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Abstract
Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with γδ T cells expressing Vγ2 Vδ2 TCRs. Although treatment with γδ T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate γδ 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 γδ T cells to secrete TNF-α 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 γδ T cells and stimulated them to secrete interferon-γ and kill tumor cells. In preclinical studies, combination therapy with compound 7 and γδ 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 γδ T cells.
Highlights
These nitrogen-containing bisphosphonates enter monocyte-lineage cells as well as tumor cells where they inhibit farnesyl diphosphate synthase (FDPS)[4, 5]
We previously showed that masking the phosphonate charges of bisphosphonates by pivoxil groups greatly enhanced their ability to inhibit tumor cell growth[43]
To determine if the stimulation of Vγ2Vδ2 T cells showed similar enhancement, EJ-1 bladder carcinoma cells were treated with seven bisphosphonate prodrugs or their corresponding active acid forms (Supplemental Fig. S1)
Summary
These nitrogen-containing bisphosphonates enter monocyte-lineage cells (including osteoclasts) as well as tumor cells where they inhibit farnesyl diphosphate synthase (FDPS)[4, 5]. Vγ2Vδ2 T cells are directly stimulated in vivo either by an IPP analog or an aminobisphosphonates in conjunction with IL-222–26. A second approach has been the ex vivo expansion of Vγ2Vδ2 T cells followed by their adoptive transfer[27,28,29,30,31,32,33,34,35,36]. This approach avoids the development of anergy by harvesting and freezing of PBMC prior to therapy or by avoiding the use of intravenous bisphosphonates. The most successful clinical trials have used intravenous zoledronic acid around the time of adoptive transfer of Vγ2Vδ2 T cells
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