{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T08:52:11Z","timestamp":1789548731096,"version":"build-2803163510"},"reference-count":61,"publisher":"SAGE Publications","issue":"15-16","license":[{"start":{"date-parts":[[2020,8,1]],"date-time":"2020-08-01T00:00:00Z","timestamp":1596240000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:p>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 \u03b2-1 (TGF\u03b2-1) 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 sTGF\u03b2RIIFc, a TGF\u03b2 decoy that can inhibit TGF\u03b2 pathways. mHAdLyp.sT is an Ad5\/48 chimeric hexon virus in which hypervariable regions (HVRs 1\u20137) of Ad5 are replaced with the corresponding Ad48 HVRs. AdLyp.sT and mHAdLyp.sT exhibited better binding, replication, and produced higher sTGF\u03b2RIIFc 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.<\/jats:p>","DOI":"10.1089\/hum.2020.078","type":"journal-article","created":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T05:14:35Z","timestamp":1589260475000},"page":"863-880","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":31,"title":["LyP-1-Modified Oncolytic Adenoviruses Targeting Transforming Growth Factor \u03b2 Inhibit Tumor Growth and Metastases and Augment Immune Checkpoint Inhibitor Therapy in Breast Cancer Mouse Models"],"prefix":"10.1177","volume":"31","author":[{"given":"Weidong","family":"Xu","sequence":"first","affiliation":[{"name":"Gene Therapy Program, Department of Medicine, NorthShore Research Institute, An Affiliate of the University of Chicago, Evanston, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuefeng","family":"Yang","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Department of Medicine, NorthShore Research Institute, An Affiliate of the University of Chicago, Evanston, Illinois, USA"},{"name":"Department of Experimental Medical Science and Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, P.R. 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