New adjuvant drives unprecedented cytotoxic T cell response providing a
potent vaccine development platform
Wells, J. (pictured left) et al. (2008). Combined Triggering of Dendritic Cell Receptors Results in Synergistic Activation and Potent Cytotoxic Immunity. J. Immunology. 181(5): 3422-3431.
Wells et al. investigated novel combinations of vaccine adjuvants and
using Pro5® MHC Class I Pentamers, showed that optimal antigen-specific
responses can be achieved using well-tolerated compounds that result in dendritic cell activation through the activation of toll-like receptors.
Initially using the ovalbumin H-2Kb/SIINFEKL epitope as a model, Pentamer staining indicated that a vaccine adjuvant referred to as a
‘combined adjuvant for synergistic activation of cellular immunity’ (CASAC)
provided the greatest antigen-specific response as indicated by H-2Kb/SIINFEKL
Pentamer+/CD8+ T cell staining. The vaccination also induced a strong
memory response upon re-injection of SIINFEKL peptide as measured by Pentamer staining. The CASAC adjuvant contained several key components
including two toll-like receptor agonists (e.g. CpG DNA+monophosphoryl
lipid A), IFN-gamma and CD40 antibody or a class II MHC peptide to induce
IL-12 production from dendritic cells. This was combined with SIINFEKL
peptide in an emulsion.
The efficacy of the CASAC adjuvant was further tested on a mouse melanoma
model using the TRP-2 tumour epitope (H-2Kb/SVYDFFVWL), which is known to
bind with a low affinity to the H-2Kb allele. Mice were injected with B16
melanoma cells and then immunized with TRP-2 peptide suspended in either
CASAC or the most potent adjuvant combination previously described
(anti-CD40 and a single TLR agonist). Pentamer-binding CD8+ cells were
only detected in mice that had received the CASAC adjuvant. Protection
from tumours was maintained after further challenge with B16 melanoma
||CASC induces potent tumor protection in a
melanoma treatment model mediated partly but not entirely by tumor-Ag
specific T cells. The figure shows staining of TRP-2 specific CD8 T
cells in blood of mice using TRP-2(180-188) H-2Kb Pentamer. SIINFEKL
Pentamer was used for the negative control stain. Mean percentage + SEM from 6-8 mice is shown.
Copyright 2008 The American Association
of Immunologists Inc.
**p<0.005 as determined by unpaired Student's t tests on the mean
The use of Pro5® MHC Pentamers to measure antigen-specific T cell
responses accurately enabled the investigators to demonstrate that a
combinatorial adjuvant approach may provide more effective protection than
current anti-cancer vaccine strategies.