First in Human Phase I Trial of 852A, a Novel SystemicToll-like Receptor 7 Agonist, to Activate Innate Immune Responses in Patients with Advanced Cancer Arkadiusz Z. Dudek, 1 Carla Yunis, 2 Lester I. Harrison, 2 Sandeep Kumar, 2 Ronald Hawkinson, 2 Sarah Cooley, 1 John P. Vasilakos, 2 Kevin S. Gorski, 2 and Jeffrey S. Miller 1 Abstract 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 the Toll-like receptor 7 agonist 852A, a small-molecule imidazoquinoline, in patients with advanced cancer. Preclinical studies showed that 852A stimu- 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, 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-a, interleukin-1 receptor antagonist, and IFN-inducible protein-10, immunologic activity, and clinical symptoms were observed in all patients receiving dose levels z0.6 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. 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, 3 allow- ing easier formulation as an injectable systemic agent. In 3 L. Harrison, personal communication. Cancer Therapy: Clinical Authors’ Affiliations: 1 University of Minnesota Cancer Center, Minneapolis, Minnesota and 2 3M Pharmaceuticals, 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 J.S. Miller). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: A.Z. Dudek and C. Yunis contributed equally to this work. L.I. Harrison and R. Hawkinson are employees of 3M Pharmaceuticals. C. Yunis, J.P. Vasilakos, K.S. Gorski, and S. Kumar are former employees of 3M Pharmaceuticals. 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: mille011@umn.edu. F 2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-1443 www.aacrjournals.org Clin Cancer Res 2007;13(23) December 1, 2007 7119