An Exploratory Study of Systemic Administration of the Toll-like Receptor-7 Agonist 852A in Patients with Refractory Metastatic Melanoma

Purpose: A topical Toll-like receptor 7 (TLR7) agonist induces regression of cutaneous melanocytic neoplasms. We explored antitumor activity of a systemically administered TLR7 agonist, 852A, in patients with metastatic melanoma. Experimental Design: We undertook a phase II, multicenter, open-label study in patients with chemotherapy-refractory metastatic melanoma. Patients received i.v. 852A, starting at 0.6 mg/m2 and increasing to 0.9 mg/m2 based on tolerance, thrice per week for 12 weeks. Clinical response was determined by Response Evaluation Criteria in Solid Tumors. Immune effects of 852A were monitored by measuring serum type I IFN and IP-10 together with assessment of immune cell markers in peripheral blood. Results: Twenty-one patients were enrolled. Thirteen patients completed the initial 12-week treatment cycle, with two discontinuing for adverse events considered to be possibly related to study drug. Four (19%) patients had disease stabilization for >100 days. One patient had a partial remission after two treatment cycles, but progressed during the third. Dose-limiting toxicity was observed in two patients. Serum type I IFN and IP-10 increased in most patients on 852A administration. Serum type I IFN increases were greater after dosing with 852A 0.9 mg/m2 than after 0.6 mg/m2 (P = 0.009). The maximal increase in IP-10 compared with baseline correlated with the maximal increase in type I IFN (P = 0.003). In the eight patients with immune cell marker data, CD86 expression on monocytes increased significantly post-first dose (P = 0.007). Conclusion: Intravenous 852A was well tolerated and induced systemic immune activation that eventually resulted in prolonged disease stabilization in some patients with stage IV metastatic melanoma who had failed chemotherapy.

[1]  C. Yunis,et al.  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 , 2007, Clinical Cancer Research.

[2]  J. McHutchison,et al.  Oral resiquimod in chronic HCV infection: safety and efficacy in 2 placebo-controlled, double-blind phase IIa studies. , 2007, Journal of hepatology.

[3]  A. Dalgleish,et al.  Phase I/II study of topical imiquimod and intralesional interleukin‐2 in the treatment of accessible metastases in malignant melanoma , 2007, The British journal of dermatology.

[4]  R. Nordquist,et al.  In situ photoimmunotherapy: a tumour‐directed treatment for melanoma , 2006, British Journal of Dermatology.

[5]  John P. Vasilakos,et al.  Cutting Edge: Activation of Murine TLR8 by a Combination of Imidazoquinoline Immune Response Modifiers and PolyT Oligodeoxynucleotides , 2006, The Journal of Immunology.

[6]  U. Yrlid,et al.  A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation , 2006, European journal of immunology.

[7]  M. Alsharifi,et al.  Exhaustion of Type I Interferon Response following an Acute Viral Infection , 2006, The Journal of Immunology.

[8]  P. Hwu,et al.  Improving Antitumor Immune Responses by Circumventing Immunoregulatory Cells and Mechanisms , 2006, Clinical Cancer Research.

[9]  Jeffrey S. Miller,et al.  Distinct indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 agonists. , 2006, International immunology.

[10]  S. Quezada,et al.  Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. , 2006, Current opinion in immunology.

[11]  R. Dummer,et al.  Randomized dose-escalation study evaluating peginterferon alfa-2a in patients with metastatic malignant melanoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Yu-Tseung Liu,et al.  Activation of anti-hepatitis C virus responses via Toll-like receptor 7. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[13]  E. Gilboa,et al.  Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. , 2005, The Journal of clinical investigation.

[14]  Weiyi Peng,et al.  Toll-Like Receptor 8-Mediated Reversal of CD4+ Regulatory T Cell Function , 2005, Science.

[15]  R. Dummer,et al.  Disease-independent skin recruitment and activation of plasmacytoid predendritic cells following imiquimod treatment. , 2005, Journal of the National Cancer Institute.

[16]  G. Trinchieri,et al.  A type I interferon autocrine–paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells , 2005, The Journal of experimental medicine.

[17]  N. Restifo,et al.  Less is more: lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. , 2005, Current opinion in immunology.

[18]  S. Rosenberg,et al.  Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  B. Beutler,et al.  The interface between innate and adaptive immunity , 2004, Nature Immunology.

[20]  P. Björck.  Dendritic Cells Exposed to Herpes Simplex Virus In Vivo Do Not Produce IFN-α after Rechallenge with Virus In Vitro and Exhibit Decreased T Cell Alloreactivity1 , 2004, The Journal of Immunology.

[21]  J. Manola,et al.  A Pooled Analysis of Eastern Cooperative Oncology Group and Intergroup Trials of Adjuvant High-Dose Interferon for Melanoma , 2004, Clinical Cancer Research.

[22]  K. Schroder,et al.  Interferon‐γ: an overview of signals, mechanisms and functions , 2004 .

[23]  Michael H. Smith,et al.  Randomized, Single-Blind, Placebo-Controlled Study of Topical Application of the Immune Response Modulator Resiquimod in Healthy Adults , 2003, Antimicrobial Agents and Chemotherapy.

[24]  H. Kerl,et al.  Topical imiquimod in the treatment of metastatic melanoma to skin. , 2003, Archives of dermatology.

[25]  I. Caramalho,et al.  Regulatory T Cells Selectively Express Toll-like Receptors and Are Activated by Lipopolysaccharide , 2003, The Journal of experimental medicine.

[26]  Ruslan Medzhitov,et al.  Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells , 2003, Science.

[27]  B. Bonnekoh,et al.  Imiquimod, a Topical Immune Response Modifier, in the Treatment of Cutaneous Metastases of Malignant Melanoma , 2002, Dermatology.

[28]  R. Noelle,et al.  Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. , 2002, Cellular immunology.

[29]  Kouji Matsushima,et al.  Pivotal Role of Dendritic Cell–derived CXCL10 in the Retention of T Helper Cell 1 Lymphocytes in Secondary Lymph Nodes , 2002, The Journal of experimental medicine.

[30]  C. Janeway,et al.  The Toll receptor family and microbial recognition. , 2000, Trends in microbiology.

[31]  G. Schuler,et al.  Topical imiquimod treatment of a cutaneous melanoma metastasis. , 2000, Journal of the American Academy of Dermatology.

[32]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[33]  M. Middleton,et al.  Adjuvant interferon in the treatment of melanoma , 1999, British Journal of Cancer.

[34]  T T Chen,et al.  Optimal flexible designs in phase II clinical trials. , 1998, Statistics in medicine.

[35]  V. Gangur,et al.  Human IP‐10 selectively promotes dominance of polyclonally activated and environmental antigen‐driven IFN‐γ over IL‐4 responses , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[36]  M. Gore,et al.  A phase I clinical trial of imiquimod, an oral interferon inducer, administered daily. , 1996, British Journal of Cancer.

[37]  M J Reiter,et al.  Inhibition of murine tumor growth by an interferon-inducing imidazoquinolinamine. , 1992, Cancer research.

[38]  E. McFadden,et al.  Toxicity and response criteria of the Eastern Cooperative Oncology Group , 1982, American journal of clinical oncology.

[39]  R. Auerbach,et al.  Immunotherapy for Melanoma , 1973 .

[40]  Y. Sekido,et al.  Hepatocyte Growth Factor Reduces Susceptibility to an Irreversible Epidermal Growth Factor Receptor Inhibitor in EGFR-T790M Mutant Lung Cancer , 2010 .

[41]  V. Preedy,et al.  European Organization for Research and Treatment of Cancer , 2010 .

[42]  J. Hasday,et al.  Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease. , 2006 .

[43]  Yong‐jun Liu,et al.  IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. , 2005, Annual review of immunology.

[44]  R. Dummer,et al.  Melanoma vaccines in development: looking to the future. , 2000, BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy.