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

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-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.

A phase I/II trial of TLR-7 agonist immunotherapy in chronic lymphocytic leukemia

“…In contrast to the experience with solid tumor patients at similar doses, 6,7 no grade 3 toxicities were seen. Adverse effects reported most frequently were chills and 'hot flashes', which seemed to decrease with repeated injections.…”

“…Patients in groups I, II and III were injected with 0.3, 0.45 and 0.6 mg/m 2 , respectively, because studies of solid tumor patients had established 1.2 mg/m 2 as the maximum tolerated dose for 852A. 7 Clinical responses were determined by standard National Cancer Institute (NCI) criteria.…”

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

“…In spite of conflicting data on TLR expression in NK cells, several groups have shown that TLR7/TLR8 agonists induce NK cell activation, as judged by CD69 expression, IFN-␥ production, and exertion of their cytotoxic effector function. However, it was also observed that this TLR7/TLR8-induced NK cell activation is crucially dependent on contact with cytokines (e.g., IL-12 or type I IFNs) produced by accessory cells in peripheral blood [24,70,70,71,[73][74][75][76]. Therefore, it is not completely clear yet if the NK activation observed after the addition of TLR7/8 agonists is partially caused by or dependent on direct activation of TLR7 and/or TLR8 in NK cells.…”

“…These agonists (like stabilized ssRNA, R-848, and 852A) have now also been tested as IRMs in preclinical models [123] and in clinical trials [75,124,125]. Until now, TLR7/8 agonists were predominantly given by topical administration because of the side effects reported after oral and systemic therapy with IRMs [126 -129].…”

“…Systemic administration of resiquimod, in turn, is associated with transient local immune insufficiency [130]. In recent reports by the groups of Miller and Urosevic [75,125], i.v. administration of the TLR7 agonist 852A was tested in patients with different tumor types.…”