Tumor suppressor immune gene therapy to reverse immunotherapy resistance

Background While immune checkpoint inhibitors are becoming a standard of care for multiple types of cancer, the majority of patients do not respond to this form of immunotherapy. New approaches are required to overcome resistance to immunotherapies. Methods We investigated the effects of adenoviral...

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Bibliographic Details
Published in:Cancer gene therapy 2022-06, Vol.29 (6), p.825-834
Main Authors: Chada, Sunil, Wiederhold, Dora, Menander, Kerstin B., Sellman, Beatha, Talbott, Max, Nemunaitis, John J., Ahn, Hyo Min, Jung, Bo-Kyeong, Yun, Chae-Ok, Sobol, Robert E.
Format: Article
Language:English
Subjects:
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Agonists
Antigen presentation
Antitumor activity
Biomedical and Life Sciences
Biomedicine
Biopsy
CD122 antigen
CD8 antigen
Endothelium
Gene Expression
Gene Therapy
Genetic Therapy
Humans
Immune Checkpoint Inhibitors
Immunotherapy
Immunotherapy - methods
Interferon
Interleukin 1
Interleukin 10
Interleukin 15
Interleukin 2
Lymphocytes T
Macrophages
Neoplasms - drug therapy
Neoplasms - therapy
p53 Protein
PD-1 protein
Statistical analysis
Therapeutic applications
Tumor Microenvironment
Tumor suppressor genes
Tumor Suppressor Protein p53 - genetics
Tumors
β-Catenin
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Summary:Background While immune checkpoint inhibitors are becoming a standard of care for multiple types of cancer, the majority of patients do not respond to this form of immunotherapy. New approaches are required to overcome resistance to immunotherapies. Methods We investigated the effects of adenoviral p53 (Ad-p53) gene therapy in combination with immune checkpoint inhibitors and selective IL2 or IL15 CD122/132 agonists in the aggressive B16F10 tumor model resistant to immunotherapies. To assess potential mechanisms of action, pre- and post- Ad-p53 treatment biopsies were evaluated for changes in gene-expression profiles by Nanostring IO 360 assays. Results The substantial synergy of “triplet” Ad-p53 + CD122/132 + anti-PD-1 therapy resulted in potential curative effects associated with the complete tumor remissions of both the primary and contralateral tumors. Interestingly, contralateral tumors, which were not injected with Ad-p53 showed robust abscopal effects resulting in statistically significant decreases in tumor size and increased survival ( p  
ISSN:0929-1903
1476-5500
DOI:10.1038/s41417-021-00369-7