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An Oncolytic Adenovirus Targeting Transforming Growth Factor β Inhibits Protumorigenic Signals and Produces Immune Activation: A Novel Approach to Enhance Anti-PD-1 and Anti-CTLA-4 Therapy

Authors
  • Yang, Yuefeng1, 2
  • Xu, Weidong1
  • Peng, Di3
  • Wang, Hao2
  • Zhang, Xiaoyan2
  • Wang, Hua2
  • Xiao, Fengjun2
  • Zhu, Yitan4
  • Ji, Yuan4
  • Gulukota, Kamalakar5
  • Helseth, Donald L. Jr.5
  • Mangold, Kathy A.6
  • Sullivan, Megan6
  • Kaul, Karen6
  • Wang, Edward7
  • Prabhakar, Bellur S.8
  • Li, Jinnan3
  • Wu, Xuejie3
  • Wang, Lisheng2
  • Seth, Prem1
  • 1 Gene Therapy Program, Department of Medicine, NorthShore Research Institute, an Affiliate of the University of Chicago, Evanston, Illinois
  • 2 cine, Beijing, China
  • 3 Department of Urology, The Third Medical Center of Chinese People's Liberation Army, Beijing, China
  • 4 Program of Computational Genomics and Medicine, Department of Surgery; NorthShore University HealthSystem, Evanston, Illinois
  • 5 Center for Personalized Medicine, Department of Surgery; NorthShore University HealthSystem, Evanston, Illinois
  • 6 Department of Pathology and Laboratory Medicine, NorthShore University HealthSystem, Evanston, Illinois
  • 7 Biostatistics and Clinical Research Informatics, Department of Surgery; NorthShore University HealthSystem, Evanston, Illinois
  • 8 Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois.
Type
Published Article
Journal
Human Gene Therapy
Publisher
Mary Ann Liebert
Publication Date
Sep 01, 2019
Volume
30
Issue
9
Pages
1117–1132
Identifiers
DOI: 10.1089/hum.2019.059
PMID: 31126191
PMCID: PMC6761593
Source
PubMed Central
Keywords
License
Unknown

Abstract

In an effort to develop a new therapy for cancer and to improve antiprogrammed death inhibitor-1 (anti-PD-1) and anticytotoxic T lymphocyte-associated protein (anti-CTLA-4) responses, we have created a telomerase reverse transcriptase promoter-regulated oncolytic adenovirus rAd.sT containing a soluble transforming growth factor receptor II fused with human IgG Fc fragment (sTGFβRIIFc) gene. Infection of breast and renal tumor cells with rAd.sT produced sTGFβRIIFc protein with dose-dependent cytotoxicity. In immunocompetent mouse 4T1 breast tumor model, intratumoral delivery of rAd.sT inhibited both tumor growth and lung metastases. rAd.sT downregulated the expression of several transforming growth factor β (TGFβ) target genes involved in tumor growth and metastases, inhibited Th2 cytokine expression, and induced Th1 cytokines and chemokines, and granzyme B and perforin expression. rAd.sT treatment also increased the percentage of CD8+ T lymphocytes, promoted the generation of CD4+ T memory cells, reduced regulatory T lymphocytes (Tregs), and reduced bone marrow-derived suppressor cells. Importantly, rAd.sT treatment increased the percentage of CD4+ T lymphocytes, and promoted differentiation and maturation of antigen-presenting dendritic cells in the spleen. In the immunocompetent mouse Renca renal tumor model, similar therapeutic effects and immune activation results were observed. In the 4T1 mammary tumor model, rAd.sT improved the inhibition of tumor growth and lung and liver metastases by anti-PD-1 and anti-CTLA-4 antibodies. Analysis of the human breast and kidney tumors showed that a significant number of tumor tissues expressed high levels of TGFβ and TGFβ-inducible genes. Therefore, rAd.sT could be a potential enhancer of anti-PD-1 and anti-CTLA-4 therapy for treating breast and kidney cancers.

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