title: Phase II study of a TLR-9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma.
abstract: Toll-like receptor-9 (TLR-9) agonists have pleotropic effects on both the innate and adaptive immune systems, including increased antigen expression, enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and T helper cell type 1 shift in the immune response. We combined a TLR-9 agonist (1018 ISS, 0.2 mg/kg sc weekly x 4 beginning day 8) with standard rituximab (375 mg/m(2) weekly x 4) in patients (n = 23) with relapsed/refractory, histologically confirmed follicular lymphoma, and evaluated immunological changes following the combination. Treatment was well-tolerated with no significant adverse events attributable to therapy. Clinical responses were observed in 48% of patients; the overall median progression-free survival was 9 months. Biologically relevant increases in ADCC and circulating CD-3 positive T cells were observed in 35% and 39% of patients, respectively. Forty-five percent of patients had increased T cells and dendritic cells in skin biopsies of 1018 ISS injection sites 24 h post-therapy. Pre- and post-biopsies of tumour tissue demonstrated an infiltration of CD8(+) T cells and macrophages following treatment. This group of patients had favourable clinical outcome despite adverse prognostic factors. This study is the first to histologically confirm perturbation of the local immune microenvironment following systemic biological therapy of follicular lymphoma.
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA. Jonathan_Friedberg@urmc.rochester.edu
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Friedberg
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Kelly
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Derick R
authors.initials: DR
authors.lastname: Peterson
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Rabih
authors.initials: R
authors.lastname: Salloum
authors.forename: Thomas
authors.initials: T
authors.lastname: Brenn
authors.forename: David C
authors.initials: DC
authors.lastname: Fisher
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ronan
authors.forename: Virginia
authors.initials: V
authors.lastname: Dalton
authors.forename: Lynn
authors.initials: L
authors.lastname: Rich
authors.forename: Diana
authors.initials: D
authors.lastname: Marquis
authors.forename: Paul
authors.initials: P
authors.lastname: Sims
authors.forename: Paul G
authors.initials: PG
authors.lastname: Rothberg
authors.forename: Jane
authors.initials: J
authors.lastname: Liesveld
authors.forename: Richard I
authors.initials: RI
authors.lastname: Fisher
authors.forename: Robert
authors.initials: R
authors.lastname: Coffman
authors.forename: Tim
authors.initials: T
authors.lastname: Mosmann
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Freedman
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics; D054357:Chemokine CXCL10 / Q000235:genetics; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D011506:Proteins / Q000235:genetics; D016601:RNA-Binding Proteins; D012008:Recurrence; D000069283:Rituximab; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; C484289:IFIT2 protein, human; D009838:Oligodeoxyribonucleotides; D011506:Proteins; D016601:RNA-Binding Proteins; D051217:Toll-Like Receptor 9; C489630:1018 oligonucleotide; D000069283:Rituximab; D007371:Interferon-gamma