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Letters
https://doi.org/10.1038/s41563-018-0028-2
1John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. 2Wyss Institute for Biologically Inspired
Engineering, Harvard University, Boston, MA, USA. 3Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
4School of Chemical Engineering, Sungkyunkwan University, Suwon, Republic of Korea. 5Department of Health Sciences and Technology, Samsung
Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Suwon, Republic of Korea. 6Biomedical Institute for Convergence
at SKKU (BICS), Sungkyunkwan University, Suwon, Republic of Korea. *e-mail: mooneyd@seas.harvard.edu
Existing strategies to enhance peptide immunogenicity for
cancer vaccination generally require direct peptide altera-
tion, which, beyond practical issues, may impact peptide pre-
sentation and result in vaccine variability. Here, we report a
simple adsorption approach using polyethyleneimine (PEI)
in a mesoporous silica microrod (MSR) vaccine to enhance
antigen immunogenicity. The MSR–PEI vaccine significantly
enhanced host dendritic cell activation and T-cell response
over the existing MSR vaccine and bolus vaccine formulations.
Impressively, a single injection of the MSR–PEI vaccine using
an E7 peptide completely eradicated large, established TC-1
tumours in about 80% of mice and generated immunological
memory. When immunized with a pool of B16F10 or CT26 neo-
antigens, the MSR–PEI vaccine eradicated established lung
metastases, controlled tumour growth and synergized with
anti-CTLA4 therapy. Our findings from three independent
tumour models suggest that the MSR-PEI vaccine approach
may serve as a facile and powerful multi-antigen platform to
enable robust personalized cancer vaccination.
Cancer vaccines targeting multiple tumour-specific antigens
can elicit broad immune responses and decrease tumour escape1,2,
and recent advances enable identification of tumour-specific muta-
tions (‘neoantigens’)3,4. Neoantigens are attractive vaccine targets
as they are not expressed in healthy tissues and are predicted to
have strong major histocompatibility complex (MHC)-binding
affinity5. Recent clinical data have shown that neoantigen vaccines
could generate T cells that specifically target heterogeneous tumour
clones6. However, neoantigen peptides exhibit rapid clearance and
low immunogenicity, which limits optimal presentation by antigen-
presenting cells to initiate strong T-cell responses7. Macro- and
nano-engineering strategies have been designed to overcome these
challenges8–11, but many approaches require chemical modification
or physical emulsification of the peptides, potentially altering their
presentation capacity. Moreover, since neoantigen vaccines typi-
cally require many peptides12, modification of individual peptides
is cumbersome for clinical translation and is likely to result in high
batch-to-batch variability.
We propose a facile strategy to enhance antigen immunogenicity
using polyethyleneimine (PEI) combined with a mesoporous silica
microrod (MSR) vaccine. The MSR vaccine can be injected using
standard needles, was shown to effectively concentrate and acti-
vate large populations of host antigen-presenting cells and induced
more potent humoral responses and prophylactic tumour protec-
tion than traditional vaccine formulations13. Moreover, the MSR
surface could potentially be modified to induce stronger responses.
Recent studies have shown that complexes based on PEI, a widely
used cationic polymer14,15, can stimulate pro-inflammatory cytokine
production16,17, and induce potent humoral responses when com-
plexed with glycoproteins18. Here, we explore the application of PEI
to co-present an antigen in a facile, layered adsorption manner in
the MSR vaccine.
MSRs were adsorbed with PEI (MSR–PEI) by simply mixing
with a PEI solution for 15 minutes; subsequently, an antigen pool
was directly adsorbed onto MSR–PEI particles (Fig. 1a). Both rela-
tive molecular mass 60,000 (60K) branched PEI (B60K) and 25K
linear PEI (L25K) absorbed to MSR with high efficiency (Fig. 1b),
with an incorporation capacity of about 20 μ g PEI per mg MSR.
Over 90% of B60K and L25K PEI polymers were adsorbed after
1 min of mixing (Fig. 1c). Zeta potential measurements confirmed
PEI incorporation (Fig. 1d). MSR–PEIs maintained the intrinsic
mesopores of MSRs (Supplementary Fig. 1a), pore structure and
bulk particle structure (Supplementary Fig. 1b–d), with reduced
surface area and pore volume as expected (Supplementary Table 1).
MSRs and MSR–PEIs showed high incorporation efficiency for
net positive and neutral example murine (Fig. 1e) and human
(Fig. 1f) peptides, but MSR–PEI enhanced the incorporation of net
negative peptides.
The underlying adjuvant effect of PEI19,20 on bone-marrow-
derived dendritic cells (BMDCs) was next examined. BMDCs take up
free PEI, reaching maximum uptake at 24 h (Supplementary Fig. 2a),
and showed a significant increase in CD86 and MHC-II expression
(Fig. 1f) and tumour necrosis factor α (TNF-α ) (Fig. 1g) and inter-
leukin-6 (IL-6) (Fig. 1h) production in a PEI dose-dependent man-
ner. BMDCs stimulated with MSR–PEI also showed significantly
increased CD86 expression (Supplementary Fig. 2b) and TNF-α
production (Supplementary Fig. 2c). MSR–PEI also triggered the
increased production of IL-1β , a key cytokine produced in response
to Nlrp3 inflammasome activation21 (Supplementary Fig. 3a). This
was probably a result of lysosomal rupture upon MSR–PEI uptake
(Supplementary Fig. 3b), leading to the release of phagosomal con-
tents into the cytosolic compartment. Interestingly, as TNF-α and
IL-6 have been shown to be Nlrp3-independent cytokines22, it is
possible that MSR–PEI particles can stimulate multiple damage-
associated molecular pattern (DAMP) receptors. The impact of PEI
A facile approach to enhance antigen response for
personalized cancer vaccination
Aileen Weiwei Li1,2, Miguel C. Sobral1,2, Soumya Badrinath3, Youngjin Choi4, Amanda Graveline2,
Alexander G. Stafford2, James C. Weaver2, Maxence O. Dellacherie1,2, Ting-Yu Shih1,2, Omar A. Ali2,
Jaeyun Kim4,5,6, Kai W. Wucherpfennig3 and David J. Mooney1,2*
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