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.
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.
Friedberg
Jonathan W
JW
James P. Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA. jonathan_friedberg@urmc.rochester.edu
Kim
Helen
H
McCauley
Mary
M
Hessel
Edith M
EM
Sims
Paul
P
Fisher
David C
DC
Nadler
Lee M
LM
Coffman
Robert L
RL
Freedman
Arnold S
AS
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
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