First in Human Phase I T rialof 852A, a Novel SystemicToll-like
Receptor 7 Agonist, toActivate Innate Immune Responses in
Patients with Advanced Cancer
Arkadiusz Z. Dudek,1Carla Yunis,2LesterI. Harrison,2Sandeep Kumar,2Ronald Hawkinson,2
Sarah Cooley,1John P. Vasilakos,2Kevin S. Gorski,2and Jeffrey S. Miller1
Purpose: Recent advances in the understanding of innate immunity suggest that an orchestra-
ted sequence of events is required to elicit a productive immune response against cancer.We
studied the systemic administration of theToll-like receptor 7 agonist 852A, a small-molecule
imidazoquinoline, inpatients with advanced cancer. Preclinical studies showed that 852Astimu-
lates plasmacytoid dendritic cells to produce multiple cytokines, such as IFN-a, interleukin-1
receptor antagonist, and IFN-inducible protein-10. Our goal was to define the tolerated dose,
pharmacokinetics, pharmacodynamics, andimmunologic effects of 852A inhumans.
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
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/m2. Serum drug levels showed dose proportionality and no
evidence of drug accumulation. The maximum tolerated dose was 1.2 mg/m2; higher doses
were limited by fatigue and constitutional symptoms. Increases in IFN-a, interleukin-1receptor
antagonist, and IFN-inducible protein-10, immunologic activity, and clinical symptoms were
observed in all patients receiving dose levels z0.6 mg/m2. 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/m2thrice 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 inpatients with cancer.
Toll-like receptors (TLR) are a highly conserved group of
pathogen recognition receptors. To date, 10 human TLRs have
been described and their central role in the activation of innate
immune responses has been clearly defined (1). 852A (3M-001)
is a small-molecule imidazoquinoline that is related to
imiquimod but is a more potent and more selective activator
of TLR7. In vitro studies have shown that 852A directly activates
antigen-presenting cells, such as dendritic cells, resulting in (a)
the production of various cytokines, including IFN-a and tumor
necrosis factor-a, which may inhibit tumor growth or viability,
(b) the expression of chemokines, including both IFN-inducible
protein-10 (IP-10) and the chemokine receptor CCR7, which is
important for dendritic cell migration to lymphoid tissue, and
(c) the expression on antigen-presenting cells of costimulatory
molecules required for T-cell activation (2–6).
The efficacy of a TLR agonist in the treatment of cancer has
been shown in superficial basal cell carcinoma, where the use of
topical imiquimod 5% cream (a compound from the same drug
class) resulted in histologic clearance rates between 79% and
82% in phase III randomized placebo-controlled studies (7). In
addition, antitumor activity has been shown using this topical
agent in a variety of other tumor types (8–11). These studies,
combined with preclinical data on 852A and the knowledge that
cytokine therapy is effective treatment for certain cancers (12),
provide the rationale for testing a systemically delivered TLR7
agonist as an anticancer agent. 852A has f40 times greater
aqueous solubility than imiquimod at physiologic pH,3allow-
ing easier formulation as an injectable systemic agent. In
3L. Harrison, personalcommunication.
Cancer Therapy: Clinical
Authors’Affiliations:1University of Minnesota Cancer Center, Minneapolis,
Minnesota and23MPharmaceuticals, St. Paul, Minnesota
Received 6/13/07; revised 7/30/07; accepted 8/17/07.
Grant support: 3M Pharmaceuticals, St. Paul, Minnesota (A.Z. Dudek and
The costs of publicationof this articlewere defrayedinpart by the paymentof page
charges.This article must therefore be hereby marked advertisement in accordance
with18 U.S.C. Section1734 solely toindicatethis fact.
Note: A.Z. Dudekand C.Yunis contributed equally to this work.
L.I. Harrisonand R. Hawkinsonare employees of 3MPharmaceuticals. C.Yunis, J.P.
Vasilakos, K.S. Gorski, and S. Kumarare former employees of 3MPharmaceuticals.
Requests for reprints: Jeffrey S. Miller, Division of Hematology, Oncology, and
Transplantation, University of Minnesota, 420 Delaware Street Southeast, Mayo
Mail Code 806, Minneapolis, MN 55455. Phone: 612-625-7409; Fax: 612-626-
4915; E-mail: email@example.com.
F2007 American Association for Cancer Research.
Clin Cancer Res 2007;13(23) December1, 2007
on October 21, 2015. © 2007 American Association forclincancerres.aacrjournals.org
2007;13:7119-7125. Clin Cancer Res
Arkadiusz Z. Dudek, Carla Yunis, Lester I. Harrison, et al.
Responses in Patients with Advanced Cancer
Toll-like Receptor 7 Agonist, to Activate Innate Immune
First in Human Phase I Trial of 852A, a Novel Systemic
Access the most recent version of this article at:
This article has been cited by 11 HighWire-hosted articles. Access the articles at:
This article cites 28 articles, 11 of which you can access for free at:
related to this article or journal. Sign up to receive free email-alerts
To request permission to re-use all or part of this article, contact the AACR Publications
. firstname.lastname@example.orgDepartment at
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
. email@example.com Department at
on October 21, 2015. © 2007 American Association for clincancerres.aacrjournals.org Downloaded from