Download 574. SynergisticalSynergistically Transcutaneous Immunotherapy

Synergistically Transcutaneous Immunotherapy Enhances Antitumor Immune Responses
through Blockade of PD1 and IDO
Yanqi Ye1, 2, Jinqiang Wang1, 2, Quanyin Hu1, 2, Gabrielle M. Hochu1, Hongliang Xin1, Chao Wang1, 2, * and Zhen Gu1, 2, 3
1
Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State
University, Raleigh, North Carolina 27695, United States; 2Molecular Pharmaceutics Division and Center for
Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599, United States; 3Department of Medicine, University of North Carolina School of Medicine, Chapel
Hill, North Carolina 27599, United States.
Statement of Purpose: Despite the promising efficacy of
immunoregulation in cancer therapy, the clinical benefit
has been restricted by inefficient infiltration of
lymphocytes in the evolution of immune evasion. Also,
the immune-related adverse events have often occurred
due to the off-target binding of therapeutics to normal
tissues after systematic treatment. In light of this, we have
developed a synergistic immunotherapy strategy that
locally
targets
the
immunoinhibitory
receptor
programmed cell death protein 1 (PD1) and
immunosuppressive enzyme indoleamine 2,3-dioxygenase
(IDO) for the treatment of melanoma through a
microneedle-based transcutaneous delivery approach.[1-4]
Methods:
The
embedded
immunotherapeutic
nanocapsules loaded with anti-PD1 antibody (aPD1) is
assembled from hyaluronic acid modified with 1-methylDL-tryptophan (1-MT), an inhibitor of IDO. The solvent
dialysis approach was employed to prepare the selfassembly of 1-MT conjugated HA (m-HA, MW=50 kDa)
encapsulating monoclonal aPD1. To target the immune
surveillance skin region at the melanoma site, we further
fabricated the MN-array patch for synergistic delivery of
aPD1 and 1-MT. For the MN preparation, the HA-NPs
were first loaded in the tips of micromolds by
centrifugation. The B16F10 mouse melanoma tumor
model, which is a highly aggressive tumor model on
female C57BL/6 mice was used to evaluate the efficacy
of synergistic immunotherapy in a clinical relevant
setting.
Results: This formulation method based on the
combination strategy of “drug A in carriers formed by
incorporation of drug B” facilitates the loading capacity
of therapeutics. Moreover, the resulting delivery device
elicits the sustained release and enhances retention of
checkpoint inhibitors in the tumor microenvironment.
Using a B16F10 mouse melanoma model, we demonstrate
that this synergistic treatment has achieved potent
antitumor efficacy, which is accompanied with enhanced
effective T cell immunity as well as reduced
immunosuppression in the local site. This work provides
an effective strategy to overcome the immune escape
mechanisms and generate a robust antitumor response.
Figure 1. The schematics of a microneedle-based
transcutaneous platform loaded with self-assembled
immunotherapeutic nanocarriers.
Conclusions: In summary, we describe a synergistic
transcutaneous immunotherapy that preferentially targets
the
immunoinhibitory
receptor
PD1
and
immunosuppressive enzyme IDO to enhance antitumor
response. The platform using MN as a carrier to deliver
checkpoint inhibitor aPD1 and 1-MT facilitates the
retention time of therapeutics in the diseased site and
potentially alleviates the side effects of systematic
administration of cancer immunotherapeutic. This work
provides a strategy to overcome the immune escape
mechanisms with a robust antitumor response. The
potential of clinical studies relies on further optimization
of bioavailability of the therapeutics in patch and
evaluation of systemic biocompatibility of the delivery
devices.
References:
[1] Ye, et al. ACS nano 10.9 (2016): 8956-8963.
[2]Wang, et al. Nano letters 16.4 (2016): 2334-2340.
[3] Yu, et al. Proceedings of the National Academy of
Sciences 112.27 (2015): 8260-8265.
[4]Lu, et al. Nature Review Materials 1(2016):16075.