TLR9 agonists enhance the efficacy of cancer vaccines

4994 We have recently developed a genetic vaccination platform based on the use of muscle DNA electroporation and adenovirus which has been shown to be effective in eliciting immune response against several viral antigens. The application of this technology to tumor associated antigens (TAA), such as Carcinoembryonic antigen (CEA) and Her2/Neu in immunologically tolerant mice resulted in the induction of measurable antigen-specific responses. Importantly, vaccines have led to significant therapeutic effects that supported the progression of the cancer vaccine program towards clinical trials. However, the general belief of cancer immunologists is that vaccination per se might have a limited impact on late-stage patients and combination therapies are needed to synergize with cancer vaccines.
 One of the most promising targets for therapeutic immune activation is TLR9, which detects unmethylated CpG dinucleotides present in viral and prokaryotic genomes, which are generally methylated in host DNA.
 Here, we have tested the ability of second generation TLR9 agonists such as immunomodulatory oligonucleotides (IMOs) to synergize with cancer genetic vaccine candidates and peptides to target TAAs.
 We show that association of cancer vaccines and IMOs was strongly effective in inducing and enhancing cellular and humoral immune response against TAAs. Most importantly, treatment resulted in significant therapeutic effect and delayed time to disease progression in BALB/NeuT transgenic mice affected by in situ mammary carcinoma and treated with HER2 vaccine and IMO combination. The antitumoral effect was associated with several immunologic parameters: increase in natural immunity, in the percentage of cell mediated immune responders and antibody isotype switch. Interestingly, we have identified a immunogenic B cell linear epitope within HER2 and vaccine-induced antibodies directed to such epitope were shown to be predictive of clinical outcome and could be evaluated as potential biomarkers.
 These results strongly support the integration of IMOs into genetic cancer vaccine clinical trials .