Transient Inhibition of PI3Kδ Enhances the Therapeutic Effect of Intravenous Delivery of Oncolytic Vaccinia Virus

Abstract

Tumor-targeting oncolytic viruses such as vaccinia virus (VV) are attractive cancer therapeutic agents that act through multiple mechanisms to provoke both tumor lysis and anti-tumor immune responses. However, delivery of these agents remains restricted to intra-tumoral administration, which prevents effective targeting of inaccessible and disseminated tumor cells. In the present study we have identified transient pharmacological inhibition of the leukocyte-enriched phosphoinositide 3-kinase δ (PI3Kδ) as a novel mechanism to potentiate intravenous delivery of oncolytic VV to tumors. Pre-treatment of immunocompetent mice with the PI3Kδ-selective inhibitor IC87114 or the clinically approved idelalisib (CAL-101), prior to intravenous delivery of a tumor-tropic VV, dramatically improved viral delivery to tumors. This occurred via an inhibition of viral attachment to, but not internalization by, systemic macrophages through perturbation of signaling pathways involving RhoA/ROCK, AKT, and Rac. Pre-treatment using PI3Kδ-selective inhibitors prior to intravenous delivery of VV resulted in enhanced anti-tumor efficacy and significantly prolonged survival compared to delivery without PI3Kδ inhibition. These results indicate that effective intravenous delivery of oncolytic VV may be clinically achievable and could be useful in improving anti-tumor efficacy of oncolytic virotherapy.

A systemically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer

“…In vivo, intratumoral accumulation of virus after intravenous delivery of VVL-21 to subcutaneous DT6606 pancreatic tumors was enhanced by pretreatment with CAL-101 administered by oral gavage 3 hours prior to viral delivery ( online supplemental figure S4A, B ). As noted previously, 16 tumor growth was controlled more effectively after three intravenous injections potentiated by CAL-101 administration compared with administration without CAL-101 ( online supplemental figure S4C ). In vivo efficacy of VVL-21 (VVLΔTK-STCΔN1L-IL21) was compared with delivery of VV CTRL (VVLΔTK-STCΔN1L) to determine the effect of IL-21 on treatment efficacy.…”

“…In vitro, this virus demonstrated cytotoxicity in a panel of murine, hamster and human PaCa cell lines (online supplemental figure S2C) and improved replication and EEV Open access release (online supplemental figure S2D-G). When delivered intravenously to established subcutaneous PaCa, using the PI3Kδ inhibitor CAL-101 to prevent macrophage uptake of the virus after intravenous injection as previously described, 16 VVLΔTK-STCΔN1L (hereafter referred to as VV CTRL) was more effective than the parental virus at replicating and spreading within tumors (figure 1A) and resulted in a modest increase in circulating NK cells and circulating and splenic effector CD8+ T cells (figure 1B). Of note, expression of STC would not be expected to enhance initial viral delivery to tumors as laboratory viral manufacture results in IMV and not EEV production.…”

“…[13][14][15] Additionally, we have developed a platform to improve intravenous delivery of VV based on transient pharmacological inhibition of PI3 Kinase δ (PI3Kδ) to prevent uptake of the virus by macrophages, a major factor limiting systemic administration. 16 This platform goes some way toward addressing the shortcomings of OVT identified above. However, in order to create a clinically valuable OVT, improvements in systemic spread and antitumor efficacy of VVLΔTKΔN1L are still required.…”

Anti-Tumor Effects of MAPK-Dependent Tumor-Selective Oncolytic Vaccinia Virus Armed with CD/UPRT against Pancreatic Ductal Adenocarcinoma in Mice

“…delivery enhances the synergistic antitumor activity of CD/UPRT-LG in combination with 5-FC. Pretreatment with PI3Kδ-selective inhibitors before intravenous delivery of VV has the potential to improve viral delivery to tumors via the inhibition of viral attachment to systemic macrophages [ 53 ]. Furthermore, multiple therapeutic cycles of CD/UPRT-armed virus and 5-FC would also increase the synergistic antitumor activity compared with that after a single treatment cycle [ 31 ], which was evaluated in this study.…”

Viroimmunotherapy for breast cancer: promises, problems and future directions

“…GLV-1h164, a Lister strain of VACV deleted of three viral genes and encoding an antibody against vascular endothelial growth factor, was shown to exert an anti-tumor effect against BrCa xenograft in mice [55]. Ferguson et al [56] studied the oncolytic activity of a VACV-encoding IL-15 in combination with an inhibitor of phosphatidylinositol-3kinase (PI3Kδ) in BrCa models. The inhibitor of PI3Kδ was found to improve intravenous delivery of virus by inhibiting virus attachment to systemic macrophages, and it increased overall oncolytic activity of the virus.…”