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: Jonathan W Friedberg, Helen Kim, Mary McCauley, Edith M Hessel, Paul Sims, David C Fisher, Lee M Nadler, Robert L Coffman, Arnold S Freedman
• Journal: Blood (Blood) Vol. 105 Issue 2 Pg. 489-95 (Jan 15 2005) ISSN: 0006-4971 [Print] United States
• PMID: 15358617 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents
• Biomarkers
• Interferon-alpha
• Oligodeoxyribonucleotides
• 1018 oligonucleotide
• Rituximab
• Interferon-beta

Topics

• Adult
• Aged
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents (administration & dosage, adverse effects)
• Biomarkers
• Female
• Gene Expression (immunology)
• Humans
• Immunotherapy
• Interferon-alpha (genetics)
• Interferon-beta (genetics)
• Lymphoma, Non-Hodgkin (drug therapy)
• Male
• Middle Aged
• Oligodeoxyribonucleotides (administration & dosage, adverse effects)
• Rituximab
• Treatment Outcome