科研之友
微信
新浪微博
Facebook
分享链接
摘要
Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with gamma delta T cells expressing V gamma 2 V delta 2 TCRs. Although treatment with gamma delta T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate gamma delta 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 gamma delta T cells to secrete TNF-alpha 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 gamma delta T cells and stimulated them to secrete interferon-gamma and kill tumor cells. In preclinical studies, combination therapy with compound 7 and gamma delta 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 gamma delta T cells.
- 出版日期2017-7-20
- 单位上海生物信息技术研究中心
