First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer.

First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Research Abstract Details 

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First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Abstract Text:

Arkadiusz Z Dudek,Carla Yunis,Lester I Harrison,Sandeep Kumar,Ronald Hawkinson,Sarah Cooley,John P Vasilakos,Kevin S Gorski,Jeffrey S Miller,Arkadiusz Z Dudek,Carla Yunis,Lester I Harrison,Sandeep Kumar,Ronald Hawkinson,Sarah Cooley,John P Vasilakos,Kevin S Gorski,Jeffrey S Miller,

PURPOSE: Recent advances in the understanding of innate immunity suggest that an orchestrated sequence of events is required to elicit a productive immune response against cancer. We studied the systemic administration of the Toll-like receptor 7 agonist 852A, a small-molecule imidazoquinoline, in patients with advanced cancer. Preclinical studies showed that 852A stimulates plasmacytoid dendritic cells to produce multiple cytokines, such as IFN-alpha, interleukin-1 receptor antagonist, and IFN-inducible protein-10. Our goal was to define the tolerated dose, pharmacokinetics, pharmacodynamics, and immunologic effects of 852A in humans. EXPERIMENTAL DESIGN: Eligible adult patients with refractory solid organ tumors received i.v. 852A thrice weekly for 2 weeks. Patients who had responses or stable disease were eligible for additional cycles. RESULTS: Twenty-five patients (median age, 55.0 years; 72% male) were enrolled in six cohorts at dose levels of 0.15 to 2.0 mg/m(2). Serum drug levels showed dose proportionality and no evidence of drug accumulation. The maximum tolerated dose was 1.2 mg/m(2); higher doses were limited by fatigue and constitutional symptoms. Increases in IFN-alpha, interleukin-1 receptor antagonist, and IFN-inducible protein-10, immunologic activity, and clinical symptoms were observed in all patients receiving dose levels > or =0.6 mg/m(2). Significant correlations were found between pharmacodynamic biomarkers and pharmacokinetic variables, and an objective clinical response was seen. CONCLUSIONS: 852A was safely administered i.v. at doses up to 1.2 mg/m(2) thrice weekly for 2 weeks with transient or reversible adverse effects. This novel Toll-like receptor 7 agonist is biologically active and holds promise for stimulating innate immune responses. Future trials are warranted to assess its therapeutic role in patients with cancer.

First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Publishing Authors By Initials

AZ Dudek,C Yunis,LI Harrison,S Kumar,R Hawkinson,S Cooley,JP Vasilakos,KS Gorski,JS Miller,AZ Dudek,C Yunis,LI Harrison,S Kumar,R Hawkinson,S Cooley,JP Vasilakos,KS Gorski,JS Miller,

For similar proteins: membrane proteins: receptors, cell surface: receptors, immunologic: receptors, pattern recognition: toll-like receptors: toll-like receptor 7 research abstracts see: proteins: membrane proteins: receptors, cell surface: receptors, immunologic: receptors, pattern recognition: toll-like receptors: toll-like receptor 7 research

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First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Clinical cancer research : an official journal of

VOLUME: 13

Page Numbers: 7119-25

Journal Abbreviation: Clin. Cancer Res.

ISSN: 1078-0432

DAY: 1

MONTH: Dec

YEAR: 2007

First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Information

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LANGUAGE: eng

NlmUniqueID: 9502500

First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Keywords Mesh Terms:

KEYWORDS: Toll-Like Receptor 7

MESH TERMS: agonists

Chemical & Substance for Abstract: First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Information

Substance Name: Toll-Like Receptor 7

Registry Number: 0

Grant and Affiliation Information for First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer.

AFFILIATION: University of Minnesota Cancer Center, Minneapolis, Minnesota and 3M Pharmaceuticals, St. Paul, Minnesota 55455, USA.

Country: United States

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MEDLINETA: Clin Cancer Res

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