Abstract
Background: CpG 7909 is a synthetic 24 mer oligodeoxynucleotide designed to provide optimal activation of immune mechanisms through the TLR9 receptors on B-cells and plasmacytoid dendritic cells. In vitro CpG can upregulate CD20 expression as well as stimulate the immune system. Radioimmunotherapy (RIT) with anti-CD20 radioimmunoconjugates such as Zevalin produces responses in approximately 80% of patients with relapsed indolent lymphoma; however, only 30% obtain a complete response and 20% have long-term disease free survival.
Objectives: To combine CpG 7909 with rituximab and Zevalin to enhance the response to RIT.
Patients and Methods: Patients were eligible if they had biopsy proven relapsed, refractory, or residual CD20+ NHL. Disease types included relapsed indolent and aggressive B-cell NHL. Patients were required to have measurable disease, a platelet count >150,000, and an absolute neutrophil count >1,500. This was a phase I study where all patients received a standard dose of Zevalin (0.4mCi/kg with a maximum of 32mCi for patients over 80kg) along with a phase I dose of CpG 7909. Four dose levels were studied—0.08mg/kg; 0.16mg/kg; 0.32mg/kg; and 0.48mg/kg. CpG was dosed on Day 6, 13, 20, and 27; rituximab was provided Day 1, 8, and 15; indium-111 Zevalin on Day 1 and 8 (followed by indium-111 Zevalin imaging); and yttrium-90 Zevalin on Day 15. Response was assessed at week 4 and week 12. Patients are also being assayed pre- and post-CpG and at multiple time points up to 1 year following treatment for changes in T-cell, NK-cell, and cytokine levels.
Results: A total of 30 patients have now been enrolled—6 at each of the first 3 dose levels and 12 at dose level 4. Three pts had relapsed diffuse large cell (DLC) and 27 pts were relapsed indolent. One of the first 6 patients at dose level 4 (0.48mg/kg) had a dose limiting toxicity (DLT - hematologic with full recovery). The other 5 patients at dose level 4 did not have DLT; and thus, 0.48mg/kg was determined to be the dose for further studies. An additional 6 patients at dose level 0.48mg/kg were accrued. Response information is available on the first 26 pts and the median follow-up is 12.4 months (range, 0–30.8). The overall response rate, to date, is 92% (24/26) – 66% (2/3) for the DLC pts and 96% (22/23) for the indolent pts. The complete remission rate is 58% (15/26). After follow-up, 7 of the 26 patients have progressed and one has died of relapsed NHL; therefore, 73% (19/26) remain in response and overall survival is 97% (29/30). As part of the study, we performed indium-111 Zevalin imaging before CpG and after 1 dose of CpG (prior to the yttrium-90 Zevalin) to evaluate the effect of CpG on the biodistribution of the radioimmunoconjugate. In the first 24 patients treated to date, review of the paired gamma camera images does not show any significant effects of CpG on tumor or normal organ biodistribution. To date, there has been no significant differences in T-cell, NK-cell, and cytokine activation by CpG dose level.
Summary: CpG 7909 can be safely combined with Zevalin RIT in patients with advanced stage relapsed B-cell NHL.