RRC ID 65607
Author Mizuta S, Tagod MSO, Iwasaki M, Nakamura Y, Senju H, Mukae H, Morita CT, Tanaka Y.
Title Synthesis and Immunomodulatory Activity of Fluorine-Containing Bisphosphonates.
Journal ChemMedChem
Abstract Immune checkpoint blockade using anti-PD-1/PD-L1 or anti-CTLA-4 monoclonal antibodies (mAbs) has revolutionized cancer treatment. However, many types of cancer do not respond and for those that do, only a minority of patients achieve durable remissions. Therefore, oncoimmunologists are working to develop adoptive cell therapies for non-hematopoietic tumors by harnessing immune effector cells such as αβ T cells and γδ T cells. In contrast to conventional αβ T cells that recognize peptides in the context of MHC class I or II molecules, γδ T cells expressing Vγ2Vδ2 T cell receptors (also termed Vγ9Vδ2) are stimulated by isoprenoid metabolites (phosphoantigens) such as isopentenyl diphosphate in a butyrophilin-3A1-dependent manner. Vγ2Vδ2 T cells kill almost all types of tumor cells that have been treated with bisphosphonates. In this study, we synthesized a series of fluorine-containing bisphosphonates based on current drugs and found that they stimulated Vγ2Vδ2 T cell killing of tumor cells. A fluorine-containing prodrug analogue of zoledronate where phosphonate moieties were masked with pivaloyloxymethyl groups markedly enhanced Vγ2Vδ2 T-cell-mediated cytotoxicity, and also promoted the expansion of peripheral blood Vγ2Vδ2 T cells. These results demonstrate that a prodrug of a fluorine-containing zoledronate analogue can sensitize tumor cells for killing as well as expand Vγ2Vδ2 T cells for adoptive cell therapy.
Volume 14(4)
Pages 462-468
Published 2019-2-19
DOI 10.1002/cmdc.201800764
PMID 30637982
PMC PMC6818088
MeSH Animals Cell Line, Tumor Diphosphonates / chemistry* Diphosphonates / pharmacology Diphosphonates / therapeutic use Fluorine / chemistry* Humans Immunologic Factors / chemical synthesis* Immunologic Factors / pharmacology Immunotherapy Intraepithelial Lymphocytes / cytology Intraepithelial Lymphocytes / drug effects Intraepithelial Lymphocytes / metabolism Lung Neoplasms / drug therapy Lung Neoplasms / metabolism Lung Neoplasms / pathology Lymphocyte Activation / drug effects Mice Prodrugs / chemical synthesis Prodrugs / pharmacology Prodrugs / therapeutic use
IF 3.124
Human and Animal Cells PC-9(RCB4455)