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Ridolfi, Ruggero; Riccobon, Angela; Galassi, Riccardo; Giorgetti, G.; Petrini, Massimiliano; Fiammenghi, Laura; Stefanelli, Monica; Ridolfi, Laura; Moretti, Andréa; Migliori, Giuseppe; Fiorentini, Giuseppe

doi:10.1186/1479-5876-2-27

Cited by 111 publications

(26 citation statements)

References 32 publications

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“…In order to assess the kinetic of DC migration after intratumoral injection DCs were labeled with 111 In that is suitable for analysis of DC migration 27 . The maximum duration of observation of DC migratory activity depends on the half-life of the radioisotope (72 hr).…”

Section: Resultsmentioning

confidence: 99%

Combination of External Beam Radiotherapy (EBRT) With Intratumoral Injection of Dendritic Cells as Neo-Adjuvant Treatment of High-Risk Soft Tissue Sarcoma Patients

Finkelstein¹,

Iclozan²,

Bui³

et al. 2012

International Journal of Radiation Oncology*Biology*Physics

107

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Purpose The goal of this study was to determine the effect of combination of intratumoral administration of dendritic cells (DC) and fractionated external beam radiation (EBRT) on tumor-specific immune responses in patients with soft tissue sarcoma (STS). Methods and Material Seventeen patients with large (>5 cm) high grade STS were enrolled in the study. They were treated in the neoadjuvant setting with 5040 cGy of EBRT, split into 28 fractions and delivered 5 days a week, combined with intratumoral injection of 107 DCs followed by complete resection. DCs were injected on the second, third, and fourth Friday of the treatment cycle. Clinical evaluation and immunological assessments were performed. Results The treatment was well tolerated. No patient had tumor-specific immune responses before combined EBRT/DC therapy; nine patients (52.9%) developed tumor-specific immune responses, which lasted from 11 to 42 weeks. Twelve of 17 patients (70.6%) were progression free after one year. Treatment caused a dramatic accumulation of T cells in the tumor. The presence of CD4+ T cells in the tumor positively correlated with tumor-specific immune responses that developed following combined therapy. Accumulation of myeloid-derived suppressor cells but not regulatory T cells negatively correlated with the development of tumor-specific immune responses. Experiments with 111In labeled DCs demonstrated that these antigen presenting cells need at least 48 hr to start migrating from tumor site. Conclusions Combination of intratumoral DC administration with EBRT was safe and resulted in induction of antitumor immune responses. This suggests that this therapy is promising and need further testing in clinical trials design to assess clinical efficacy.

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Section: Resultsmentioning

confidence: 99%

Combination of External Beam Radiotherapy (EBRT) With Intratumoral Injection of Dendritic Cells as Neo-Adjuvant Treatment of High-Risk Soft Tissue Sarcoma Patients

Finkelstein¹,

Iclozan²,

Bui³

et al. 2012

International Journal of Radiation Oncology*Biology*Physics

107

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“…In a clinical trial of DC for cancer therapy, it was verified that radiolabeled DC injected intradermally had a higher migration rate to lymph nodes than DC injected subcutaneously. Also, mature DC showed greater migratory activity than immature DC [119]. In these studies, DC were detected in lymph nodes 20–60 min after injection, and the maximum concentration was reached after 48–72 h. Although the purpose of this study was to induce immunostimulatory (rather than tolerogenic) effects, the observations highlight the possible effect of phenotypic maturation on the migratory capacity of the injected DC.…”

Section: Critical Factors Related To Clinical DC Therapymentioning

confidence: 97%

Tolerogenic dendritic cells and their role in transplantation

Ezzelarab

Thomson

2011

Seminars in Immunology

146

130

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The pursuit of clinical transplant tolerance has led to enhanced understanding of mechanisms underlying immune regulation, including the characterization of immune regulatory cells, in particular antigen-presenting cells (APC) and regulatory T cells (Treg), that may play key roles in promoting operational tolerance. Dendritic cells (DC) are highly-efficient APC that have been studied extensively in rodents and humans, and more recently in non-human primates. Owing to their ability to regulate both innate and adaptive immune responses, DC are considered to play crucial roles in directing the alloimmune response towards transplant tolerance or rejection. Mechanisms via which they can promote central and peripheral tolerance include clonal deletion, the induction of Treg, and inhibition of memory T cell responses. These properties have led to the use of tolerogenic DC as a therapeutic strategy to promote organ transplant tolerance. In rodents, infusion of donor- or recipient-derived tolerogenic DC can extensively prolong donor-specific allograft survival, in association with regulation of the host T cell response. In clinical transplantation, progress has been made in monitoring DC in relation to graft outcome, including studies in operational liver transplant toleranceAlthough clinical trials involving immunotherapeutic DC for patients with cancer are ongoing, implementation of human DC therapy in clinical transplantation will require assessment of various critical issues. These include cell isolation and purification techniques, source, route and timing of administration, and combination immunosuppressive therapy. With ongoing non-human primate studies focused on DC therapy, these logistics can be investigated seeking the optimal approaches. The scientific rationale for implementation of tolerogenic DC therapy to promote clinical transplant tolerance is strong. Evaluation of technical and therapeutic logistic issues is an important next step prior to the application of “therapeutic” DC in clinical organ transplantation.

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“…However, the basic biology of mo-DCs remains uncovered, and vaccines based on mo-DCs still display a limited efficacy. One major bottleneck is the reduced migratory capacity of mo-DCs relative to the highly mobile natural DCs [3]. The clinical efficacy of these mo-DC-based vaccines lies in the accomplishment of two important steps: i) exit from the bloodstream to the tissue space and ii) subsequent homing to the draining lymph nodes, where antigen-specific T-cell stimulation takes place.…”

Section: Introductionmentioning

confidence: 99%

Sialyl Lewisx-dependent binding of human monocyte-derived dendritic cells to selectins

Silva

Tong

Cabral

et al. 2011

Biochemical and Biophysical Research Communications

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The limited efficacy of monocyte-derived dendritic cell (mo-DC)-based vaccines is primarily attributed to the reduced mo-DC migratory capacity. One undefined aspect is the initial binding of mo-DCs to endothelial cells and vascular selectins. In this study, we investigated the role and modulation of the selectin binding determinant sialyl Lewisx (sLex) in selectin-dependent mo-DC binding. Our data reveal that sLex is required for maximal binding of mo-DCs to tumor necrosis factor (TNF)-α-activated endothelial cells under static conditions, as evidenced by the use of sialidase. Sialidase treatment also abrogated mo-DC cell tethering to immobilized, purified P-, L- or E-selectin under flow. The requirement of sLex-dependent binding of mo-DC to selectins was further substantiated by using sLex free sugar and anti-sLex antibody, which significantly suppressed mo-DC-selectin binding. P-selectin glycoprotein ligand-1 is required for mo-DC binding to both P- and L-selectin, but it is dispensable for E-selectin recognition. Interestingly, the extent of mo-DC tethering was maximal on P-selectin, followed by E- and L- selectin. Accordingly, L-selectin mediated faster mo-DC rolling than E- or P-selectin. Interferon (IFN)-γ induces a significant increase in mo-DC surface sLex expression, which is probably due to the enhanced synthesis of C2GnT-I. These findings may contribute to improving mo-DC-based vaccination protocols.

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Cited by 111 publications

References 32 publications

Combination of External Beam Radiotherapy (EBRT) With Intratumoral Injection of Dendritic Cells as Neo-Adjuvant Treatment of High-Risk Soft Tissue Sarcoma Patients

Combination of External Beam Radiotherapy (EBRT) With Intratumoral Injection of Dendritic Cells as Neo-Adjuvant Treatment of High-Risk Soft Tissue Sarcoma Patients

Tolerogenic dendritic cells and their role in transplantation

Sialyl Lewisx-dependent binding of human monocyte-derived dendritic cells to selectins

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