Transient Inhibition of PI3Kδ Enhances the Therapeutic Effect of Intravenous Delivery of Oncolytic Vaccinia Virus.
Adenine
/ analogs & derivatives
Administration, Intravenous
/ methods
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Cell Survival
Class I Phosphatidylinositol 3-Kinases
/ antagonists & inhibitors
Combined Modality Therapy
/ methods
Female
Immunotherapy
/ methods
Mice
Mice, Inbred BALB C
Oncolytic Virotherapy
/ methods
Oncolytic Viruses
/ immunology
Purines
/ pharmacology
Quinazolines
/ pharmacology
Quinazolinones
/ pharmacology
Transplantation, Homologous
Treatment Outcome
Tumor Burden
Vaccinia virus
/ immunology
breast cancer
colorectal cancer
immunotherapy
intravenous delivery
macrophage
oncolytic virus
phosphoinositide 3-kinase δ
vaccinia virus
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
06 05 2020
06 05 2020
Historique:
received:
28
10
2019
revised:
21
01
2020
accepted:
25
02
2020
pubmed:
8
3
2020
medline:
8
6
2021
entrez:
8
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32145202
pii: S1525-0016(20)30126-X
doi: 10.1016/j.ymthe.2020.02.017
pmc: PMC7210704
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
IC 87114
0
Purines
0
Quinazolines
0
Quinazolinones
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Adenine
JAC85A2161
idelalisib
YG57I8T5M0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1263-1275Subventions
Organisme : Versus Arthritis
ID : 19867
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M023230/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A12008
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C23338/A2572
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C16420/A16373
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A25137
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M015696/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N027655/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 25722
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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