Targeting human {gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer
Francesco Dieli,David Vermijlen,Fabio Fulfaro,Nadia Caccamo,Serena Meraviglia,Giuseppe Cicero,Andrew Roberts,Simona Buccheri,M. D'Asaro,Nicola Gebbia,Alfredo Salerno,Matthias Eberl,Adrian Hayday +12 more
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TLDR
Zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered.Abstract:
The increasing evidence that gammadelta T cells have potent antitumor activity suggests their value in immunotherapy, particularly in areas of unmet need such as metastatic carcinoma. To this end, we initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility and consequences of using the gammadelta T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood gammadelta cells. Nine patients were enlisted to each arm. Neither treatment showed appreciable toxicity. Most patients were treated with zoledronate + IL-2, but conversely only two treated with zoledronate displayed a significant long-term shift of peripheral gammadelta cells toward an activated effector-memory-like state (T(EM)), producing IFN-gamma and perforin. These patients also maintained serum levels of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), consistent with a parallel microarray analysis showing that TRAIL is produced by gammadelta cells activated via the T-cell receptor and IL-2. Moreover, the numbers of T(EM) gammadelta cells showed a statistically significant correlation with declining prostate-specific antigen levels and objective clinical outcomes that comprised three instances of partial remission and five of stable disease. By contrast, most patients treated only with zoledronate failed to sustain either gammadelta cell numbers or serum TRAIL, and showed progressive clinical deterioration. Thus, zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered. Moreover, gammadelta cell phenotypes and possibly serum TRAIL may constitute novel biomarkers of prognosis upon therapy with zoledronate + IL-2 in metastatic carcinoma.read more
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Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer
Michael Gnant,Brigitte Mlineritsch,Walter Schippinger,G. Luschin-Ebengreuth,Sabine Pöstlberger,Christian Menzel,Raimund Jakesz,Michael Seifert,Michael Hubalek,Vesna Bjelic-Radisic,Hellmut Samonigg,C. Tausch,Holger Eidtmann,Guenther G. Steger,Werner Kwasny,Peter Dubsky,M. Fridrik,Florian Fitzal,Michael Stierer,Ernst Rücklinger,Richard Greil +20 more
TL;DR: The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer.
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Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity.
TL;DR: Recent observations reveal the ability of γδ T cells to rapidly produce cytokines that regulate pathogen clearance, inflammation and tissue homeostasis in response to tissue stress, and insights are provided into how they acquire these properties.
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Remarkable potential of the α-aminophosphonate/phosphinate structural motif in medicinal chemistry.
TL;DR: The tetrahedral transition state is believed to be specifically stabilized in enzyme active sites, which has inspired numerous studies on their applications in regulating the activity of proteases, including the development of many potent inhibitors of various enzymes, such as the antihypertensive drug fosinopril.
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γδ T Cells and the Lymphoid Stress-Surveillance Response
Adrian Hayday,Adrian Hayday +1 more
TL;DR: The investigation of gammadelta T cells has identified a rapid lymphoid stress-surveillance response to microbial and nonmicrobial tissue perturbation that provides an immediate source of cytokines, chemokines, and other functions that can substantially affect downstream, adaptive immunity.
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Peter J. Mullen,Rosemary Yu,Rosemary Yu,Joseph Longo,Joseph Longo,Michael C. Archer,Linda Z. Penn,Linda Z. Penn +7 more
TL;DR: This Review summarizes recent advances and discusses unique opportunities for immediately targeting this metabolic vulnerability in cancer with agents that have been approved for other therapeutic uses, such as the statin family of drugs, to improve outcomes for cancer patients.
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