LyP-1-Modified Oncolytic Adenoviruses Targeting Transforming Growth Factor β Inhibit Tumor Growth and Metastases and
Weidong Xu1, Yuefeng Yang1,2, Zebin Hu1,3
1Gene Therapy Program, Department of Medicine, NorthShore Research Institute, An Affiliate of the University of Chicago, Evanston, Illinois, USA.
Abstract:
We report here the development of oncolytic adenoviruses (Ads) that have reduced toxicity, enhanced tumor tropism, produce strong antitumor response, and can overcome resistance to immune checkpoint inhibitor therapy in breast cancer. We have shown that LyP-1 receptor (p32) is highly expressed on the surface of breast cancer cells and tumors from cancer patients, and that increased stromal expression of transforming growth factor β-1 (TGFβ-1) is associated with triple-negative breast cancer. Therefore, we constructed oncolytic Ads, AdLyp.sT and mHAdLyp.sT, in which the p32-binding LyP-1 peptide was genetically inserted into the adenoviral fiber protein. Both AdLyp.sT and mHAdLyp.sT express sTGFβRIIFc, a TGFβ decoy that can inhibit TGFβ pathways. mHAdLyp.sT is an Ad5/48 chimeric hexon virus in which hypervariable regions (HVRs 1-7) of Ad5 are replaced with the corresponding Ad48 HVRs. AdLyp.sT and mHAdLyp.sT exhibited better binding, replication, and produced higher sTGFβRIIFc protein levels in breast cancer cell lines compared with Ad.sT or mHAd.sT control viruses without LyP-1 peptide modification. Systemic delivery of mHAdLyp.sT in mice resulted in reduced hepatic/systemic toxicity compared with Ad.sT and AdLyp.sT. Intravenous delivery of AdLyp.sT and mHAdLyp.sT elicited a strong antitumor response in a human MDA-MB-231 bone metastasis model in mice, as indicated by bioluminescence imaging, radiographic tumor burden, serum TRACP 5b and calcium, and body weight analyses. Furthermore, intratumoral delivery of AdLyp.sT in 4T1 model in immunocompetent mice inhibited tumor growth and metastases, and augmented anti-PD-1 and anti-CTLA-4 therapy. Based on these studies, we believe that AdLyp.sT and mHAdLyp.sT can be developed as potential targeted immunotherapy agents for the treatment of breast cancer.
Insights
New oncolytic adenoviruses targeting breast cancer show reduced toxicity and enhanced tumor targeting. These modified viruses overcome resistance to immune checkpoint inhibitors, offering a promising new immunotherapy approach.
Area of Science:
- Oncology
- Virology
- Immunotherapy
Background:
- LyP-1 receptor (p32) is highly expressed on breast cancer cells.
- Transforming growth factor β-1 (TGFβ-1) is associated with triple-negative breast cancer.
Purpose of the Study:
- Develop oncolytic adenoviruses (Ads) with reduced toxicity and enhanced tumor tropism for breast cancer.
- Overcome resistance to immune checkpoint inhibitor therapy in breast cancer.
Main Methods:
- Constructed AdLyp.sT and mHAdLyp.sT by inserting LyP-1 peptide into adenoviral fiber protein.
- These Ads express sTGFβRIIFc, a TGFβ decoy, to inhibit TGFβ pathways.
- mHAdLyp.sT is an Ad5/48 chimeric hexon virus.
Main Results:
- AdLyp.sT and mHAdLyp.sT showed improved binding, replication, and sTGFβRIIFc production in breast cancer cells.
- mHAdLyp.sT demonstrated reduced hepatic/systemic toxicity in mice.
- Both viruses elicited strong antitumor responses in mouse models and augmented anti-PD-1/anti-CTLA-4 therapy.
Conclusions:
- AdLyp.sT and mHAdLyp.sT are potential targeted immunotherapy agents for breast cancer treatment.
- These oncolytic adenoviruses offer a promising strategy to overcome resistance to current therapies.
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