Intradermal CpG-B Activates Both Plasmacytoid and Myeloid Dendritic Cells in the Sentinel Lymph Node of Melanoma Patients

Molenkamp, Barbara G.; Leeuwen, Paul A. M. van; Meijer, Sybren; Sluijter, Berbel J.R.; Wijnands, Pepijn G.J.T.B.; Baars, Arnold; Eertwegh, Alfons J.M. van den; Scheper, Rik J.; Gruijl, Tanja D. de

doi:10.1158/1078-0432.ccr-07-0050

Cited by 119 publications

(106 citation statements)

References 47 publications

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“…In this setting, PF-3512676 was shown to induce the release of inflammatory cytokines and decrease the number of regulatory T cells observed in sentinel lymph nodes of patients with stage I to III melanoma (Molenkamp et al, 2007). Furthermore, both myeloid and pDCs were activated (Molenkamp et al, 2007), indicating that PF-3512676 clearly has immunomodulatory activity. In a different phase II study in patients (N ¼ 20) with metastatic melanoma treated with s.c. PF-3512676, two (10%) patients had a PR and three (15%) patients had stable disease (SD) (Pashenkov et al, 2006).…”

Section: Skin Cancersmentioning

confidence: 87%

“…Treatment was associated with increased levels of serum interleukin (IL)-6, IL12p40 and IP-10 in some patients, and cellular infiltrates of CD8 þ lymphocytes were found after treatment in most lesions. In a different trial involving patients with clinical stage I/II melanoma, surgical resection of the primary tumor was followed by randomization to receive either saline or PF-3512676 (8 mg) intradermally at the excision site, followed 1 week later by a sentinel lymph node procedure (Molenkamp et al, 2007). In this setting, PF-3512676 was shown to induce the release of inflammatory cytokines and decrease the number of regulatory T cells observed in sentinel lymph nodes of patients with stage I to III melanoma (Molenkamp et al, 2007).…”

Section: Skin Cancersmentioning

confidence: 99%

“…In a different trial involving patients with clinical stage I/II melanoma, surgical resection of the primary tumor was followed by randomization to receive either saline or PF-3512676 (8 mg) intradermally at the excision site, followed 1 week later by a sentinel lymph node procedure (Molenkamp et al, 2007). In this setting, PF-3512676 was shown to induce the release of inflammatory cytokines and decrease the number of regulatory T cells observed in sentinel lymph nodes of patients with stage I to III melanoma (Molenkamp et al, 2007). Furthermore, both myeloid and pDCs were activated (Molenkamp et al, 2007), indicating that PF-3512676 clearly has immunomodulatory activity.…”

Section: Skin Cancersmentioning

confidence: 99%

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Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

2008

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Although still early in clinical development, agonists of Tolllike receptor 9 (TLR9) have demonstrated potential for the treatment of cancer. TLR9 agonists directly induce activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. Preclinical and early clinical data support the use of TLR9 agonists in patients with solid tumors and hematologic malignancies. In preclinical studies, TLR9 agonists have shown activity not only as monotherapy, but also in combination with multiple other therapies, including vaccines, antibodies, cellular therapies, other immunotherapies, antiangiogenic agents, radiotherapy, cryotherapy and some chemotherapies. Phase I and II clinical trials have indicated that these agents have antitumor activity as single agents and enhance the development of antitumor T-cell responses when used as therapeutic vaccine adjuvants. The activity and safety of these novel anticancer agents are being explored in a wide range of tumor types as part of a variety of therapeutic strategies with the goal of harnessing the immune response to fight cancer.

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Section: Skin Cancersmentioning

confidence: 87%

Section: Skin Cancersmentioning

confidence: 99%

Section: Skin Cancersmentioning

confidence: 99%

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Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

2008

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“…Most likely, pDCs are not properly activated on uptake of tumor-derived substances because of the lack of danger signals (12). Recent studies have shown that in vivo TLR triggering with TLR-Ls, such as CpG, induced pDC activation, resulting in antitumor immunity and partial tumor regression (42)(43)(44). Furthermore, activated human pDCs pulsed with a tumor Ag primed IFN-g secreting Ag-specific CTLs (45).…”

Section: Discussionmentioning

confidence: 99%

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

Tel

Lambeck

Cruz

et al. 2010

The Journal of Immunology

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“…27,41 Next to creating a beneficial milieu for inducing tumor-directed immunity, specific or enhanced targeting of TAAs to DCs has shown beneficial effects, for example by conjugating TAA to TLR ligands, 42 or generating antibody-antigen complexes. 43 These strategies may also be applied to apoptotic bleb-based vaccines.…”

Section: 1332mentioning

confidence: 99%

In situloading of skin dendritic cells with apoptotic bleb-derived antigens for the induction of tumor-directed immunity

et al. 2014

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The generation and loading of dendritic cells (DC) ex-vivo for tumor vaccination purposes is laborious and costly. Direct intradermal (i.d.) administration of tumor-associated antigens could be an attractive alternative approach, provided that efficient uptake and cross-presentation by appropriately activated skin DCs can be achieved. Here, we compare the efficiency of i.d. delivery of relatively small apoptotic blebs (diameter »0.1-1 mm) derived from MART-1 transduced acute myeloid leukemia (AML) HL60 cells, to that of larger apoptotic cell remnants (ACR; 2-10 mm) in a physiologically highly relevant human skin explant model. Injection of either fluorescently-labelled ACRs or blebs alone did not affect the number or distribution of migrated DC subsets from skin biopsies after 48 hours, but resulted in a general up-regulation of the co-stimulatory molecules CD83 and CD86 on skin DCs that had ingested apoptotic material. We have previously shown that i.d. administration of GM-CSF and IL-4 resulted in preferential migration of a mature and highly T cell-stimulatory CD11 hi CD1a C CD14 ¡ dermal DC subset. Here, we found that co-injection of GM-CSF and IL-4 together with either ACRs or blebs resulted in uptake efficiencies within this dermal DC subset of 7.6% ( §6.1%) and 19.1% ( §15.9%), respectively, thus revealing a significantly higher uptake frequency of blebs (P < 0.02). Intradermal delivery of tumor-derived blebs did not affect the T-cell priming and T H -skewing abilities of migratory skin DC. Nevertheless, in contrast to i.d. administration of ACR, the injection of blebs lead to effective cross-presentation of MART-1 to specific CD8 C effector T cells. We conclude that apoptotic bleb-based vaccines delivered through the skin may offer an attractive, and broadly applicable, cancer immunotherapy.

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Intradermal CpG-B Activates Both Plasmacytoid and Myeloid Dendritic Cells in the Sentinel Lymph Node of Melanoma Patients

Cited by 119 publications

References 47 publications

Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

In situloading of skin dendritic cells with apoptotic bleb-derived antigens for the induction of tumor-directed immunity

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