title: Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-alpha/beta-inducible gene expression, without significant toxicity.
abstract: CpG oligodeoxynucleotides (CpG-ODNs) affect innate and adaptive immune responses, including antigen presentation, costimulatory molecule expression, dendritic cell maturation, and induction of cytokines enhancing antibody-dependent cell-mediated cytotoxicity (ADCC). We conducted a phase 1 study evaluating 4 dose levels of a CpG-ODN (1018 ISS) with rituximab in 20 patients with relapsed non-Hodgkin lymphoma (NHL). Patients received CpG once a week for 4 weeks beginning after the second of 4 rituximab infusions. Adverse events were minimal. Quantitative polymerase chain reaction (PCR) measurements of a panel of genes inducible by CpG-ODN and interferons were performed on blood samples collected before and 24 hours after CpG. A dose-related increase was measured in the expression of several interferon-inducible genes after CpG and correlated with serum levels of 2'-5' oligoadenylate synthetase (OAS), a validated interferon response marker. Genes induced selectively by interferon-gamma (IFN-gamma) were not significantly induced by CpG. In conclusion, we have defined a set of gene expression markers that provide a sensitive measure of biologic responses of patients to CpG therapy in a dose-related manner. Moreover, all the genes significantly induced by this CpG are regulated by type 1 interferons, providing insight into the dominant immune mechanisms in humans. CpG treatment resulted in no significant toxicity, providing rationale for further testing of this exciting combination immunotherapy approach to NHL.
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA. jonathan_friedberg@urmc.rochester.edu
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Friedberg
authors.forename: Helen
authors.initials: H
authors.lastname: Kim
authors.forename: Mary
authors.initials: M
authors.lastname: McCauley
authors.forename: Edith M
authors.initials: EM
authors.lastname: Hessel
authors.forename: Paul
authors.initials: P
authors.lastname: Sims
authors.forename: David C
authors.initials: DC
authors.lastname: Fisher
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Freedman
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D016898:Interferon-alpha / Q000235:genetics*; D016899:Interferon-beta / Q000235:genetics*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D000069283:Rituximab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D015415:Biomarkers; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; C489630:1018 oligonucleotide; D000069283:Rituximab; D016899:Interferon-beta