Abstract 5623: Synergy of the immunomodulators GM-CSF and imiquimod for peptide-based therapeutic vaccines

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8_Supplement), p.5623-5623
• Main Authors: Hilf, Norbert, Pawlowski, Nina, Flohr, Sylvia, Schoor, Oliver, Weinschenk, Toni, Singh, Harpreet
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-5623

All approved immunomodulators currently in use with therapeutic peptide-based cancer vaccines in are of only moderate efficacy in terms of direct activation of antigen-presenting cells which is a key prerequisite for efficient priming of cytotoxic T cells (CTLs). Moreover, induction of immune responses against tumor-associated antigens (TAAs) is further hampered by an in most cases immunosuppressive environment in cancer patients and by effective tolerization of the immune system against self-antigens, as the majority of TAAs is not exclusively expressed in tumors but also to some extent present on normal tissues. Because the reliable induction of tumor-directed immune responses is crucial for the efficacy of therapeutic cancer vaccines, novel immunomodulator regimens have to be introduced into clinical testing to achieve a better clinical outcome. Therefore, we analyzed safety and efficacy of several approved immunomodulatory substances and combinations thereof in a dedicated pre-clinical screening program. The combination of subcutaneously (s.c.) applied granulocyte-macrophage colony-stimulating factor (GM-CSF) with topical application of the TLR7 ligand imiquimod resulted in synergistic enhancement of peptide-vaccine induced CTL responses without any signs of toxicity or cumulated adverse effects. GM-CSF applied s.c. combined with imiquimod cream applied topically to the shaved skin of C57BL/6 mice at the vaccination site significantly increased the number of vaccine-specific CTLs induced by s.c. vaccinations with model MHC class I-binding peptides compared with either substance alone. The induced immune response was comparable to the effect of CpG deoxyoligonucleotides or poly-IC, two potent immunomodulators currently not approved and therefore not widely available for clinical trials in humans. However, the timing of imiquimod application in relation to the vaccination schedule is crucial, as the synergistic effect of imiquimod and GM-CSF was only observed, if imiquimod was applied at the day of vaccination and/or 24 h later, but not if imiquimod was applied the day before peptide vaccination. In total, 45 mice were immunized with the combination of GM-CSF and imiquimod without any signs of local or systemic toxicities. Further results from in vitro activation assays with human PBMCs and isolated antigen-presenting cells and the distinct molecular mechanisms of immunostimulation employed by both substances provide further support for the anticipated s