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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5866_Библиотеки_им_академика_М_И_Перельмана
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136 Alexander M. Cryer and Natalie Artzi
target site, which also reduces dose-limiting immunotoxicity. Furthermore, the devices
themselves can have varying degrees of immunoactivity depending on the materials used
to synthesize them, which can also be of benefit in certain contexts.
The heterogeneity and composition of solid tumors provide many axes to regulate,
although typically these tumors possess an immunosuppressed phenotype encompassing
protumorigenic inflammation, notable genetic, epigenetic and metabolic remodeling,
and an immune cell infiltrate conducive to promoting tumor growth and maintaining
a tolerogenic environment. Broadly, the components of the TME can be split into
two categories from a modulatory perspective, the cellular component, and the acellular
component. In brief, modulating the cellular component involves relieving the suppression of immune effector cells [cytotoxic and helper T-cells, dendritic cells (DCs),
proinflammatory macrophages, natural killer (NK) cells, B cells], depleting immunosuppressive cells [myeloid-derived suppressor cells (MDSCs), T regulatory cells (Tregs),
antiinflammatory macrophages), and transforming the tumor-associated vasculature.
Modulating the acellular component is typified by remodeling the extracellular matrix
(ECM). However, there is substantial crossover as stromal cells (cancer-associated fibroblasts, myofibroblasts, mesenchymal stromal cells) are the predominant cell types in the
ECM, and cancer cells also play a pivotal role in shaping the immune microenvironment.
Modalities that possess the ability to modulate the TME go beyond traditional immunotherapy (e.g., cytokines, immune checkpoint inhibitors, adjuvants) and include radiotherapy, phototherapy, chemotherapy, and miscellaneous therapies such as metabolic
inhibition (Fig. 1A). In this chapter, we will discuss, in the context of cancer curation,
how engineered devices (Fig. 1B) can modulate the immune microenvironment of the
TME, the manner by which they do this, and the downstream immunological consequences. We will stratify the following sections by mode of administration—local, transdermal, and systemic—as each delivery route relies on different delivery and
immunological principles to achieve a full therapeutic effect.
2. Local delivery of engineered devices for tumor immune
modulation
The traditional advantages of local delivery systems are that the release kinetics of
the payload can be controlled, side effects resulting from systemic administration are typically attenuated, and more therapeutic agent is present at the disease site. Biomaterial
devices designated for local delivery can be rationally engineered to respond to specific
stimuli within the TME (such as enzymes, pH, redox), or external stimuli (heat, light,
magnetism), as well as permit appropriate spatiotemporal coordination of payload delivery, often consisting of multiple components, such that optimal immune activation can
occur.
137Engineered devices for tumor microenvironment immune modulation
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Fig. 1 The spectrum of immunomodulatory parameters of the TME and engineered devices with
which to moderate it. (A) Selected factors that play a role in the immunoactivation and immunosuppression of the TME. A complex interplay between many different parameters, ranging from the vasculature, cell types and their composition, metabolic conditions and a plethora of cytokines,
chemokines and growth factors govern the immune state of the TME. Indeed each of these factors
Continued
138 Alexander M. Cryer and Natalie Artzi
Hydrogels and porous scaffolds are among the central pillars of local delivery and are
some of the most common engineered devices used to achieve immunological tumor
control via modulatory effects. Hydrogels are hydrophilic polymeric materials that are
cross-linked to form a three-dimensional macrostructure, the internal cavity of which
can be loaded with a variety of components such as cells, biological agents (e.g., cytokines), NPs, or immunoactive small molecules. Porous scaffolds are similar macroscale
structures that can also act as biomimetic matrices and drug delivery depots. These
two types of constructs can be comprised of many different materials including natural
polymers—polysaccharides, including chitosan, hyaluronic acid (HA), alginate, dextran,
mucin—, synthetic polymers—polyethylene glycol (PEG), poly(lactic-co-glycolic acid)
(PLGA), poly(vinyl alcohol) (PVA)—, polypeptides (collagen, fibrin, gelatin), proteins,
nucleic acids, or inorganic materials (e.g., mesoporous silica). A major consideration in
device design, along with the therapeutic entity to be delivered, is the method of local
delivery. The choice of surgical implantation, minimally invasive needle injection, or
catheter injection will be informed by the mechanical properties of the hydrogel or scaffold, the crosslinking chemistry used and the size of the formed material. Considerations
for injectable devices include the method of in situ formation (e.g., thermal, chemical).
Due to the diversity of materials and deliverable cargo using these devices, there are many
examples of immune modulation of the TME using hydrogels or scaffolds. Here, we will
describe examples that utilize various and differing axes of immunomodulation. Further
examples can be found in the following literature [1–3].
Chemotherapy and radiotherapy are currently mainstay therapeutic options in the
clinical armamentarium, and along with photothermal and photodynamic therapy
(PTT and PDT respectively), can induce immunogenic cell death (ICD). ICD results
in the release of tumor-associated antigens and damage-associated molecular patterns
(DAMPs) which are taken up by surveilling DCs and other antigen-presenting cells
(APCs), leading to priming of T-cells and an adaptive immune response. This phenomenon can be potentiated using hydrogels or scaffolds, for example, a pore-forming injectable alginate hydrogel was constructed, containing the chemotherapy agent doxorubicin
Fig. 1, cont’d can act as a therapeutic intervention point to activate the TME. (B) Small molecules,
nucleic acids, peptides, and proteins can be used as immunomodutors of the TME, but effective delivery and the therapeutic effect typically require engineered devices, such as nanoparticles (NPs), scaffolds, hydrogels, or needle patches. These devices can be constructed from a wide range of materials
including polymers, lipids, metals or biologically derived constructs (e.g., cell membranes) depending
on the device and its indication. (Reproduced with permission from Popel AS. Immunoactivating the
tumor microenvironment enhances immunotherapy as predicted by integrative computational model.
PNAS 2020:117(9):4447-49. https://doi.org/10.1073/pnas.2001050117 (2020) Copyright 2020, National
Academy of Science of the United States of America. Reproduced with permission from Yan S, et al. Improving cancer immunotherapy outcomes using biomaterials. Angew Chem Int Ed 2020;59:17332– 43. http://
doi.org/10.1002/anie.202002780 (2020). Copyright 2020, Wiley-VCH.)
conjugated to iRGD (which is a tumor penetrating peptide, Dox-iRGD), CpG (a syn-
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thetic single-stranded oligodeoxynucleotide and agonist of Toll-like receptor 9) and
granulocyte-macrophage colony-stimulating factor (GM-CSF, a migratory maturation
cytokine for DCs) [4]. Dox-iRGD successfully induced ICD in a murine breast cancer
model. In combination with the other therapeutic elements of the hydrogel and systemic
immune checkpoint inhibition (ICI), in this case, antiprogrammed cell death protein
(PD)-1, this combination was able to prolong the survival of tumor-bearing mice, reduce
the number of pulmonary metastases, and prevent a postoperative recurrence. The cellular populations in the TME were found to have shifted, whereby an increase in CD8
T-cells and activated APCs (predominantly DCs and macrophages) was noted in treated
groups [4]. In a similar vein, an alginate hydrogel that gelled in situ was loaded with radiolabeled (
131
I) catalase and CpG [5]. The principles behind this system are that, upon gelation, catalase converts hydrogen peroxide found in the hypoxic TME to oxygen, thus
relieving hypoxia. The radioisotope provides localized and concentrated irradiation of
the tumor and CpG acts as an adjuvant in addition to the irradiated tumor cells. When
combined with ICI in the form of anti-cytotoxic T-lymphocyte-associated protein
(CTLA)-4, this intratumorally (IT) injected platform was able to effectively regress
established tumors and reduce metastatic burden in a murine model of breast and colon
cancer as well as a leporine tumor model. In mice, a robust antitumor response was characterized by increased infiltration of CD8
+
T-cells in the TME, a higher CD8+/Treg
ratio, and a more pronounced proinflammatory cytokine presence in the serum, particularly interferon (IFN)-γ and tumor necrosis factor (TNF)-α [5].
A common approach to utilizing PTT is the incorporation of NPs with high light
absorbance, typically inorganic materials such as gold, iron, and other metals, upconverting NPs, carbon nanotubes, graphene oxide, or small molecule dyes [6]. The heat
generated by these materials in the TME can induce ICD and other danger signals such
as heat shock proteins. However, further adjuvanticity is usually required to achieve full
tumor remediation. An innovative approach was recently outlined whereby a hydrogel
was created using CpG DNA and loaded with the stimulator of interferon genes
(STING) agonist cyclic-di-guanosine monophosphate (GMP) and finally coated with
melanin [7]. This system therefore comprised of two separate adjuvants and melanin, that
could provide heat-induced ICD upon near-infrared (NIR) irradiation. Local administration of this hydrogel, along with NIR irradiation, was found to eliminate primary
tumors with evidence of DC maturation in the tumor-draining lymph node (tdLN)
and accompanying TME changes such as increased cytotoxic T-cells and decreased
Tregs. Furthermore, cured mice that were rechallenged at a distant site were found to
reject the tumors, implying the formation of tumor-specific memory T-cells [7]. PDT
has also been successfully used in local biomaterial formulations for TME immunomodulation. A miniature type of scaffold known as a metal-organic framework
(MOF) was synthesized from a novel chlorin derivative (acting as a photosensitizer)
139Engineered devices for tumor microenvironment immune modulation
+
140 Alexander M. Cryer and Natalie Artzi
and within the cavities of the MOF was loaded an indoleamine 2,3-dioxygenase (IDO)
inhibitor. IDO is an enzyme that catalyzes the degradation of tryptophan into kynurenine
which drives the production of immunosuppressive regulatory T cells and tolerogenic
myeloid cells; inhibition of IDO is, therefore, an intriguing prospect. IT injection of
the MOF, upon irradiation, induced the generation of singlet oxygen species, resulting
in ICD, and combined with IDO inhibition led to the regression of both lateral and contralateral tumors in two models of murine colorectal cancer. This regression was accompanied by immunophenotypic changes in the TME such as increased leucocytes and both
flavors of T-cell [8].
The use of hydrogels and scaffolds to deliver specific immunomodulatory agents has
also shown to be an effective strategy to reprogram the TME. The use of a HA hydrogel
to prolong the release of a variety of therapeutic entities was found to be an effective
strategy to restrain the recurrence of tumor growth [9]. Using a surgical resection model
of orthotopic breast cancer whereby the hydrogel was placed in the resection site after
surgery, the HA hydrogel was loaded with one of the various immunotherapies; antiPD-1, anti-CTLA-4, interleukin-15 superagonist (IL-15sa), 2
030
-cyclic guanosine monophosphate adenosine monophosphate (cGAMP, a STING agonist), resiquimod (R848, a
TLR7/8 agonist), lenalidomide (immunomodulatory drug), or celecoxib (a cyclooxygenase two inhibitor). Innate immune agonists were the top performers in this preliminary
screen (assessed by reduction in tumor burden) and were found to be efficacious only when
released from the hydrogel and not as free molecules injected IT. Prolonged-release of
R848 from the hydrogel induced significant changes within the TME including
increased numbers of NK cells, activated DCs, and T-cells accompanied by transient
but profound increases in type I IFNs in the plasma, all hallmarks of an antitumor
response [9]. These findings are particularly interesting as it suggests that a large source
of tumor antigens may not be required to achieve antigen presentation and adaptive
immune response, although the optimal repertoire and amount of antigen is still
unknown. Using another surgical resection model of aggressive murine melanoma, calcium carbonate (CaCO
) NPs loaded with anti-CD47 were encapsulated within a fibrin
3
matrix that could be sprayed inside the resection site (Fig. 2). The fibrin reacts with the
fibrinogen and thrombin in the wound site to form a gel and the CaCO
acts as a proton
3
scavenger such that within the slightly acidic environment of the TME, anti-CD47 is
released. The anti-CD47 prevents CD47-signal regulatory protein (SIRP)α interactions
which promote antiphagocytic “don’t eat me” signals; therefore, blockade of this interaction enhances the phagocytic capacity of APCs such as DCs and tumor-associated macrophages (TAMs), which is beneficial for antitumor immunity. Application of the
immunotherapeutic gel to the tumor resection site reduced the population of M2 macrophages (thought of as tumor-promoting, immunosuppressive macrophages) and
increased the population of M1 macrophages (thought of as proinflammatory, antitumorigenic, and highly phagocytic). This was accompanied by greater infiltration of
141Engineered devices for tumor microenvironment immune modulation
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Fig. 2 Schematic and characterization of the in situ formed immunotherapeutic fibrin gel.
(A) Schematic showing the in situ sprayed bioresponsive fibrin gel containing aCD47@CaCO3
nanoparticles within the postsurgery tumor bed. aCD47@CaCO3 nanoparticles encapsulated in
fibrin scavenge protons in the surgical wound site and release aCD47, thus promoting both polarization of TAMs to an M1 -like phenotype and blockade o f the “don’ t eat me” signal in cancer cells.
(B) Transmission electron microscopy (TEM) image of aCD47@CaCO3 nanoparticles. Scale bar,
100 nm. Experiments were repeated three times; a representative image is shown.
(C) Representative scanning TEM images of aCD47@CaCO3 nanoparticles showing the calcium
(green),oxygen(red), and gadolinium labeled aCD47 (blue). Experiments were repeated three times.
(D) Average hydrodynamic size of aCD47@CaCO3 nano particles determined by dynamic light scat-
tering. (E and F) Representative cryoscanning electron microscope (SEM) images of fibrin gel loaded
with aCD47@CaCO3 nanoparticles. Scale bars, 1 μm. (Reproduced with permission from Wu Y, Li Q,
Shim G, Oh Y-K. Melanin-loaded CpG DNA hydrogel for modulation of tumor immune microenvironment. J Control Release 2020;330:540–53. http://doi.org/10.1016/j.jconrel.2020.12.040 (2020). Copyright
2019, Nature Publishing Group.)
142 Alexander M. Cryer and Natalie Artzi
T-cells (both CD8+and CD4+) and corresponding increases in proinflammatory cytokines in the serum, including IFN-γ, TNFα, and IL-12p70 which is the predominant
cytokine secreted by M1 macrophages. This macrophage polarization from an M2 to
M1 phenotype was partly attributable to the 50% tumor recurrence rate that was seen
using the full fibrin gel formulation compared with 100% tumor recurrence seen in all
other treatment groups [10].
Another strategy is to use a scaffold to house a source of tumor antigens and recruit
APCs to the scaffold such that they encounter antigens more effectively and can thus
mount a successful antitumor response, as a type of cancer vaccine. Mesoporous silica
microrods coated with the cationic polymer polyethylenimine (MSR-PEI) were fabricated to complex the adjuvant CpG, GM-CSF, and a pool of antigens specific for the
tumor type. The MSR vaccine was able to regress several types of tumors corresponding
with the neoantigen pool of peptides used upon inoculation. For example, vaccination of
melanoma-bearing mice was able to recruit significant populations of tumor-infiltrating
lymphocytes which were positive for IFN-γ, TNF-α, or granzyme B, all markers of
immune cell activation. This was aligned with a marked reduction in tumor growth, particularly in combination with anti-CTLA4, and upon intravenous administration of melanoma cells to mimic lung metastasis, vaccination greatly reduced the number of
metastatic foci. A similar result was witnessed in a colon cancer model and in an
E7-peptide expressing lung cancer model when the appropriate antigen pool was inoculated. Indeed, the MSR-PEI scaffold was found to promote the recruitment and activation of DCs which was theorized to aid in enhanced CTL priming and therefore
therapeutic efficacy [11].
NPs are a powerful drug delivery vehicle for a plethora of therapeutic cargo and have
been successfully used to modulate the immune component of the TME. A lipid NP
(LNP) formulation has recently been developed for IT injection of messenger RNA
(mRNA) encoding IL-23, IL-36γ, and OX-40L to relieve the immunosuppressive
TME. IL-1 family members such as IL-36γ are involved in type-1 immune responses
and it acts on professional APCs and T-cells whereas IL-12 family members such as
IL-23 act as central coordinators of the immune response by bridging innate and adaptive
immunity (for example, positively modulating innate lymphoid cells, NKT-cells, γδ
T-cells). OX-40L is the ligand for OX-40 which is a costimulatory molecule and can
enhance effector T cell function as well as their expansion and survival. This threepronged mRNA delivery strategy was found to be effective in multiple murine tumor
models such as checkpoint inhibitor-sensitive MC38-S colon adenocarcinoma tumors
and checkpoint inhibitor-refractory tumors MC38-R and B16F10-AP3 melanoma.
Interestingly, this triple mRNA combination was able to shift to TME immune environment such that ICIs were effective in the traditionally resistant models. This TME shift
was typified by both innate immune activation and lymphocyte mobilization. Specifically, increased activation of various DC subsets in the tdLN as identified by increased
CD86 expression was noted as well as upregulation of gene transcripts associated with
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immune activation such as those involved in antigen processing and costimulatory genes.
Confirming the importance of DCs in antitumor responses, mice deficient in crosspresenting DCs (Batf3
wild-type mice all rejected their tumors. Increased activated NK, CD4
/
) eventually succumbed to their tumor burden whereas
+
, and CD8+,
and γδ T-cells were observed in the tdLN and tumor, however, the antitumor response
was dependent on CD8
+
T-cells as their abrogation diminished the survival benefit seen
in wild type mice [12]. This, and a similar platform using LNPs for delivery of IL-12
mRNA [13], has reached trials in humans and is enabled by choosing the appropriate
LNP formulation to protect vulnerable mRNA from degradation but allow for effective
transfection without overt toxicity.
LNPs can also be used to deliver different varieties of nucleic acid apart from mRNA,
as illustrated by the clinical approval of LNPs for siRNA delivery. Another type of RNA,
known as self-replicating RNA (replicons) can, once introduced into the cell, produce
further copies of itself and the protein for which it encodes. Utilizing this strategy, a replicon was designed to encode for the cytokine IL-12 fused with lumican separated by an
albumin spacer which was intended to bind the collagenous ECM, which is present
within the TME. To deliver the replicons, an LNP was constructed that contained an
ionizable lipid named TT3 which, when delivering a replicon encoding green fluorescent protein (GFP), was able to induce ICD in cancer cells and activated TLR3, although
TLR activation appeared to be attributed to the replicon and not the LNP. A single IT
injection was able to induce regression of multiple murine tumor models including colon
and two melanoma variants, with a high percentage of mice in each model rejecting their
tumors. The TME was modulated such that after IT injection of LNP-replicon there was
a marked infiltration of granulocytes and CD8
+
T cells along with the notable presence of
IL-12 in the tumor, even 7 days post IT injection. Tumor rejection was found to be
dependent on cross-presenting DCs and CD8
+
T-cells as confirmed by depletion studies.
Notably, deletion of STING or the innate immune sensor myeloid differentiation primary response (MyD)88 also resulted in the loss of tumor control, suggesting inactivity
of downstream proinflammatory coordinators such as NF-κB is deleterious in this
context [14].
As with hydrogels and scaffolds, there is a diversity of materials that can be used for the
fabrication of particles to modulate the TME beyond LNPs. Biodegradable PLGA
microparticles (MPs) were designed for the pulsatile release of the STING against
cGAMP after a single IT injection (Fig. 3). Three different variants of PLGA MP were
injected together to permit the differential release of cGAMP several days apart which
was due to the composition of each type of MP, resulting in different degradation rates
and therefore cargo release. Indeed, a single injection of MPs prolonged the survival of
melanoma and breast tumor-bearing mice to the same extent as four IT injections of free
cGAMP. The TME was reprogrammed in treated mice, demonstrated by increased
143Engineered devices for tumor microenvironment immune modulation
144 Alexander M. Cryer and Natalie Artzi
Fig. 3 Design and fabrication of a PLGA-MP system for pulsatile STING agonist release. (A) Schematics
of single-injection drug delivery platform for cancer immunotherapy. Different PLGA microparticles
reside in the tumor after a single intratumoral injection, release encapsulated STING agonist in pulses
at discrete time points, and promote infiltration of TILs. (B) Schematics of the fabrication process of
PLGA-MPs, which are prepared by filling cargo of interest into particle bases and then sealing the bases
with corresponding particle caps by briefly applying heat. (C–E) Representative scanning electron
microscopy images of EP bases (C) and a sealed array of particles (D) or an individual particle (E). Scale
bars, 500 μm (C and D) and 100 μm (E). (F) Representative high-resolution x-ray CT image of a sealed
particle encapsulating 3
(G) Representative optical image of an array of sealed particles encapsulating Alexa Fluor 647-labeled
dextran. Scale bar, 1 mm. (Reproduced with permission from Lu X, et al. Engineered PLGA microparticles
for long-term, pulsatile release of STING agonist for cancer immunotherapy. Sci Transl Med 2020;12:
eaaz6606. http://doi.org/10.1126/scitranslmed.aaz6606. Copyright 2020, The Authors.)
030
-cGAMP. The red color represents dried 3030-cGAMP. Scale bar, 100 μm.
CD8+, CD4+T cells, including memory linages as well as NK cells and activated DCs.
Furthermore, the macrophage population in the TME was repolarized to a more
proinflammatory phenotype. The applicability of the system was further extended as
other therapeutic moieties such as CpG or the chemotherapy agent pemetrexed were
also shown to exhibit a pulsatile release profile [15]. IT injection of other polymeric systems containing STING agonists also demonstrated robust antitumor efficacy, including
polymersomes designed to disassemble in the endosome to release cGAMP by virtue of
protonation of specific functional groups within the polymer backbone upon endocytosis
[16]. Cationic polymers such as dendrimers [17] and poly(β-amino esters) [18] can effi-
ciently electrostatically complex with negatively charged cyclic dinucleotide (CDNs)
STING agonists such as cGAMP and upon IT injection-induced marked tumor reduction and a proinflammatory TME, due to effective transfection of CDNs and robust local
STING activation.
Taken together, local delivery of immunomodulating agents, using hydrogels, scaf-
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folds, or NPs, is a powerful tool for directly transforming the immunosuppressive environment precisely where it is needed (i.e., the tumor). The ability to control the release
kinetics of a payload or potentially target specific cellular populations (e.g., TAMs) within
the tumor are evidently potent therapeutic concepts. Indeed, controlled release of ICIs
from a Pluronic F-127 hydrogel injected ipsilaterally to the tumor improved efficacy
compared with hydrogels with ICI injected contralaterally and free antibody, which
was attributed to greater accumulation of antibody in the tdLN [19]. Depending on
the nature of the response and the cargo delivered this can even result in systemic immune
responses and induction of the abscopal effect-mediated clearance of distal tumors, a
highly desirable outcome in metastatic scenarios.
3. Transdermal delivery of engineered devices for tumor
immune modulation
The arena of transdermal delivery has typically been dominated by the use of
microneedle platforms as a means of traversing the skin in a minimally invasive and painless manner. These microneedle platforms afford controlled or stimulus-responsive
release of immunotherapeutic cargo from within the needles to the immune cell-laden
dermis, which may also be retrieved as a means of tracking the immunological state of the
treated area in real-time. Consequently, the doses required to elicit an immune response
are lessened and the responsiveness to therapy can be determined promptly. Microneedle
arrays are typically composed of a biodegradable and biocompatible polymer such as HA,
chitosan, polylactic acid, gelatin, other polymers such as polymethyl methacrylate, polycarbonate, or other materials such as silicon or stainless steel. Thus, a wide variety of
materials can be used for the synthesis of microneedle patches, and a diversity of methods
are used for their fabrication including wet or dry etching, lithography, micromolding,
and laser-based technologies [20].
Indeed, the spectrum of materials available for microneedle fabrication has generated
innovative transdermal delivery platforms for a range of immunotherapeutic cargo. HA
microneedles were loaded with acid-responsive dextran NPs containing anti-PD-1,
which could disassemble when exposed to the slightly acidic environment created by
conversion of tissue glucose to gluconic acid by glucose oxidase within the NP. In a
murine model of melanoma, a single administration of this microneedle patch was able
to induce a robust immune response and significantly extend the lifespan of the mice,
compared with nonresponsive NPs and intratumoral injection of anti-PD-1, suggesting
effective activation of the local immune environment [21]. Similarly, HA microneedles
were used to deliver pH-sensitive acetal-modified dextran NPs containing anti-CTLA-4
and the photosensitizer zinc phthalocyanine. In a murine model of breast cancer known
to be poorly immunogenic and resistant to ICI, laser-irradiation of microneedles induced
145Engineered devices for tumor microenvironment immune modulation
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