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 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.
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.
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.
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.
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ABSTRACT: This Phase 1, open-label, uncontrolled, ascending-dose study explored the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacology of the TLR8 agonist VTX-2337 in subjects with advanced solid tumors or lymphoma. VTX-2337 doses (0.1-3.9 mg/m2) were administered subcutaneously on Days 1, 8, and 15 of each 28-day cycle. Safety/tolerability assessments included adverse events (AEs); physical, ophthalmologic, and laboratory evaluations; and electrocardiograms. Dose-limiting toxicities (DLTs) were evaluated during the first cycle. Pharmacokinetics were evaluated after the first dose. Plasma samples were quantitatively assessed for chemokines, cytokines, and other inflammatory mediators. Anti tumor activity was assessed. Thirty-three subjects were enrolled in 8 cohorts and received an average of 2 treatment cycles (range: 1-8 cycles). Most AEs were grade 1-2; the most common drug-related AEs were injection site reactions, chills, pyrexia, and influenza-like illness. One DLT was reported: grade 3 hypotension (3.9 mg/m2). The MTD was considered the highest dose administered. Peak drug plasma levels and total systemic exposure were generally dose proportional. At doses greater than or equal to 0.4 mg/m2, increases above baseline levels were observed for plasma levels of G-CSF, MCP-1, MIP-1β, and TNFα. Eight subjects (24.2%) had a best response of stable disease (median duration: 54.5 days). VTX-2337 is clinically well tolerated and biologically active with a predictable pharmacokinetic profile. Suitable doses for testing in combination studies were identified. Phase II placebo-controlled studies of VTX-2337 in combination with doxorubicin in ovarian cancer, and in combination with platinum chemotherapy, 5FU, and cetuximab in head and neck cancer have been initiated.Clinical Cancer Research 05/2014; 20(14). DOI:10.1158/1078-0432.CCR-14-0392 · 8.19 Impact Factor
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ABSTRACT: Background Conventional chemotherapy and radiotherapy for the treatment of lymphoma have notable drawbacks, and passive immunotherapy using a monoclonal antibody is restricted to CD20-positive B cell lymphoma. Therefore, new treatment types are urgently required, especially for T cell lymphoma. One type of new antitumour therapy is the use of active immunotherapeutic agents, such as agonists of the Toll-like receptors (TLRs), which facilitate the induction of prolonged antitumour immune responses. Methods We have synthesised a novel TLR7 agonist called SZU-101 and investigated the systemic antitumour effect on a murine model of T cell lymphoma in vivo. Results Here, we report that the intratumoural administration of SZU-101 enhanced the effectiveness of a conventionally used chemotherapeutic agent, doxorubicin (DOX). SZU-101 administration improved tumour clearance in a murine model of T cell lymphoma. The novel combination of intratumourally administered SZU-101 and DOX generated strong cytokine production and enhanced the cytotoxic T lymphocyte response, leading to the eradication of both local and distant tumours in tumour-bearing mice. Conclusions These findings suggested that combined active immunotherapy can be developed as a promising treatment for T cell lymphoma, which may further improve the effectiveness of the current standard cyclophosphamide, DOX, vincristine and prednisone (CHOP) therapy. Electronic supplementary material The online version of this article (doi:10.1186/s13045-015-0121-9) contains supplementary material, which is available to authorized users.Journal of Hematology & Oncology 03/2015; 8(1). DOI:10.1186/s13045-015-0121-9 · 4.93 Impact Factor
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ABSTRACT: From the numerous Toll-like receptor agonists, only TLR7 agonists have been approved for cancer treatment, although they are current restricted to topical application. The main target cells of TLR7 agonists are plasmacytoid dendritic cells, producing IFN-α and thus acting on other immune cells. Thereby dendritic cells acquire enhanced costimulatory and antigen-presenting capacity, priming an adaptive immune response. Besides NK cells, antigen-specific T cells are the main terminal effectors of TLR7 agonists in tumor therapy. This qualifies TLR7 agonists as vaccine adjuvants, which is currently being tested in clinical trials. However, the systemic application of TLR7 agonists shows insufficient efficacy, most likely owing to toxicity-limited dosing. The use of TLR7 agonists in combinational therapy holds the promise of synergistic activity and lower required doses.Immunotherapy 10/2014; 6(10):1085-95. DOI:10.2217/imt.14.75 · 2.44 Impact Factor