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146 Alexander M. Cryer and Natalie Artzi
a robust T cell response, increasing the cytotoxic to regulatory T cell ratio, a hallmark of
an immunogenic response [22]. The microneedle platform is highly modular, as NPs or
other therapeutic entities can be interchanged based on the tumor type and immune status (i.e., hot or cold tumors, T-cell rich or deficient). The immunosuppressive TME is
caused by a multiplicity of factors working in concert, including metabolism. Using
hyaluronidase-sensitive microneedles, an IDO inhibitor delivered transdermally in combination with anti-PD-1 was able to significantly prolong the survival of melanoma-bearing
mice [23]. Hollow microneedles composed of polyvinylpyrrolidone and polyvinyl alcohol
were used to transdermally deliver cold atmospheric plasma (CAP) and ICI, specifically
anti-PD-L1, to melanoma tumors. CAP was shown to induce the generation of reactive
oxygen and nitrogen species which led to immunogenic cell death. This process results in
the release of tumor antigens that can be taken up by resident immature DCs and presented to T-cells in the tumor-draining lymph node, to enact an antitumor response. Not
only was this platform able to induce local tumor control, but also systemic immunity, as
untreated tumors on the opposite flank of mice treated with the microneedle combination therapy was also seen to regress. Further evidence of this abscopal effect was
witnessed by the detection of proinflammatory cytokines such as IFN-γ, IL-12, and
TNF-α in the serum after treatment [24].
The skin hosts a rich population of APCs, specifically Langerhans cells, which are
essential for coordinating immune responses at a biological barrier that is constantly in
contact with pathogens. Thus, these cells are attractive targets for biomaterials to enlist
in an antitumor response by more direct delivery, uptake, and residence time of antigens
and adjuvants. For instance, polymethyl vinyl ether/maleic anhydride microneedles were
loaded with PLGA NPs that contained the antigen ovalbumin (OVA). Transdermal
delivery of the NPs resulted in the local deposition and uptake of NPs in APCs with consequent priming and expansion of OVA-specific T cells. Moreover, the microneedles
dissolved within 15 min which helped promote a localized and specific immune response
in the dermis. In a melanoma model expressing OVA, this system was able to induce
potent CD8
+
and Th1-skewed CD4+T cell responses against the tumor [25]. Indeed,
this system was able to promote the retention and stability of antigen within the dermis
until endocytosed by APCs that subsequently trafficked to the draining lymph node
where T-cell priming occurs. An innovative approach has been employed using microneedles impregnated with the natural biological pigment melanin and whole tumor lysate
(Fig. 4). When exposed to near-infrared light, the melanin generated heat which induced
the production of proinflammatory cytokines and other dangerous signals from the
endogenous tissue, culminating in the recruitment of immune cells. Thus, phagocytic
APCs were able to uptake tumor antigen and successfully present it to T cells; in a mouse
melanoma model, almost total tumor rejection was achieved using this approach [26].
147Engineered devices for tumor microenvironment immune modulation
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Fig. 4 Me lanin imbued microneedle patch for transdermal cancer immunotherapy. (A) Schematic
illustration of MN-based transdermal vaccination. T
cell, T helper cell; Tccell, cytotoxic T cell.
H
(B) Photograph of representative MN patches without (W/o) melanin and with (W/) melanin (scale
bar, 4 mm). (C) Scanning electron microscopy image of the MN patch (scale bar, 400 μm).
(D) Fluorescence cross-sectional images of a representative M N. Actin filaments in cells were visualized by Alexa Fluor 488 phalloidin (green), cell DNA fragments were stained with Hoechst (blue),
and hyaluronic acid polymer matrix was labeled with rhodamine B (red) (scale bar, 200 μm).
(E) Fluorescence imaging of a representati ve MN patch that contained the Alexa Fluor 488
phalloidin-labeled tumor lysate and rhodamine B-labeled hyaluronic acid (scale bar, 400 μm).
(Reproduced with permission from Ye Y, et al. A melanin-mediated cancer immunotherapy patch.
Sci Immunol 2017;2:eaan5692. http://doi.org/10.1126/sciimmunol.aan5692. Copyright 2017, The
Authors.)
148 Alexander M. Cryer and Natalie Artzi
Other work has demonstrated transdermal delivery of CD40 (dendritic cell marker)
targeted HA-glycerol monostearate transfersomes encapsulating the tumor-associated
antigen tyrosinase-related protein-2 (Trp-2), the adjuvant poly I:C and anti-PD-1 facilitated accumulation within the tumor-draining lymph nodes and subsequently enacted a
robust antitumor response [27].
Microneedle platforms have also been used to deliver nucleic acid-based tumor vaccines which are promising as they can encode for the desired antigen of interest and have
shown promising therapeutic and prophylactic efficacy. Again, the overarching goal is to
target APCs, or at least increase the probability that they encounter the antigen of interest. A transcutaneous vaccination strategy was employed that utilized microneedles for
the delivery of mannosylated PEI complexed with Trp-2 DNA. Mannose was chosen
as it is a ligand for CD206, or the mannose receptor, which is expressed by APCs such
as skin DCs, and the PEI was further decorated with a cell-penetrating peptide known as
a transactivator of transcription (TAT) to facilitate internalization within target cells. This
strategy provided protection against Trp-2 expressing malignant melanoma inoculation
and therapeutic efficacy due to induction of CD8
+
and CD4+T cells and subsequent
proinflammatory cytokine production, such as IL-12 and IFN-γ [28]. Illustrating the
broader applicability of microneedles to different cancers, polyvinyl alcohol-based arrays
were developed for the transdermal delivery of plasmid DNA encoding prostate stem cell
antigen (PSCA) which were complexed with cationic repetitive arginine alanine leucine
alanine (RALA) NPs. The microneedles could dissolve after insertion into the skin and
be found to effectively facilitate the delivery of the NP/DNA complexes, resulting in
endogenous PSCA production and a robust and specific antitumor response against
PSCA-expressing TRAMP-C1 prostate tumors [29]. Another approach involved using
polycarbonate microneedles coated with dopamine to bestow a positive charge. A layerby-layer strategy was then used to alternatively coat the microneedles with the adjuvant
poly I:C, which is negatively charged, and a pH-responsive sulfamethazine conjugated
poly beta-amino urethane, which is positively charged. Finally, a complex of plasmid
DNA coding for the antigen OVA and PEI was applied to the microneedles. Thus, this
system was predicated on electrostatic interactions, which is often the case when delivering nucleic acids. The microneedles were able to activate both cellular (CD8
+
T cell
activity) and humoral (serum anti-OVA IgG) immunity in a more robust fashion than the
soluble DNA formulation without microneedles [30].
Microneedle platforms can therefore be used to either directly modulate the TME by
facilitating potent and efficacious transdermal delivery of immune-active molecules, or
indirectly by delivering immunological information to the rich APC population in
the skin, in the form of tumor antigens or nucleic acids coding for tumor antigens, which
then go on to orchestrate a response against the tumor and remodel the TME. Both
strategies are viable and innovative immunotherapeutic approaches made possible by
transdermal delivery platforms. It is also notable that direct subcutaneous injection of
NP-based vaccine formulations have also proven to be effective in preclinical tumor
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models (see refs. [31–33]).
4. Systemic delivery of engineered devices for tumor immune
modulation
The principals and considerations for systemic delivery of immune modulatory
agents differ from that of local or transdermal approaches. NPs are the vehicle of choice
for systemic delivery as bulkier macromolecular structures are not appropriate. Key considerations for systemic NP delivery are the half-life of the NP in the blood, the biodistribution of the NP and off-target toxicities induced by either the NP itself or the
encapsulated cargo. Several decades of engineering NPs for systemic delivery of a variety
of cargo have led to clinically approved therapies and many more promising preclinical
candidates.
The systemic nature of these therapies means that tumor immune modulation is indirect, in that the TME acts in response to what is delivered instead of the TME being the
epicenter of the response which typically occurs with local or transdermal delivery. An
interesting example that has reached clinical trials involves the use of cationic lipids 1,2di-O-octadecenyl-3-trimethylammonium propane (DOTMA), 1,2dioleoyl-3-trimethylammonium propane (DOTAP), and zwitterionic 1,2-dioleoyl-snglycero-3-phosphoethanolamine (DOPE) in the preparation of liposomes after complexation with anionic mRNA. Altering the RNA-to-lipid ratio and therefore the surface
charge of the NP (from positive to negative), shifted NP accumulation from the lungs
and liver to the spleen after intravenous administration. The lead candidate NP was,
therefore, able to access large numbers of DC in the spleen and lymphoid tissues and
deliver mRNA coding for tumor antigens which were subsequently expressed and presented to T-cells. This mediated potent rejection of multiple models of murine tumors
depending on which antigens the mRNA coded for, presumably due to significantly
increased numbers of activated APCs in the spleen leading to robust innate immune cell
and T-cell infiltration into tumors. This work also highlighted the notion that surface
charge plays a dominant role in the BD of NPs, which can be exploited for immunotherapeutic approaches that require interaction with immune cells [34]. Exploring this further, intravenously injected polymersomes encapsulating the STING agonist cGAMP
were found not only to accumulate in the tumor but also the liver, spleen, kidneys,
and lungs, as expected when systemically delivering NPs. Indeed, STING was found
to be activated in the tumor which was theorized to be responsible for the altered
TME including increased numbers of CD4
panied by decreased numbers of macrophages. Pronounced therapeutic efficacy and
increased survival were observed in two melanoma and a breast cancer tumor model.
+
and CD8+T-cells as well as DCs accom-
149Engineered devices for tumor microenvironment immune modulation
150 Alexander M. Cryer and Natalie Artzi
Interestingly, transcripts of Ifnb1 which codes for IFN-β, were found to be most elevated
in the spleen 1 hour postinjection which tapered off shortly thereafter; this was accompanied by an acute but transient increase in plasma IFN-β. It was observed that within the
spleen, DCs and macrophages most avidly internalized the NPs, suggesting these cells
were partly responsible for the systemic surge in IFN-β production [35].
A calcium phosphate (CaP)-thymine modified dendrimer complex core-NP was
developed which efficiently condensed siRNA against PD-L1 and pDNA encoding
the immunostimulatory cytokine IL-2 (Fig. 5). The shell of the NP was composed of
the lipids 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA), DOTAP, and a lipid-PEG to
improve in vivo stability. Finally, the NP was decorated with a targeting peptide specific
for hepatocellular carcinoma (HCC) cells. Intravenous administration of NPs, along with
the intraperitoneal injection of HCC cells expressing GM-CSF as part of a whole-cell
hepatoma vaccine, was found to reprogram the HCC TME. Marked increases of
Fig. 5 Multicomponent NP for systemic delivery and TME immune modulation. Active tumor targeting
was achieved through the addition of the HCC-targeted SP94 peptide to the surface of the NPs. The
thymine-capped PAMAM dendrimer/CaP complexes achieved highly efficient gene transfection efficacy by enhancing nuclear delivery of the pDNA. Furthermore, thymine-capped PAMAM dendrimers
stimulate the STING pathway and serve as an adjuvant to promote the maturation of intratumoral DCs.
Efficient tumor-targeted codelivery of PD-L1 siRNA and IL-2 pDNA achieves tumor-specific expression
of IL-2 and down-regulation of PD-L1, increases infiltration and activation of CD8
induces a strong tumor-suppressive effect in HCC in synergy with a vaccine. CaP, calcium phosphate;
TIDC, tumor-infiltrating dendritic cell; TT-LDCP NPs, tumor-targeted lipid-dendrimer-calcium-phosphate
NPs; IFN-γ, interferon-γ. (Reproduced with permission from Huang K-W, et al. Highly efficient and tumor-
selective nanoparticles for dual-targeted immunogene therapy against cancer. Sci Adv 2020;6:eaax5032.
http://doi.org/10.1126/sciadv.aax5032. Copyright 2020, The Authors.)
+
T cells in HCC, and
granzyme B+and IFN-γ+CD8+T-cells were observed which correlated with significant
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tumor reduction, fewer metastatic lesions in the lung, and doubled life span compared to
untreated mice. Adoptive transfer of CD8
+
T-cells from treated mice into naı¨ve mice
bearing orthotopic HCC tumors significantly attenuated tumor burden and lung metastases. Interestingly, the thymine capped dendrimer component of the NP was found to
activate STING which may have been due to the presence of localized and concentrated
nucleotides within the cytoplasm upon dendrimer transfection [36]. PEGylated graphene
oxide (GO) was functionalized with a peptide that binds to the integrin αvβ6, which is
overexpressed by a variety of tumors. GO was further coated with the photosensitizer
[2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-alpha, HPPH], giving rise to
GO-HPPH. Upon irradiation at 665 nm, systemically administered GO-HPPH brought
about the activation of DCs and significant recruitment of CD4 and CD8 T-cells into the
TME due to PDT, resulting in restrained tumor growth and lung metastases in a challenging and relatively immunoresistant murine breast tumor model [37].
It is apparent that despite not reaching the tumor as efficiently as local and trans dermal approaches, systemic delivery of engineereddevicessuchasNPscanstillmodulate
the immune component of the TME, whether that is due to tumor-based effects,
organ-based effects or both. An attractive prospect for metastatic disease or prophylactic vaccination, systemic delivery requires a delicate balance between sufficient
immune activation whilst avoiding off-target toxicities. However, this delivery route
may be able to mobilize immune populations in lymphoid tissues such as the spleen that
may not otherwise participate in the antitumor immune response.
151Engineered devices for tumor microenvironment immune modulation
5. Limitations, perspectives and future work
It is increasingly apparent that modulating the immune system, particularly the
immune component of the TME, has curative therapeutic potential. Engineered devices
can provide spatiotemporal and combinatorial immune control that traditional pharmacological interventions cannot. However, each subtype of device whether hydrogel, scaffold, MNs, NPs, or other types, have unifying and individual challenges associated with
them. The biomaterials used to construct these devices must be biocompatible and, if
clinically translatable, amenable to scale-up. Typically, preclinical studies involve multicomponent immunotherapies which often stymies manufacturing scale-up, increases
costs, and complicates regulatory approval. Despite the use of biomaterials, even in
humans, for decades, our understanding of how exactly the immune system and biomaterials interact and what factors are responsible for these interactions are not fully understood. Future studies directed at unraveling the relative contributions of the intrinsic
properties of engineered devices as well as their cargo, especially longitudinally, would
be particularly insightful. Understanding the spatiotemporal relationship of combination
152 Alexander M. Cryer and Natalie Artzi
immunotherapies in the immune response is possible using engineered devices and
would aid in understanding the kinetics of TME modulation for optimal therapeutic
intervention. In the case of combination therapy, the use of different delivery routes
may be necessary and beneficial depending on the therapeutic entities, as the optimal
administration route will differ depending on the molecule, its properties, the regimen,
and the status of the individual receiving them.
Local administration is, by definition, restricted to the site of implantation or injection
which may limit the types of TMEs that can be modulated, however, this can be overcome by inducing systemic immune responses. Furthermore, this administration route
requires devices with particular biophysical properties (e.g., scaffold strength, gelation
time, retention at administration site) to achieve a therapeutic effect. Devices for transdermal delivery requires fabrication using materials with the appropriate stiffness to penetrate the skin which limits the scope of materials that can be used. Moreover, the amount
of cargo that can be delivered is restricted by the holding capacity of the needles, and
retrieval of biological fluids for analysis is similarly restricted. Systemic delivery of devices
such as NPs, although the most directly translational application, has several challenges,
which explains the paucity of formulations in clinical use despite the myriad of encouraging preclinical data. The need for physiologically relevant models aside, systemic delivery is the avenue of administration that induces dose-limiting side effects, which can be
attenuated with NPs, but still occur depending on the material. How better to deliver
NPs to specific destinations within the body such as the tumor is an ongoing pursuit
within the field. Investigations into how the protein corona affects BD and immunogenicity, the role of targeting moieties (e.g., peptides), which immune cells interact with
and the downstream fate of these NPs would be insightful. Indeed, tumor modulation
may occur due to indirect activation of off-site immune populations, for instance in
the spleen. It is clear that engineered devices can dramatically modulate the immune
composition of the TME, even if they are not directly active at the tumor site, however
further work is still needed to realize the full potential of these devices in the context of
human cancer.
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CHAPTER SIX
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Tumor-on-a-chip devices for cancer
immunotherapy
Xuan Mu and Yu Shrike Zhang
Division of Engineering in Medicine, Brigham and Women’s Hospital, Department of Medicine, Harvard Medical School,
Cambridge, MA, United States
Contents
1. Introduction 155
2. Microfluidics 157
2.1 Microfabrication 158
2.2 Flow at the microscale 160
3. Recapitulating the tumor microenvironment 161
3.1 Angiogenesis 162
3.2 Extravasation 165
3.3 Lymphocyte trafficking 168
4. Predicating therapeutic efficacy 171
5. Production of therapeutic cells 174
5.1 T cells 174
5.2 Exosomes 178
5.3 Fused hybrid cells 180
6. Screening immune cells 181
6.1 Droplet-based approaches 181
6.2 Hydrodynamics-based approaches 184
7. Conclusion 184
References 185
1. Introduction
Cancer immunotherapy has made substantial progress in the past decades [1]. Several breakthroughs, including cancer vaccines, T-cell therapy, and immune checkpoint
blockade therapy, have opened up a new landscape for leveraging the immune system to
fight against cancer [2]. Despite the huge success, many challenges exist that prevent
unleashing the full potential of cancer immunotherapy [3]. One challenge is the lack
of crucial and specific features of human immunity in conventional preclinical models,
based on 2D planar cell cultures and animals. These features include the composition of
Engineering Technologies and Clinical Translation Copyright © 2022 Elsevier Inc.
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