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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5346_Библиотеки_им_академика_М_И_Перельмана
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64 Khushbu Bhatt et al.
costimulatory signals [9]. The nature of costimulatory cues and the inflammatory context
results in the priming of effector T-cell responses or leads to tolerogenic responses [10].The
priming of effector T cells induces their activation, proliferation, and subsequently their
migration to the tumor microenvironment (TME). Upon activation, CD8+ T cells are
differentiated into cytotoxic T lymphocytes (CTLs) [9]. CTLs trigger the cytotoxicity process by recognizing the antigen-MHC complex on the tumor cell surface and releasing
cytotoxic granules containing perforin and granzyme [11]. This mechanism leads to the
destruction of tumor cells [11]. Whereas CD4+ T cells, upon their activation and differentiation into helper T cells, secrete proinflammatory cytokines. This process promotes
T-cell priming and activation as well as the activity of NK cells and CTLs [12–14].Additionally, CD4+ T cells help in generating CTL memory responses [15].Despitethepresence of antitumor immune responses, tumor cells evade CTL-mediated destruction by
creating an immunosuppressive environment [16,17]. In the TME, tumor cells and immu-
nosuppressive cells such as regulatory T cells (Tregs), tumor-associated macrophages
(TAMs), and myeloid-derived suppressor cells (MDSCs), secrete inhibitory molecules
which further impair DC recruitment and T-cell function [16,17]. Tumor cells induce
T-cell suppression by upregulating ligands for multiple inhibitory receptors such as
CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) and PD-1 (programmed cell death
protein 1) to induce T-cell dysfunction and facilitate tumor growth and invasion [18].
Cancer immunotherapy modulates immune cell function to explicitly target tumor
cells. ICIs such as anti-CTLA-4 and anti-PD-1, which block the inhibitory receptors
on T cells, have demonstrated remarkable efficacy in various cancers [19]. However,
despite promising clinical results, only a small subset of patients (20%–30%) respond favorably to this therapy, likely due to tumor heterogeneity and overlapping mechanisms of
immunosuppression [17,20,21]. Furthermore, ICIs have been associated with unwanted
side effects, such as cardiotoxicity, hepatitis, diarrhea, endocrine dysfunction, and autoimmune disorders [19,22,23]. Adoptive cell-based therapies, another form of immunotherapy, have been used to increase the number of tumor-specific CTLs by ex vivo expansion of
autologous T cells. Currently, three types of adoptive therapies for T cells are being developed: (i) tumor-infiltrating lymphocytes (TILs), (ii) T cells genetically modified with highaffinity T-cell receptors (TCRs), and (iii) T cells modified with chimeric antigen receptors
(CAR) against tumor cell-surface antigens [23]. However, in addition to high cost and
lengthy processing times, adoptive T-cell therapy is marred by severe adverse reactions,
including cytokine release syndrome, neurotoxicity, and disease relapse with antigennegative tumor cells [24–27]. Furthermore, many challenges prevail for solid tumors, most
likely due to the hypoxic stress exerted by the TME, leading to tumor progression, metastasis, treatment failure, and escape from immunosurveillance [28]. Another form of adop-
tive transfer therapy uses DCs that are loaded with antigen and transferred back into the
patients [29]. Likewise, DC-based cancer vaccines consisting of peptides, whole cells,
or tumor cell lysate in combination with adjuvants have been investigated clinically.
However, these approaches have shown limited therapeutic efficacy in patients with
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advanced malignancies [30]. Additionally, proinflammatory cytokines such as
granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2),
interleukin-12 (IL-12), interleukin-15 (IL-15), and interleukin-21 (IL-21) have been
employed for inducing DC maturation and proliferation, as well as for expansion and
survival of natural killer (NK) cells and CTLs [31–33]. However, the systemic administration of these cytokines requires multiple high doses to induce potent antitumor efficacy,
which is often associated with systemic toxicities [31–33].
Despite the promising clinical outcome of cancer immunotherapies when administered systemically, many challenges persist, such as off-target toxicity and inadequate
response in “cold” tumors, limiting their therapeutic benefit. Therefore, methods that
deliver immunomodulators locally in the TME alongside platforms to combine various
immunostimulatory molecules are needed to reverse local immunosuppression and trigger robust anticancer immune responses. The use of biomaterials is an excellent strategy
to address this issue either by delivering the immunomodulatory cargo to a targeted location or by locally releasing drugs/bioactive molecules at the tumor site thereby circumventing side effects associated with systemic exposure. However, it is technically
challenging to target tumors that are accessible only by invasive surgeries [34] . To address
these shortcomings, approaches to prime antitumor responses in peripheral tissues are
warranted as antitumor T cells activated in the peripheral lymphoid organs can traffic
throughout the body and reach distant tumor sites [34]. Therefore, it is essential to
effectively deliver tumor antigens and immunomodulatory factors to the peripheral
tissue-resident DCs and lymph node-resident DCs [34]. For this purpose, the use of biomaterials such as nanoparticles is a viable strategy since they can facilitate the controlled
delivery of stimulatory cues to DCs in the periphery and tumor-draining lymph nodes
[34]. However, while nanoparticles can be taken up by the phagocytic cells in the periph-
ery, only DCs can mount an effective antitumor response. Since more macrophages than
DCs are found in the peripheral tissues, priming robust antitumor immune responses by
targeting peripheral DCs is challenging [35]. As a result, the use of biocompatible scaffolds
in the form of injectable or in situ-gelling matrices is an attractive strategy to recruit DCs
while delivering tumor antigens and immunostimulatory cues, thereby maximizing the
number of activated DCs and downstream T-cell priming [34].
Novel polymeric scaffold-based approaches can thereby overcome the limitations of
current therapies while enhancing patient safety and improving clinical outcomes. Polymeric scaffolds can be engineered to target specific cell types and act as a delivery vehicle
protecting their cargo while controlling the in vivo release and pharmacokinetic profile of
immunotherapeutic drugs. Multiple immunomodulatory factors such as antigens, adjuvants, and cytokines can be encapsulated in a single scaffold system for a synergistic combinatorial approach to mitigate cancer. Principles of biomaterial science, tissue
engineering, drug delivery, and cell biology can be employed to design a suitable scaffold
65Polymeric scaffolds for antitumor immune cell priming
66 Khushbu Bhatt et al.
system to attract and host immune cells, as well as to promote cell–cell interaction, cell
activation, and cell expansion. Polymeric scaffolds have the potential to offer localized,
targeted, and controlled drug delivery, minimizing multiple high-dose related toxicities
and enhancing efficacy compared to systemic therapeutics.
This chapter offers a comprehensive summary of the polymeric scaffold systems
explored for priming key immune cells and consolidating adaptive immune responses
against cancer. First, we describe different types of polymers and scaffold systems that have
been investigated. Next, we discuss the current efforts to leverage these biomaterials for
priming specifically DCs and T cells. Finally, we highlight the challenges and future perspectives of these unique biomaterials for cancer immunotherapy and their potential clinical translation.
2. Polymeric materials and scaffold systems
Polymeric scaffolds are three-dimensional (3-D) matrices fabricated using natural
or synthetic polymers [36–38]. They can be used to stimulate cell–biomaterial or cell-cell
interaction, serve as a vehicle to deliver biomolecules and promote cell recruitment, survival, and proliferation while exhibiting minimum toxicity [39,40]. To determine the
suitability of polymeric scaffolds to prime immune cells, various considerations must
be taken into account [41,42]. The foremost criterion for any scaffold is that it needs
to be biocompatible and must not induce any severe inflammatory reactions or cause
the body to reject it. In scenarios where scaffolds are not designed to be permanent
implants, they must be biodegradable, and their degradation products should be nontoxic
[43–45]. However, in certain cases, scaffolds are specifically fabricated to be
nonbiodegradable—for permanent implants or when they are intended to be explanted
after the desired therapeutic effect. Polymeric scaffolds should exhibit high porosity and
an interconnected pore network to facilitate cell penetration and survival as well as adequate diffusion and delivery of nutrients, oxygen, and biomolecules [46–48]. The pore
size should be large enough to allow cell infiltration into the scaffold. At the same time,
pores should be small enough to create a high specific surface area while allowing sufficient ligand density for optimal cell binding to the scaffold. Typically, the mechanical
properties of the scaffold should be consistent with the physiological location in which
it is implanted. The scaffold must be mechanically resilient to facilitate surgical handling
during the injection or implantation [41,42]. Generally, the mechanical properties and
pore size of the scaffold are inversely related to each other. Therefore, it is essential to
maintain a balance between the porosity and the mechanical properties of the polymer
scaffold for the desired application [41,42]. The scaffold surface is the primary site where
surrounding cells and tissues interact with the scaffold. Surfaces can be functionalized
with cell-adhesive peptides (e.g., Arg-Gly-Asp or RGD) and proteins such as collagen
and fibronectin to increase scaffold integration and improve hosting of cells [41,42].
To ensure successful clinical translation, the polymeric scaffold should be cost-effective
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and scalable from laboratory-scale to large-scale good manufacturing practice (GMP)
grade production. Furthermore, off-the-shelf availability is preferred for ease of administration by clinicians.
The choice of polymer for fabricating the scaffold is the final criterion on which most
of the above factors are dependent. Polymers used for scaffold systems can be broadly
classified into natural and synthetic, biodegradable and nonbiodegradable, injectable,
and surgically implantable [40,49,50]. Most of the natural polymers are biodegradable
whereas synthetic polymers can be either biodegradable or nonbiodegradable [40].
The choice of polymers is governed by various features such as functional groups, biological and mechanical properties, degradation rate, biocompatibility, and immunogenicity [42,51].
Naturally derived polymers are foremost in the category of biodegradable materials
used in a clinical setting and have, therefore, been explored extensively [52]. They are
further characterized into three types: (i) proteins such as collagen, gelatin, keratin, actin,
myosin, fibrinogen, and silk; (ii) polysaccharides such as hyaluronic acid (HA), dextran,
glycosaminoglycans, cellulose, chitin, alginate, and amylose; and (iii) nucleic acids, such
as DNA and RNA (Table 1) [40,50]. Since most natural polymers are bioactive and biocompatible, they provide enhanced cellular interactions with minimal inflammatory
responses compared to synthetic polymers [49,50,52,53]. Other features of natural polymers include natural remodeling, cell adhesion, low protein-adsorptive properties, and
susceptibility to enzymatic and hydrolytic degradation [49,50,52,53]. However, the rate
of degradation is dependent on the implantation site and the availability of suitable
enzymes at necessary concentrations. Additionally, the chemical modification of polymers can significantly change the rate of degradation [49,50,52,53]. Although widely
used, naturally derived polymers have many disadvantages, including complex purification protocols, batch-to-batch variations, the potential for disease transmission, and
impurity-mediated stimulation of undesired immune reactions. Despite these challenges,
their ability to stimulate specific cellular responses might supersede the benefits of synthetic polymers and play an important role in polymer selection [49,50,52,53].
On the other hand, synthetic polymers are devoid of many shortcomings of natural
polymers. They are biologically inert and can be produced with batch-to-batch uniformity, leading to more predictable properties [52]. Furthermore, they are relatively pliable in terms of mechanical and structural design, allowing their properties to be tailored
to specific applications [51]. The physical properties of synthetic polymeric scaffolds, such
as their degradation rates and mechanical properties are predictable and reproducible.
Since these polymers are often cheaper than their natural counterparts, they can be produced in bulk quantities with consistency and longer shelf life [40]. However, synthetic
polymers possess several major drawbacks, including poor cell-material interactions and
host inflammatory responses, increasing the risk of implant failure [42,53].
67Polymeric scaffolds for antitumor immune cell priming
Table 1 Characteristics of natural polymers [50,52–55].
Type Polymer Properties Advantages Disadvantages
Proteins Collagen Important extracellular matrix
(ECM) protein, binds to
integrin receptors on cells, role
in natural wound healing,
enzymatically degraded by
collagenases/
metalloproteinases.
Gelatin Obtained from hydrolysis of
collagen.
Fibrin Complex network formed by
polymerization of fibrinogen in
the presence of thrombin,
presence of several ECM
proteins like fibronectin.
Silk Produced by silkworms, contains
70%–80% fibroin (a fibrous
protein comprising the core of
silk) and
20%–30% sericin (adhesive
protein).
Polysaccharides Hyaluronic
acid
(HA)
Native component of ECM, binds
to cell surface receptor CD44,
enzymatically degraded by
hyaluronidase.
Cellulose Derived from plants and bacteria. Low manufacturing costs.
Biocompatible, good cell
recognition, naturally celladhesive.
Biocompatible, slow degradation,
excellent mechanical
properties.
Biocompatible, bioadhesive,
biofunctional, biodegradable,
injectable.
Biocompatible, induce improved
cellular interaction, adjustable
degradation, robust mechanical
performance.
Modulates inflammatory
response, unique viscoelastic
properties, injectable.
Poor physicochemical and
mechanical properties, mild
immunogenicity, high cost of
pure collagen, risk of infectious
disease transmission with
bovine collagen.
Susceptible to temperature
changes.
Lengthy procedure to cleanse
secondary toxic protein,
sericin, which mediates
macrophage response.
Nonadhesive.
Chitosan Derived from partial deacetylation
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of chitin found in crustacean
exoskeletons, insects and fungal
cell walls. Inherently insoluble
at physiological pH but can be
solubilized with glycerol
phosphate. Can undergo
temperature-controlled phase
transition in the presence of
phosphate salts.
Alginate Originates from seaweed,
structurally similar to natural
glycosaminoglycans. Its
inherent hydrophilicity and
chemical functionalities permit
in-solution electrostatic
crosslinking to form macroscale
scaffolds without covalent
crosslinking.
Agarose Obtained from seaweed,
resemblance to ECM.
Biocompatible, biodegradable,
nontoxic, ability to condense
DNA to form complexes,
injectable, naturally celladhesive, can be used to form
thermosensitive scaffold.
Biocompatible, low
immunogenicity, low
manufacturing costs, nontoxic,
suitable for cell encapsulation
and controlled drug release.
High water uptake capability,
suitable for cell encapsulation
and controlled/localized drug
delivery.
Minimal inflammatory response,
stimulatory properties on
macrophages, chemoattractive
properties on neutrophils.
Nonbiodegradable but its
degradability can be modified,
nonadhesive cell properties.
70 Khushbu Bhatt et al.
Synthetic polymers can be either biodegradable or nonbiodegradable. Commonly
used biodegradable synthetic polymers can be further classified according to their chemical compositions: (i) Polyesters—(i
) poly(α-hydroxy acids) such as poly(glycolic acid)
1
(PGA), poly(lactic acid) (PLA) and their copolymer poly(lactic-co-glycolic acid)
(PLGA), (i
) Polylactones such as poly(caprolactone) (PCL), (i3) Poly(propylene fuma-
2
rates) (PPF); (ii) Polyanhydrides; and (iii) Polyphosphazenes [40,42,50,52,53,56].
Whereas, examples of nonbiodegradable polymers include poly(vinyl alcohol) (PVA),
poly(ethylene glycol) (PEG), ethyl vinyl acetate (EVA), polyisocyanate,
poly(hydroxyalkyl methacrylate) (PHAM), poly(ether ether ketone) (PEEK), poly(Nisopropylacrylamide) (PNIPAAm), poly(acrylonitrile-co-vinyl chloride) (PAN/PVC),
poly(acrylic acid) (PAA), and poly(2-hydroxyethyl methacrylate) (PHEMA) (Table 2)
[40,42,50,53,56].
Nondegradable or biostable polymers are of particular interest for encapsulation,
where their cargo is intended to be protected from the host immune system using a physical membrane [50]. Polymeric membranes are designed to allow the passive diffusion of
therapeutics, oxygen, nutrients, and waste products but not larger immunoglobulins [50].
For instance, transplanted immune cells can produce the relevant biomolecules for
extended time while being protected from host immune responses [50]. This can counter
the limitations of traditional protein delivery, including the need of administering multiple doses [50]. Additionally, biostable polymers are employed in a matrix-like system for
sustained drug delivery applications [54]. In this case, the drug is uniformly dispersed in
the polymer matrix and the release is governed by Fickian diffusion, thus providing a slow
drug release [54]. Certain challenges remain, such as efficient cell encapsulation,
maintaining long-term cell viability and function, and avoiding immunological rejection
to the implanted biomaterial itself [50]. Another limitation is their long-term persistence
in the body or the need to be chemically modified to ensure their clearance [56]. Examples of nondegradable polymers include PAN/PVC, PVA, PHEMA, and PAA [50].
Whereas, PNIPAAm is a smart polymer that has been exploited for designing thermally
responsive scaffolds and drug delivery systems [50]. PEG is another nondegradable, nonionic, and minimally immunogenic polymer used for scaffold formation [41,58,59].Itis
highly hydrophilic, exhibits excellent solubility properties and allows limited cell adhesion. Due to its protein-repellant feature, it can be utilized as an inert background that can
be modified to include specific biological cues [56].
Polymeric scaffolds can also be described as surgically implantable or injectable.
Implantable scaffolds are biomaterials that can be preloaded with desired therapeutic biomolecules, and even cells, prior to insertion via a surgical procedure in a resected tissue or
subcutaneous space [49]. Bioactive molecules can then be controllably released from the
implanted porous polymeric scaffold to recruit immune cells, thus acting as durable
depots [60,61]. This supports antigen presentation and regulates immune cell trafficking
and programming. However, implantable polymeric constructs have certain
Table 2 Characteristics of synthetic polymers [41,50,52–57].
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Type Polymer Properties Advantages Disadvantages
Polyesters Poly(α-hydroxy acids) such as Hydrophobic and lack of
cellular interaction.
Poly(lactic acid) (PLA) Hydrophobic polyester
formed from
polymerization of
L-lactide obtained from
starch.
Biocompatible,
biodegradable, can be
fabricated as injectable
polymer.
Slow degradation rate (few
months), degrades into
highly crystalline
L-isomer of lactic acid,
which induces
inflammatory reactions.
PLA is obtained as a
combination of
L- and D-
isoforms which lacks
crystallinity and is
degraded more rapidly
with better
biocompatibility.
Poly(glycolic acid) (PGA) Highly crystalline and rigid
polymer.
Biocompatible,
biodegradable, strong
mechanical properties.
Completely degraded
within several months in
vivo into glycine which is
excreted in the urine or
is converted into water
and carbon dioxide
). Hydrolytic
(CO
2
degradation of both
PGA and PLA produces
, which lowers the
CO
2
pH and leads to tissue
necrosis.
Continued
Table 2 Characteristics of synthetic polymers [41,50,52–57]—cont’d
Type Polymer Properties Advantages Disadvantages
Poly(lactic-co-glycolic acid)
(PLGA)
Copolymer of PLA and
PGA polyesters. Higher
ratio of PLA increases
the solubility whereas
increasing the ratio of
PGA escalates the
degradation rate.
Biocompatible, FDA
approved, faster and
controllable degradation
rate, can be customized
with surface
modifications, produces
large pores that can be
utilized for loading
biomolecules and cells,
strong mechanical
properties.
Polylactones such as
Polycaprolactone (PCL) Bioresorbable, semi-
crystalline polyester,
superior blend
compatibility and
solubility characteristics,
hydrophobic.
FDA approved,
biocompatible,
biodegradable, elastic,
high drug permeability,
produces less acidic
degradation products,
low cost.
Poly(propylene fumarates)
(PPF)
Linear polyester, used to
increase the
Biodegradable, injectable,
high strength.
hydrophobicity of PLA,
PGA, PCL.
Polyanhydrides Low hydrolytic stability Biocompatible, degrades
rapidly by surface
erosion, suitable for
short-term controlled
delivery system.
Polyphosphazenes Inorganic-organic hybrid
polymer
Structural adaptability,
control over degradation
and crystallinity.
Acidity of its byproducts
when produced in large
quantities hampers rapid
metabolization in the
body. This can be
addressed by using
higher PGA content to
simultaneously decrease
the degradation rate and
the production of acidic
byproducts.
Hydrophobic, low cell-
adhesion properties, not
suitable for short-term
delivery applications due
to its extremely slow
degradation rate
(2–4 years).
Nonadhesive
Poly (vinyl alcohol) (PVA) Water-soluble, forms
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crystallizing hydrogels.
Poly (ethylene glycol) (PEG) Nonionic polymer,
extremely hydrophilic,
excellent solubility,
optimal
physicochemical and
biological properties.
Poly(N-isopropylacrylamide)
(PNIPAAm)
Poly(2-hydroxyethyl
methacrylate) (PHEMA)
Poly(ethylene-vinyl-acetate)
(PEVA)
Undergoes sol-gel
transition with
increasing temperatures.
Combination of
hydrophilic amide and
hydrophobic isopropyl
groups imparts
temperature-responsive
properties.
Thermoplastic copolymer
of ethylene and vinyl
acetate (VA). VA
content influences
stiffness, crystallinity and
melting point.
Biocompatible, nontoxic,
FDA approved, higher
elasticity, swelling
properties, bioadhesive.
Biocompatible, minimally
immunogenic.
Thermally reversible
Biocompatible, high
stability upon
implantation, soft,
tunable mechanical
properties.
FDA approved,
biocompatible, drug
release profile can be
tailored by changing the
vinyl acetate/ethylene
ratio.
Nonbiodegradable,
reduced protein binding
tendency.
Nonbiodegradable,
protein-repellant,
limited cell adhesion that
can be modified with
cell-adhesive peptides.
Nonbiodegradable
Nonbiodegradable
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