Abstract Book 2010 - CIMT Annual Meeting

L121 Pawlowski | Therapeutic vaccination
Synergy of the immunomodulators GM-CSF and Imiquimod for
peptide-based therapeutic vaccines
Nina Pawlowski, Norbert Hilf, Sylvia Flohr, Toni Weinschenk, Oliver Schoor, Harpreet Singh
immatics biotechnologies GmbH, Tuebingen, Germany
All FDA- or EMA-approved drugs currently used
as immunomodulators with therapeutic peptidebased
cancer vaccines 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). 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 colonystimulating 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 injected s.c. combined with imiquimod
cream applied topically to the skin of C57BL/6
mice at the vaccination site significantly increased
the number of vaccinespecific 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 FDA-/
EMA-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 safety of this regimen
in humans.
GM-CSF and imiquimod is therefore considered as
a promising and safe alternative immunomodulator
regimen for upcoming immunotherapeutic approaches
and is currently explored by the authors
in a clinical trial in colorectal cancer patients.
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