Τίτλος:
Immunotherapy combined with metronomic dosing: An effective approach for the treatment of nsclc
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Συγγραφείς:
Skavatsou, E.
Semitekolou, M.
Morianos, I.
Karampelas, T.
Lougiakis, N.
Xanthou, G.
Tamvakopoulos, C.
Περιοδικό:
Blood cancer journal
Λέξεις-κλειδιά:
gamma interferon; gemcitabine; granulocyte macrophage colony stimulating factor; interleukin 10; programmed death 1 ligand 1; programmed death 1 receptor; thrombospondin 1; tumor necrosis factor; vasculotropin A, angiogenesis; animal cell; animal experiment; animal model; animal tissue; antineoplastic activity; antiproliferative activity; area under the curve; Article; cancer chemotherapy; cancer immunotherapy; controlled study; cytokine production; cytokine release; drug efficacy; drug safety; drug tolerability; human; human cell; in vitro study; in vivo study; lung metastasis; male; maximum plasma concentration; metastasis inhibition; mouse; non small cell lung cancer; nonhuman; protein expression; regulatory T lymphocyte; T lymphocyte subpopulation; tumor microenvironment
DOI:
10.3390/cancers13081901
