{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:03:58Z","timestamp":1790935438832,"version":"4.1.0"},"reference-count":18,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"\n Background<\/jats:title>\n We conducted an analysis of previous adenoviral p53 (Ad-p53) treatment data in recurrent head and neck squamous cell carcinoma (HNSCC) patients to identify optimal Ad-p53 treatment methods for future clinical trials.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n The analysis involved recurrent HNSCC patients treated with Ad-p53 for whom p53 genotyping and immunohistochemistry tumor biomarker studies had been performed (n = 70). Ad-p53 tumor treatment responses defined by RECIST 1.1 criteria were correlated with Ad-p53 dose and tumor p53 biomarkers. Gene expression profiles induced by Ad-p53 treatment were evaluated using the Nanostring IO 360 panel.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Ad-p53 dose based upon the injected tumor volume had a critical effect on tumor responses. All responders had received Ad-p53 doses greater than 7 \u00d7 10\n 10<\/jats:sup>\n viral particles\/cm\n 3<\/jats:sup>\n of tumor volume. There was a statistically significant difference in tumor responses between patients treated with greater than 7 \u00d7 10\n 10<\/jats:sup>\n viral particles\/cm\n 3<\/jats:sup>\n compared to patients treated at lower Ad-p53 doses (Tumor Response 31% (9\/29) for Ad-p53 &gt; 7 \u00d7 10\n 10<\/jats:sup>\n viral particles\/cm\n 3<\/jats:sup>\n versus 0% (0\/25) for Ad-p53 &lt; 7 \u00d7 10\n 10<\/jats:sup>\n viral particles\/cm\n 3<\/jats:sup>\n ; p = 0.0023). All responders were found to have favorable p53 biomarker profiles defined by less than 20% p53 positive tumor cells by immunohistochemistry (IHC), wild type p53 gene sequence or p53 deletions, truncations, or frame-shift mutations without functional p53 tetramerization domains. Preliminary gene expression profiling results revealed that Ad-p53 treatment increased interferon signaling, decreased TGF-beta and beta-catenin signaling resulting in an increased CD8\n +<\/jats:sup>\n T cell signature which are associated with increased responses to immune checkpoint blockade.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our findings have important implications for future p53 targeted cancer treatments and identify fundamental principles to guide Ad-p53 gene therapy. We discovered that previous Ad-p53 clinical trials were negatively impacted by the inclusion of patients with unfavorable p53 biomarker profiles and by under dosing of Ad-p53 treatment. Future Ad-p53 clinical trials should have favorable p53 biomarker profiles inclusion criteria and Ad-p53 dosing above 7 \u00d7 10\n 10<\/jats:sup>\n viral particles\/cm\n 3<\/jats:sup>\n of injected tumor volume. Preliminary gene expression profiling identified p53 mechanisms of action associated with responses to immune checkpoint blockade supporting evaluation of Ad-p53 in combination with immune checkpoint inhibitors.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fonc.2021.645745","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T09:03:46Z","timestamp":1619082226000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Analysis of Adenoviral p53 Gene Therapy Clinical Trials in Recurrent Head and Neck Squamous Cell Carcinoma"],"prefix":"10.3389","volume":"11","author":[{"given":"Robert E.","family":"Sobol","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin 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