Recombinant Adenovirus Expressing a Soluble Fusion Protein PD-1/CD137L Subverts the Suppression of CD8+ T Cells in HCC.

Abstract

Oncolytic viruses are an excellent platform for developing effective strategies in cancer immunotherapy. Several challenges remain in the use of viro-immunotherapy for cancer, such as the lack of costimulatory signals and negative regulation of immune checkpoints. In this study, we designed a novel adenovirus expressing a soluble fusion protein, programmed cell death protein 1 (PD-1)/CD137L, which contains the extracellular domains of PD-1 and CD137L at each terminus (Ad5-PC). Ad5-PC preserved the costimulatory activity of CD137L and facilitated the persistence of activated CD8+ T cells. Ad5-PC induced strikingly increased antitumor activity in both ascitic and subcutaneous hepatocellular carcinoma (HCC) tumor models, with 70% and 60% long-term cure rates, respectively. The improved antitumor effect of Ad5-PC was attributed to the sustained high-level lymphocyte activation and interferon (IFN)-γ production in the tumor microenvironment, and was essentially dependent on CD8+ T cells rather than natural killer (NK) cells. Moreover, Ad5-huPC-expressing human soluble PD-1/CD137L fusion protein was effective in suppressing tumor growth and improving survival in a humanized mouse model. We confirmed that Ad5-PC induced tumor-specific and systematic protection against tumor rechallenges at both in situ and distant sites. Thus, Ad5-PC harnesses several distinct functions to efficiently overcome several major hurdles of viro-immunotherapy.

• Authors: Yonghui Zhang, Hailin Zhang, Mei Wei, Tao Mou, Tao Shi, Yanyu Ma, Xinyu Cai, Yunzheng Li, Jie Dong, Jiwu Wei
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 27 Issue 11 Pg. 1906-1918 (11 06 2019) ISSN: 1525-0024 [Electronic] United States
• PMID: 31466933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• 4-1BB Ligand
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Recombinant Fusion Proteins
• TNFSF9 protein, human

Topics

• 4-1BB Ligand (genetics, metabolism)
• Adenoviridae (genetics)
• Animals
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Carcinoma, Hepatocellular (genetics, immunology, pathology, therapy)
• Cell Line, Tumor
• Disease Models, Animal
• Gene Expression
• Genetic Therapy
• Genetic Vectors (administration & dosage, genetics)
• Humans
• Immunomodulation (genetics, immunology)
• Liver Neoplasms (genetics, immunology, pathology, therapy)
• Lymphocyte Activation (immunology)
• Mice
• Oncolytic Virotherapy
• Oncolytic Viruses (genetics)
• Programmed Cell Death 1 Receptor (genetics, metabolism)
• Recombinant Fusion Proteins (genetics)
• Signal Transduction
• Treatment Outcome
• Xenograft Model Antitumor Assays