evaluate the efficacy of HYPR-Ad-mIL4 in these new models.…”

Anticancer activity of oncolytic adenovirus vector armed with IFN-α and ADP is enhanced by pharmacologically controlled expression of TRAIL

“…RC Ad vectors support replication of coinfected RD Ad leading to amplification of transgene expression from the RD vector. 6,20,22,23,31,42 rtTA, used in the TetON system, is known to have some affinity for TetO sequences within the TRE in the absence of Dox, leading to low basal expression of the transgene in the absence of inducer. 19,43 Together, the presence of the helper virus plus Dox mediated up to 231-fold activation of SEAP expression from the TetON-SEAP vector.…”

“…The combination of RC Ad oncolytic activity with the expression of TRAIL was shown to be superior to either modality alone in suppressing breast cancer cells in vitro and in vivo, 23 and it revealed synergistic caspase activation in hepatoma cells in vitro. 37 To assess whether regulatable expression of TRAIL from TetON-TRAIL improves the oncolytic activity of the conditionally replicative Ads KD3 and KD3-IFN, Hep3B and DLD-1 cells were [38][39][40][41] TRAIL-mediated induction of apoptosis, therefore, could potentially decrease oncolytic Ad yields when these two modalities are combined.…”

“…It is known that RC Ad can trans-complement replication of an RD vector resulting in amplification of transgene expression. [20][21][22][23] Therefore, we expected that KD3-IFN would serve as a helper for replication of TetON-TRAIL leading to increased TRAIL expression. IFN-activated signaling pathways were shown to sensitize tumor cells to apoptosis mediated by TRAIL; 24 synergistic apoptotic activity of the combination of type I IFN (IFN-a or IFNb) and TRAIL was demonstrated in various cancer cells in vitro.…”

Genetic immunotherapy of lung cancer using conditionally replicating adenovirus and adenovirus-interferon-β

“…However, we did not know whether this would occur in the mouse cancer cell line. Guo et al 29 previously reported that D24 aided in the replication of ad-TRAIL in mouse breast cancer cells (4T1). Several experiments were carried out to investigate this question.…”