{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:33:49Z","timestamp":1783420429082,"version":"3.54.6"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T00:00:00Z","timestamp":1618444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013209","name":"Hellenic Foundation for Research and Innovation","doi-asserted-by":"publisher","award":["1030-ARTIC"],"award-info":[{"award-number":["1030-ARTIC"]}],"id":[{"id":"10.13039\/501100013209","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013209","name":"Hellenic Foundation for Research and Innovation","doi-asserted-by":"publisher","award":["3303- REACTION"],"award-info":[{"award-number":["3303- REACTION"]}],"id":[{"id":"10.13039\/501100013209","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013209","name":"Hellenic Foundation for Research and Innovation","doi-asserted-by":"publisher","award":["270"],"award-info":[{"award-number":["270"]}],"id":[{"id":"10.13039\/501100013209","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Pioneering studies on tumor and immune cell interactions have highlighted immune checkpoint inhibitors (ICIs) as revolutionizing interventions for the management of NSCLC, typically combined with traditional MTD chemotherapies, which usually lead to toxicities and resistance to treatment. Alternatively, MTR chemotherapy is based on the daily low dose administration of chemotherapeutics, preventing tumor growth indirectly by targeting the tumor microenvironment. The effects of MTR administration of an oral prodrug of gemcitabine (OralGem), alone or with anti-PD1, were evaluated. Relevant in vitro and in vivo models were developed to investigate the efficacy of MTR alone or with immunotherapy and the potential toxicities associated with each dosing scheme. MTR OralGem restricted tumor angiogenesis by regulating thrombospondin-1 (TSP-1) and vascular endothelial growth factor A (VEGFA) expression. MTR OralGem enhanced antitumor immunity by increasing T effector responses and cytokine release, concomitant with dampening regulatory T cell populations. Promising pharmacokinetic properties afforded minimized blood and thymus toxicity and favorable bioavailability upon MTR administration compared to MTD. The combination of MTR OralGem with immunotherapy was shown to be highly efficacious and tolerable, illuminating it as a strong candidate therapeutic scheme for the treatment of NSCLC.<\/jats:p>","DOI":"10.3390\/cancers13081901","type":"journal-article","created":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T12:11:00Z","timestamp":1618488660000},"page":"1901","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Immunotherapy Combined with Metronomic Dosing: An Effective Approach for the Treatment of NSCLC"],"prefix":"10.3390","volume":"13","author":[{"given":"Eleni","family":"Skavatsou","sequence":"first","affiliation":[{"name":"Division of Pharmacology-Pharmacotechnology, Clinical, Experimental Surgery &amp; Translational Research Center, Biomedical Research Foundation Academy of Athens (BRFAA), 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Semitekolou","sequence":"additional","affiliation":[{"name":"Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Morianos","sequence":"additional","affiliation":[{"name":"Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2825-7188","authenticated-orcid":false,"given":"Theodoros","family":"Karampelas","sequence":"additional","affiliation":[{"name":"Division of Pharmacology-Pharmacotechnology, Clinical, Experimental Surgery &amp; Translational Research Center, Biomedical Research Foundation Academy of Athens (BRFAA), 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0582-4415","authenticated-orcid":false,"given":"Nikolaos","family":"Lougiakis","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7944-2343","authenticated-orcid":false,"given":"Georgina","family":"Xanthou","sequence":"additional","affiliation":[{"name":"Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"Tamvakopoulos","sequence":"additional","affiliation":[{"name":"Division of Pharmacology-Pharmacotechnology, Clinical, Experimental Surgery &amp; Translational Research Center, Biomedical Research Foundation Academy of Athens (BRFAA), 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. 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