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Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug.


ABSTRACT: Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with ?? T cells expressing V?2?V?2 TCRs. Although treatment with ?? T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate ?? T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodrugs has led to important drugs for hepatitis C and HIV. Using a similar approach, we synthesized bisphosphonate prodrugs and found that they efficiently limit tumor cell growth. Pivoxil bisphosphonate esters enter cells where esterases convert them to their active acids. The bisphosphonate esters stimulated ?? T cells to secrete TNF-? in response to a variety of tumor cells more efficiently than their corresponding acids. The most active compound, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1- bisphosphonate (7), specifically expanded ?? T cells and stimulated them to secrete interferon-? and kill tumor cells. In preclinical studies, combination therapy with compound 7 and ?? T cells prolonged survival of mice inoculated with either human bladder cancer or fibrosarcoma cells. Therefore, bisphosphonate prodrugs could enhance the effectiveness of adoptive cancer immunotherapy with ?? T cells.

SUBMITTER: Tanaka Y 

PROVIDER: S-EPMC5519590 | BioStudies | 2017-01-01T00:00:00Z

REPOSITORIES: biostudies

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