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Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2019 Nov 06; Vol. 27 (11), pp. 1892-1905. Date of Electronic Publication: 2019 Sep 16. - Publication Year :
- 2019
-
Abstract
- Immune checkpoint blockade has shown anti-cancer efficacy, but requires systemic administration of monoclonal antibodies (mAbs), often leading to adverse effects. To avoid toxicity, mAbs could be expressed locally in tumors. We developed adeno-associated virus (AAV) and Semliki Forest virus (SFV) vectors expressing anti-programmed death ligand 1 (aPDL1) mAb. When injected intratumorally in MC38 tumors, both viral vectors led to similar local mAb expression at 24 h, diminishing quickly in SFV-aPDL1-treated tumors. However, SFV-aPDL1 induced >40% complete regressions and was superior to AAV-aPDL1, as well as to aPDL1 mAb given systemically or locally. SFV-aPDL1 induced abscopal effects and was also efficacious against B16-ovalbumin (OVA). The higher SFV-aPDL1 antitumor activity could be related to local upregulation of interferon-stimulated genes because of SFV RNA replication. This was confirmed by combining local SFV-LacZ administration and systemic aPDL1 mAb, which provided higher antitumor effects than each separated agent. SFV-aPDL1 promoted tumor-specific CD8 T cells infiltration in both tumor models. In MC38, SFV-aPDL1 upregulated co-stimulatory markers (CD137/OX40) in tumor CD8 T cells, and its combination with anti-CD137 mAb showed more pronounced antitumor effects than each single agent. These results indicate that local transient expression of immunomodulatory mAbs using non-propagative RNA vectors inducing type I interferon (IFN-I) responses represents a potent and safe approach for cancer treatment.<br /> (Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
B7-H1 Antigen genetics
B7-H1 Antigen metabolism
Cell Line
Dependovirus genetics
Disease Models, Animal
Female
Genetic Therapy methods
Genetic Vectors administration & dosage
Humans
Immunomodulation drug effects
Immunophenotyping
Injections, Intralesional
Mice
Neoplasms pathology
Neoplasms therapy
Recombinant Fusion Proteins genetics
Semliki forest virus genetics
Survival Rate
T-Lymphocyte Subsets immunology
T-Lymphocyte Subsets metabolism
Tumor Burden
Antibodies, Monoclonal genetics
Antibodies, Monoclonal pharmacology
B7-H1 Antigen antagonists & inhibitors
Gene Expression
Genetic Vectors genetics
Neoplasms genetics
Neoplasms immunology
RNA Viruses genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0024
- Volume :
- 27
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 31563534
- Full Text :
- https://doi.org/10.1016/j.ymthe.2019.09.016