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Clin Cancer Res. 2011 Aug 1;17(15):5140-51. doi: 10.1158/1078-0432.CCR-10-3105. Epub 2011 Jun 8.

Comparison of clinical and immunological effects of intravenous and intradermal administration of α-galactosylceramide (KRN7000)-pulsed dendritic cells.

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1
Division of Medicine, University of Queensland, Brisbane, Australia. anic9909@bigpond.net.au

Abstract

PURPOSE:

Human Vα24+Vβ11+ natural killer T-cells (NKT cells) have antitumor activity via direct cytotoxicity and by induction of antitumor actions of T and NK cells. Activation of NKT cells is crucial for their antitumor activity and is induced by α-galactosylceramide (α-GalCer, KRN7000) presented by CD1d on dendritic cells (DC). We conducted a phase I clinical trial of therapy with α-GalCer-pulsed DC to determine safety, tolerability, immune effects and an optimal dose, and administration route.

EXPERIMENTAL DESIGN:

Twelve subjects (3 cohorts) with metastatic malignancy received 4 treatments of α-GalCer-pulsed DC, 2 treatments intravenously (IV), and 2 treatments intradermally (ID). Each successive cohort received a log higher cell dose. Clinical and immunological outcomes were evaluated, including secondary effects on NK and T cells.

RESULTS:

Substantial effects on peripheral blood NKT cells were observed but were greater following IV treatment. Secondary immune effects including activation of T and NK cells, increases in T- and NK-cell cytoplasmic interferon-γ, and increases in serum interferon-γ levels were seen after IV but not after ID treatment. Therapy was well tolerated, but 9 of 12 subjects had tumor flares with clinical findings consistent with transient tumor inflammation. Disease response (minor) or stabilization of disease progressing up to enrollment was observed in 6 of the 12 subjects. Stabilization of previously progressive disease lasted for at least one year in three subjects.

CONCLUSION:

We conclude that therapy with α-GalCer-pulsed DC induced clinically beneficial immune responses that are highly dependent on cell dose and administration route.

PMID:
21653690
DOI:
10.1158/1078-0432.CCR-10-3105
[Indexed for MEDLINE]
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