126 Background: CpG oligodeoxynucleotide (CpG ODN) (K3), a toll-like receptor 9 agonist, is a novel synthetic single-strand DNA immune adjuvant for cancer immunotherapy. CpG ODN(K3) induces the production of type 1 IFNs and pro-inflammatory cytokines in innate immune cells, leading to a potential Th1-type adaptive immune response against cancer cells, leading to an immunogenic tumor microenvironment. To determine the recommended dose (RD) of CpG ODN(K3) via subcutaneous injection (sc) or intravenous administration (iv) and to investigate the immune response induced by CpG ODN(K3) in advanced lung cancer patients, we designed an open-labeled, dose-escalation phase I study. Methods: Pts with advanced lung cancer who had achieved CR, PR or SD after the prior Pt-based chemotherapy were enrolled. The primary endpoint was the proportion of DLTs at each dose level. Secondary endpoints included safety profile, immune response including dynamic changes of immune cell and cytokine production, and PFS. In a 3+3 dose-escalation design, the dosage levels for CpG ODN (K3) were 5 or 10 mg/body sc and 0.2 or 0.6 mg/kg iv on day1, 8, 15 and 29. Pts without PD or unacceptable toxicity were allowed to receive CpG ODN(K3) up to a maximum of 6 months. Results: 6 pts were treated in sc part. 5 had NSCLC (3 had adenocarcinoma, 1 squamous cell carcinoma, and 1 mucoepidermoid carcinoma) and 1 had SCLC. There were no DLTs at any dose levels. Treatment-related toxicities were limited to G1 and G2 including local skin reactions. No pts experienced serious AEs including immune-related AEs. Some pts exhibited the dynamic change of immune-related cells and the immediate production of inflammatory cytokines and chemokines, such as IL1-beta, CCL2, and CXCL10, and Th1 cytokines including IFN-gamma, in response to CpG ODN(K3), suggesting that CpG ODN(K3) elicited innate immunity followed by Th1 adaptive immune response. Conclusions: This was the first clinical application of CpG ODN(K3) for cancer pts. CpG ODN(K3) sc was well-tolerated and was expected to activate innate immunity followed by Th1 adaptive immune response. Clinical trial information: UMIN000023276.
Innate immunity regulates adaptive immune response: lessons learned from studying the interplay between NK and CD8+ T cells during MCMV infection