Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia

Merli, Pietro; Algeri, Mattia; Galaverna, Federica; Milano, Giuseppe Maria; Bertaina, Valentina; Biagini, Simone; Girolami, Elia; Palumbo, Giuseppe; Sinibaldi, Matilde; Becilli, Marco; Leone, G; Boccieri, Emilia; Grapulin, Lavinia; Gaspari, Stefania; Airoldi, Irma; Strocchio, Luisa; Pagliara, Daria; Locatelli, Franco

doi:10.3389/fimmu.2020.00699

Cited by 23 publications

(26 citation statements)

References 74 publications

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“…Despite decreasing γδ T cell counts, the incidence of GvHD and transplant-related mortality were lower in patients receiving ≥3 ZOL infusions. 188 , 189 These studies suggest that in vivo activation of γδ T cells with ZOL is a useful treatment option after HSC transplantation with αβ T cell/CD19 B-cell-depleted stem cell preparations. However, even though objective responses were observed in some patients (see the abovementioned reviews), continuous therapy with ZOL and low-dose IL-2 is not an efficient option for γδ T cell immunotherapy of patients with solid cancers (also in view of the effect of low-dose IL-2 in Treg activation 190 ) but might be useful as a transient procedure together with other strategies.…”

Section: How To Activate and Target γδ T Cells In Vivomentioning

confidence: 99%

Cancer immunotherapy with γδ T cells: many paths ahead of us

et al. 2020

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γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of γδ T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of γδ T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of γδ T cells, the optimization of in vitro expansion protocols, and the development of gene-modified γδ T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.

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Section: How To Activate and Target γδ T Cells In Vivomentioning

confidence: 99%

Cancer immunotherapy with γδ T cells: many paths ahead of us

et al. 2020

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“…This was also reported in a subsequent clinical trial that evaluated 46 pediatric patients with acute leukemia and reported that 3 or more repeated ZOL infusions offer a lower rate of transplant-related death, lower occurrence of relapses and absence of GvHD. Global disease-free survival is also improved ( 272 ).…”

Section: The State-of-the-art For Clinical Trialsmentioning

confidence: 99%

γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

et al. 2021

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Recently, many discoveries have elucidated the cellular and molecular diversity in the leukemic microenvironment and improved our knowledge regarding their complex nature. This has allowed the development of new therapeutic strategies against leukemia. Advances in biotechnology and the current understanding of T cell-engineering have led to new approaches in this fight, thus improving cell-mediated immune response against cancer. However, most of the investigations focus only on conventional cytotoxic cells, while ignoring the potential of unconventional T cells that until now have been little studied. γδ T cells are a unique lymphocyte subpopulation that has an extensive repertoire of tumor sensing and may have new immunotherapeutic applications in a wide range of tumors. The ability to respond regardless of human leukocyte antigen (HLA) expression, the secretion of antitumor mediators and high functional plasticity are hallmarks of γδ T cells, and are ones that make them a promising alternative in the field of cell therapy. Despite this situation, in particular cases, the leukemic microenvironment can adopt strategies to circumvent the antitumor response of these lymphocytes, causing their exhaustion or polarization to a tumor-promoting phenotype. Intervening in this crosstalk can improve their capabilities and clinical applications and can make them key components in new therapeutic antileukemic approaches. In this review, we highlight several characteristics of γδ T cells and their interactions in leukemia. Furthermore, we explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of γδ T cells against the tumor. Finally, we outline our perspectives on their therapeutic applicability and indicate outstanding issues for future basic and clinical leukemia research, in the hope of contributing to the advancement of studies on γδ T cells in cancer immunotherapy.

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“…By this approach, it has been shown that Zol infusion after transplantation promoted immune reconstitution and reduced disease recurrence and risk of post-infection-related complications in pediatric acute leukemia patients. 50 Several clinical studies such as Austrian Breast and Colorectal Cancer Study Group trial 12 (ABCSG-12), Zometa-Femara Adjuvant Synergy Trial (ZO-FAST), and Adjuvant Zoledronic acid to reduce recurrence (AZURE) studies demonstrated modulation of immune-suppressing regulatory T (Treg) cells by inhibiting its proliferative capacity via downregulating CCR4, PD-1, CTLA-4 and cells the immunomodulatory effects of Zol by receptor activator of nuclear factor kappa-B ligand (RANKL) on Treg cells. 51 Furthermore, a seminal study by Weber and colleagues demonstrated that Zol alone and in combination with surgical trauma significantly increased infiltration and shifted systemic macrophage polarization toward M1 type in spleen, lung, and skin of Wister rat model.…”

Section: Discussionmentioning

confidence: 99%

Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling

et al. 2022

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Summary Background Radiation therapy (RT) has a suboptimal effect in patients with pancreatic ductal adenocarcinoma (PDAC) due to intrinsic and acquired radioresistance (RR). Comprehensive bioinformatics and microarray analysis revealed that cholesterol biosynthesis (CBS) is involved in the RR of PDAC. We now tested the inhibition of the CBS pathway enzyme, farnesyl diphosphate synthase (FDPS), by zoledronic acid (Zol) to enhance radiation and activate immune cells. Methods We investigated the role of FDPS in PDAC RR using the following methods: in vitro cell-based assay, immunohistochemistry, immunofluorescence, immunoblot, cell-based cholesterol assay, RNA sequencing, tumouroids (KPC-murine and PDAC patient-derived), orthotopic models, and PDAC patient's clinical study. Findings FDPS overexpression in PDAC tissues and cells ( P < 0.01 and P < 0.05) is associated with poor RT response and survival ( P = 0.024). CRISPR/Cas9 and pharmacological inhibition (Zol) of FDPS in human and mouse syngeneic PDAC cells in conjunction with RT conferred higher PDAC radiosensitivity in vitro ( P < 0.05, P < 0.01, and P < 0.001) and in vivo ( P < 0.05). Interestingly, murine ( P = 0.01) and human ( P = 0.0159) tumouroids treated with Zol+RT showed a significant growth reduction. Mechanistically, RNA-Seq analysis of the PDAC xenografts and patients-PBMCs revealed that Zol exerts radiosensitization by affecting Rac1 and Rho prenylation, thereby modulating DNA damage and radiation response signalling along with improved systemic immune cells activation. An ongoing phase I/II trial (NCT03073785) showed improved failure-free survival (FFS), enhanced immune cell activation, and decreased microenvironment-related genes upon Zol+RT treatment. Interpretation Our findings suggest that FDPS is a novel radiosensitization target for PDAC therapy. This study also provides a rationale to utilize Zol as a potential radiosensitizer and as an immunomodulator in PDAC and other cancers. Funding National Institutes of Health (P50, P01, and R01).

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Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia

Cited by 23 publications

References 74 publications

Cancer immunotherapy with γδ T cells: many paths ahead of us

Cancer immunotherapy with γδ T cells: many paths ahead of us

γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling

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