TNF-α inhibitor reduces drug-resistance to anti-PD-1: A mathematical model

Drug resistance is a primary obstacle in cancer treatment. In many patients who at first respond well to treatment, relapse occurs later on. Various mechanisms have been explored to explain drug resistance in specific cancers and for specific drugs. In this paper, we consider resistance to anti-PD-1...

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Bibliographic Details
Published in:PloS one 2020-04, Vol.15 (4), p.e0231499-e0231499
Main Authors: Lai, Xiulan, Hao, Wenrui, Friedman, Avner
Format: Article
Language:English
Subjects:
Animals
Anticancer properties
Antigens
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Apoptosis
Biology and Life Sciences
Cancer therapies
Cell death
Chemotherapy
Computer simulation
Cytokines
Cytotoxicity
Dendritic cells
Drug resistance
Drug Resistance, Neoplasm - drug effects
Immunotherapy
Kinases
Ligands
Lymphocytes
Lymphocytes T
Mathematical analysis
Mathematical models
Medicine and Health Sciences
Melanoma
Mice
Models, Theoretical
Mutation
Neoplasm Recurrence, Local - drug therapy
Neoplasm Recurrence, Local - metabolism
Partial differential equations
PD-1 protein
Physical Sciences
Programmed Cell Death 1 Receptor - antagonists & inhibitors
Proteins
Schedules
Tumor Burden - drug effects
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor necrosis factor-α
Tumors
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Summary:Drug resistance is a primary obstacle in cancer treatment. In many patients who at first respond well to treatment, relapse occurs later on. Various mechanisms have been explored to explain drug resistance in specific cancers and for specific drugs. In this paper, we consider resistance to anti-PD-1, a drug that enhances the activity of anti-cancer T cells. Based on results in experimental melanoma, it is shown, by a mathematical model, that resistances to anti-PD-1 can be significantly reduced by combining it with anti-TNF-α. The model is used to simulate the efficacy of the combined therapy with different range of doses, different initial tumor volume, and different schedules. In particular, it is shown that under a course of treatment with 3-week cycles where each drug is injected in the first day of either week 1 or week 2, injecting anti-TNF-α one week after anti-PD-1 is the most effective schedule in reducing tumor volume.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0231499