Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses.

Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses.

Publication date: Nov 06, 2019

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.

Ballesteros-Briones, M.C., Martisova, E., Casales, E., Silva-Pilipich, N., Bu~nuales, M., Galindo, J., Manche~no, U., Gorraiz, M., Lasarte, J.J., Kochan, G., Escors, D., Sanchez-Paulete, A.R., , Melero, Prieto, J., Hernandez-Alcoceba, R., Hervas-Stubbs, S., and Smerdou, C. Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses. 24709. 2019 Mol Ther (27):11.

Concepts Keywords
Blockade Medical specialties
Cancer Medicine
CD8 Branches of biology
Immunomodulatory Immune system
Interferon Immunology
LacZ Immune checkpoint
Ligand PD-L1
Monoclonal Antibodies CD137
OVA Viral vector
Toxicity Mab
Tumor Antibodies
Vectors
Viral Vectors
Virus

Semantics

Type Source Name
gene UNIPROT CD274
disease MESH cancer
disease DOID cancer
disease MESH separated
gene UNIPROT TNFRSF9
disease MESH colorectal cancer
disease DOID colorectal cancer
pathway BSID Colorectal cancer
disease MESH melanoma
disease DOID melanoma
pathway BSID Melanoma

Original Article

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