دورية أكاديمية
أعرض في EDS

Oxazaphosphorines combined with immune checkpoint blockers: dose-dependent tuning between immune and cytotoxic effects.

التفاصيل البيبلوغرافية
العنوان: Oxazaphosphorines combined with immune checkpoint blockers: dose-dependent tuning between immune and cytotoxic effects.
المؤلفون: Delahousse J; Molecular Radiotherapy and Innovative Therapeutics, Unité Mixte de Recherche 1030 INSERM, Gustave Roussy, F-94805, Villejuif, France.; Vectorology and Anticancer Therapies, Unité Mixte de Recherche 8203 Centre National de la Recherche Scientifique, Gustave Roussy, F-94805, Villejuif, France., Skarbek C; Vectorology and Anticancer Therapies, Unité Mixte de Recherche 8203 Centre National de la Recherche Scientifique, Gustave Roussy, F-94805, Villejuif, France., Desbois M; Laboratoire d'immunomonitoring En Oncologie, Gustave Roussy, F-94805, Villejuif, France., Perfettini JL; Molecular Radiotherapy and Innovative Therapeutics, Unité Mixte de Recherche 1030 INSERM, Gustave Roussy, F-94805, Villejuif, France., Chaput N; Laboratoire d'immunomonitoring En Oncologie, Gustave Roussy, F-94805, Villejuif, France.; Laboratory of Genetic Instability and Oncogenesis, Unité Mixte de Recherche 8200 Centre National de la Recherche Scientifique, Gustave Roussy Institute, F-94805, Villejuif, France.; Faculté de Pharmacie, Université Paris-Saclay, F-92296, Chatenay-Malabry, France., Paci A; Molecular Radiotherapy and Innovative Therapeutics, Unité Mixte de Recherche 1030 INSERM, Gustave Roussy, F-94805, Villejuif, France angelo.paci@gustaveroussy.fr.; Faculté de Pharmacie, Université Paris-Saclay, F-92296, Chatenay-Malabry, France.; Pharmacology Department, Gustave Roussy, Villejuif, France.
المصدر: Journal for immunotherapy of cancer [J Immunother Cancer] 2020 Aug; Vol. 8 (2).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Print Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE
أسماء مطبوعة: Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd.
Original Publication: London : BioMed Central, 2013-
مواضيع طبية MeSH: Antineoplastic Agents/*therapeutic use , Cyclophosphamide/*therapeutic use , Immune Checkpoint Inhibitors/*therapeutic use , Phosphoramide Mustards/*therapeutic use, Animals ; Antineoplastic Agents/pharmacology ; Cyclophosphamide/pharmacology ; Disease Models, Animal ; Female ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Mice ; Phosphoramide Mustards/pharmacology
مستخلص: Background: Oxazaphosphorines (cyclophosphamide (CPA), ifosfamide (IFO)) are major alkylating agents of polychemotherapy protocols but limiting their toxicity and increasing their efficacy could be of major interest. Oxazaphosphorines are prodrugs that require an activation by cytochrome P450 (CYP). CPA is mainly metabolized (>80%) to phosphoramide mustard while only 10%-50% of IFO is transformed in the alkylating entity, isophosphoramide mustard and 50%-90% of IFO release chloroacetaldehyde, a nephrotoxic and neurotoxic metabolite. Geranyloxy-IFO (G-IFO) was reported as a preactivated IFO to circumvent the toxic pathway giving directly the isophosphoramide mustard without CYP metabolization. The similarity in structure of CPA and IFO and the similarity in metabolic balance of CPA and G-IFO have led us to explore immunomodulatory effect of these components in mice and to investigate the combination of these oxazaphosphorines with immune checkpoint blockers (ICB).
Methods: The investigation of the immunomodulatory properties of IFO and G-IFO compared with CPA has been conducted through immune cell phenotyping by flow cytometry and analysis of the cytokine profile of T cells after ex-vivo restimulation. T cell-mediated antitumor efficacy was confirmed in CD4 + and CD8 + T cell-depleted mice. A combination of oxazaphosphorines with an anti-programmed cell death 1 (PD-1) antibody has been studied in MCA205 tumor-bearing mice.
Results: Studies on a MCA205 mouse model have demonstrated a dose-dependent effect of IFO and G-IFO on T cell immunity. These components in particular favored Th1 polarization when used at low dose (150 and eq. 100 mg/kg, respectively). Antitumor activity at low dose was abolished in mice depleted in CD4 + and CD8 + T cells. G-IFO at low dose (eq. 100 mg/kg) in combination with anti-PD-1 antidody showed high synergistic antitumor efficacy compared with IFO.
Conclusion: Oxazaphosphorines are characterized by a dual mechanism of antitumor action; low-dose schedules should be preferred in combination with ICB, and dose escalation was found to have better utility in polychemotherapy protocols where a conventional direct cytotoxic anticancer effect is needed. G-IFO, the novel oxazaphosphorine drug, has shown a better metabolic index compared with IFO as its metabolization gives mainly the alkylating mustard as CPA (and not IFO) and a best potential in combination with ICB.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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فهرسة مساهمة: Keywords: drug evaluation, preclinical; drug therapy, combination; immunomodulation; immunotherapy
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Immune Checkpoint Inhibitors)
0 (Phosphoramide Mustards)
6A4U6NN813 (isophosphamide mustard)
8N3DW7272P (Cyclophosphamide)
تواريخ الأحداث: Date Created: 20200814 Date Completed: 20210915 Latest Revision: 20210915
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC7418776
DOI: 10.1136/jitc-2020-000916
PMID: 32784216
قاعدة البيانات: MEDLINE
الوصف
تدمد:2051-1426
DOI:10.1136/jitc-2020-000916