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Blood, 15 January 2005, Vol. 105, No. 2, pp. 489-495.
Prepublished online as a Blood First Edition Paper on September 9, 2004; DOI 10.1182/blood-2004-06-2156.
 Previous Article | Next Article 
Submitted June 7, 2004
Accepted August 25, 2004
Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin's lymphoma: increased interferon- / -inducible gene expression, without significant toxicity
Jonathan W Friedberg*, Helen Kim, Mary McCauley, Edith M Hessel, Paul Sims, David C Fisher, Lee M Nadler, Robert L Coffman, and Arnold S Freedman
James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, USA
Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Dynavax Technologies, Berkley, CA, USA
* Corresponding author; email: jonathan_friedberg{at}urmc.rochester.edu.
CpG oligodeoxynucleotides (CpG-ODN) affect innate and adaptive immune responses, including antigen presentation, costimulatory molecule expression, dendritic cell maturation, and induction of cytokines enhancing ADCC. We conducted a phase I study evaluating 4 dose levels of a CpG-ODN (1018 ISS, Dynavax Technologies) with rituximab in 20 patients with relapsed NHL. Patients received CpG weekly x 4 beginning after the second of 4 rituximab infusions. Adverse events were minimal. Quantitative PCR measurements of a panel of genes inducible by CpG-ODN and interferons were performed on blood samples collected prior to and 24 hours after CpG. A dose-related increase was measured in the expression of several IFN-inducible genes following CpG, and correlated with serum levels of 2-5-OAS, a validated interferon response marker. Genes induced selectively by 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 patient biological responses to CpG therapy in a dose-related manner. Moreover, all of the genes significantly induced by this CpG are regulated by type-1 interferons, providing insights into the dominant immune mechanisms in humans. CpG treatment had no significant toxicity, providing rationale for further testing of this exciting combination immunotherapy approach to NHL.
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