Nanoparticle Interaction With Immune Cells for Nanoparticle-Mediated (Anticancer) Immunotherapy

3 Nanoparticle Interaction With Immune Cells for NanoparticleMediated (Anticancer) Immunotherapy Per Hydbring1, Juan Du2 1

D E P AR T MEN T O F O NC O L O GY AN D PA T HO L OGY, VISIONSGATAN 4 , K AROLINSKA INS TIT UT ET , S -17 16 4 ST OCK HOLM , SW EDEN 2 DEPARTMENT OF MICROBIOLOGY, TUMOR AND CELL BIOLOGY, CENT RE FOR TRANSLATIONAL MICROBIOME R ESEARCH (CTMR ), VISIONSGATAN 4, KAROLINSKA I NSTITUT ET , S -17 16 4 STO CK HOLM, SW EDEN

3.1 Introduction 3.1.1 Nanoparticles Nanoparticles are vesicular-like vehicles with a diameter of less than 1 μm. Their properties include systemic stability, target site specificity, and level of solubility. These properties are mainly affected by the molecular structure of the vehicle surface along with the size and shape of the particle, which can all be modified through customized synthetic chemistry [1,2], providing a vast number of possible downstream biological approaches [1,2]. The field of nanoparticles has been thoroughly summarized in numerous review articles [3,4]. However, nanoparticles have not until recently been extensively exploited for their ability to tune the response output of immune cells. Before going deeper into the various examples of immune cell targeting by nanoparticles, it is important to briefly introduce the different classes of nanoparticles. While many nanoparticles used for therapeutic applications are synthetic, there are also naturally formed nanoparticles used for such purposes. The main classes of therapeutic nanoparticles are: liposomal nanoparticles, dendritic nanoparticles, metal-based nanoparticles, silica-based nanoparticles, and carbon-based nanoparticles (Fig. 3 1). The surface properties (e.g., charge and solubility) along with the particle size determine target specificity and efficiency (Fig. 3 2). Liposomal nanoparticles are popular for the delivery of nucleic acid material since their properties protect the negatively charged DNA while allowing for cellular uptake. The major drawback with liposomal nanoparticles is their limited systemic stability. Hence, a liposomal nanoparticle may be an excellent choice for a particular cell type but a poor choice for another. Dendritic nanoparticles are readily Theranostic Bionanomaterials. DOI: https://doi.org/10.1016/B978-0-12-815341-3.00003-1 © 2019 Elsevier Inc. All rights reserved.

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FIGURE 3–1 Schematic representation of the main classes of nanoparticles [5]. Reprinted/adapted by permission from the Royal Society of Chemistry: Elsevier. Theranostic Bionanomaterials by Juan Du and Per Hydbring. Elsevier Ltd. All rights reserved. 2018.

FIGURE 3–2 Nanoparticle properties and impact on the immune system [6]. Reprinted/adapted by permission from Springer Nature: Elsevier. Theranostic Bionanomaterials by Juan Du and Per Hydbring. Elsevier Ltd. All rights reserved. 2018.

used for encapsulation of drugs due to basic preparation protocols. However, dendritic nanoparticles generally possess low solubility in water with concomitant toxicity, requiring customized modifications. Another popular nanoparticle class is metal-based nanoparticles. Synthesis of metal-based nanoparticles is straightforward and easily customized. However, as with dendritic nanoparticles, toxicity is a major concern, although for distinct reasons. Metal-based nanoparticles may penetrate the cell nucleus and have been associated with reports of increased oxidative stress. Silica-based nanoparticles can be used for a large

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variety of cargo encapsulations. They are overall considered to possess low toxicity and high stability, but as with most nanoparticle classes, toxicity is highly influenced by particle size and surface charge. Carbon-based nanoparticles are hydrophobic particles that cannot be employed unmodified due to insolubility. Following surface modification they can be used for carrying a variety of cargoes. Overall, the degree of surface modification will dictate the stability and biodistribution of carbon-based nanoparticles, making it difficult to compare them in generalized terms to other classes of nanoparticles. However, if properly functionalized they are considered to possess high delivery efficacy with limited toxicity [6]. The biological repertoire of nanoparticles used to target the immune system includes not only the transportation of modulating agents but also vaccination therapies. Further, while this chapter focuses on cancer, there are various other diseases investigated for immunomodulatory nanoparticles [7 11]. A range of physical properties, including elasticity, density, shape, charge, size, and surface functionalization of nanoparticles dictate their efficacy for cellular internalization, vascular transportation as well as impact on the immune system, and they have been extensively described elsewhere [12]. In this chapter, we focus on the biological output resulting from the interaction between nanoparticles and the immune system.

3.1.2 Innate Immune System What is the best biological approach to target immune cells for anticancer therapy? This depends on the particular cancer disease, the genetic/epigenetic landscape of immune system components in that cancer, and whether the cancer has developed any addiction to that landscape signature. Further, it is unlikely that modulation of any immune system component is equally efficient for a particular cancer. Therefore, in order to tailor a nanoparticle immune system therapy, we first have to understand the biological basis of the immune system. Using a very crude categorization, the immune system consists of innate immunity and adaptive immunity. While the innate immunity responds very rapidly to intruding molecules, its response is rather nonspecific. It commences when innate immune cells utilize, among other receptors, pattern recognition receptors (PRRs) to bind pathogenassociated molecular pattern (PAMP) molecules [13,14], initiating a signaling cascade leading to substantial gene expression alterations with the output of altered secretion of chemokines and cytokines. Such secretion attracts specific immune cells belonging to the innate immune system, including neutrophils, macrophages, and natural killer cells, leading to elimination of pathogens [13,14]. In contrast, adaptive immunity executes a slower but more focused response initiating from the innate immunity or from specific exhibition of antigens. The exhibition of antigens is facilitated by so-called major histocompatibility complex (MHC) molecules. MHC molecules are presented on macrophages and dendritic cells (DCs) but not on other immune cells. A common name for cells harboring the ability to present antigens is antigen-presenting cells (APCs) [15 17]. Although nanoparticle therapy can be tailored in a way that specific immune components are targeted, it is crucial to remember that a change in an individual immune component may completely alter immune system pathway signaling since components of the innate and adaptive immunity are closely connected.

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For example, in addition to their role as APCs, DCs express receptors of importance for innate immunity as well. Therefore, they possess the biological properties to connect innate immunity with adaptive immunity [15 17]. In order to trigger a response of the innate immune system, nanoparticles are often engulfed by APCs. Through their PRRs [e.g., C-type lectin receptors (CLRs), Toll-like receptors (TLRs), RIG-I-like receptors, NOD-like receptors (NLRs)], macrophages and DCs interact with a variety of PAMPs [15 17]. Nanoparticle targeting of APCs usually involves specific targeting of TLRs, although a limited number of studies have investigated targeting of NLRs and CLRs as well. As for TLRs, nanoparticles may interact with both intracellular receptors and surface receptors (Fig. 3 3). No matter which specific TLR, the output will be a significant immune system boost, resulting in activation of the innate immune system [19 21].

FIGURE 3–3 Schematics of nanoparticle uptake by APCs, and induction of innate immunity. APCs including DCs express PRRs, for example, TLR, NLRs, RLRs, and CLRs, which are localized either at the plasma membrane or intracellularly. PRRs, which recognize PAMP molecules, can be targeted by nanoparticles. The activation of PRRs recruits adaptors and ligands to trigger downstream signaling. This results in release of inflammatory cytokines and activation of additional cells belonging to innate immunity [18]. APCs, Antigen-presenting cells; CLRs, C-type lectin receptors; DCs, dendritic cells; NLRs, NOD-like receptors; PAMP, pathogen-associated molecular pattern; PRRs, pattern recognition receptors; RLRs, RIG-I-like receptors; TLR, Toll-like receptors. Reprinted/adapted by permission from Elservier: Elsevier. Theranostic Bionanomaterials by Juan Du and Per Hydbring. Elsevier Ltd. All rights reserved. 2018.

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3.1.3 Adaptive Immune System As previously mentioned, the adaptive immune system executes slower but more specific responses to foreign substances. The adaptive immune system consists of specialized lymphocytes called B and T cells. Activated B cells, so called plasma cells, produce highly specific antibodies binding to foreign antigens. Activated T cells recognize these antigens after engulfment by APCs and exhibition through MHCs. There are numerous subgroups of T cells with the most dominant being CD8 1 T cells and CD4 1 T cells executing distinct responses to external stimuli, partly due to their activation of the T cell receptor (TCR) by different types of MHCs. CD8 1 T cells are activated by MHC-I molecules while CD4 1 T cells are activated by MHC-II molecules. For a successful nanoparticle therapeutic approach, it is necessary to understand the nature of these adaptive immune cells [15 17]. As mentioned above, activated B cells are the main producers of antibodies, which in turn bind antigens and are taken up by APCs. Antibodies, or immunoglobulins (Ig), are divided into five major classes; IgA, D, E, G, M, each possessing an enormously extensive antigen recognition repertoire [15 17]. Through this antibody library, B cells communicate with T cells. CD8 1 T cells, also referred to as cytotoxic T cells, are activated through direct antigen presentation by unhealthy cells, including cancer cells [15 17]. For the utilization of nanoparticles in anticancer therapeutics, many investigations involve modulation of the responses of the T cells [22], T cells migrate to the site of the tumor [23], specific activation of T cells [24], as well as help nanoparticles alter the proportion of T cell subtypes [25,26]. The antitumor immune response of CD4 1 T cells is greatly influenced by their cytokines and the activation of CD4 1 T cell membrane receptors [27]. As shown in Fig. 3 4, naïve T cells can be differentiated into large subsets of CD4 1 T cells. T helper 1 (Th1) and T helper 2 (Th2) cells produce IFN-γ and interleukin (IL)-4, which keep the balance in the microenvironment of cellular and humoral immunity responses for the clearance of cancer cells [28]. Regulatory T cells (Treg), on the other hand, are considered as powerful inhibitors of antitumor immunity response by IL-10 and TGF-β1 secretion. These cytokines block the activation of DC cells and the antitumor responses from effector T cells such as Th1 and Th2 [29,30]. Strategies in immunotherapy have been investigated for modulation of Treg cells [31]. Again, modulation of the adaptive immune system by nanoparticles may either occur through direct nanoparticle uptake to a specialized cell type, or through a nonspecific APC uptake. In order for an effect to be limited to a specific cell type, the nanoparticle targeting would need to happen further down the immune system cascade, for example, to activated T cells, and would require protein adaptors highly specific for that cell type conjugated on the nanoparticle shell [15 17]. In summary, the immune system can be targeted by nanoparticles either in a nonspecific or highly specific way. The end output is that all approaches somehow enhance the responses of activated T cells. The chemistry of the nanoparticle is essential for the level of specificity and efficacy in any immune system targeting approach.

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FIGURE 3–4 Schematics of nanoparticle-mediated activation of adaptive immunity. Nanoparticles activate the maturation of T cells and B cells either indirectly, through uptake by APCs, or directly, by targeting surface receptors on T cells and B cells. Activation of adaptive immune cells requires the antigens to be presented through MHC molecules. After maturation, both T cells and B cells differentiate into multiple subpopulations, including memory cells, which are essential for long-term immune responses. In addition, B cells differentiate into plasma cells, which generate antigen-specific antibodies used to neutralize foreign substances. Differentiation of T cells, particularly CD4 1 T cells, is dictated by various stimulation signals including cytokines. Subpopulations of CD4 1 T cells are distinguished based on expression levels of surface protein markers, and on the identity of secreted cytokines. Differentiated T cells cooperate with other immune cells to either promote or suppress adaptive immune responses [18]. APCs, Antigen-presenting cells; MHC, major histocompatibility complex. Reprinted/adapted by permission from Elservier: Elsevier. Theranostic Bionanomaterials by Juan Du and Per Hydbring. Elsevier Ltd. All rights reserved. 2018.

3.1.4 Immunotherapy The main current immunotherapy approaches cover cancer vaccines, and various antibodies including checkpoint inhibitors. Examples of biological material used for cancer vaccine strategies are cancer proteins, dead tumor cells, pulsed DCs, and viral proteins. The majority of cancer vaccine strategies include tumor-derived antigens or adjuvants to promote the proliferation and activation of cytotoxic T cells. FDA approval has already been accomplished for the CTLA-4 antibody ipilimumab as well as for PD-1/PD-L1 antibodies, also referred to as checkpoint inhibitors. Tumor cells often display an elevated expression of PD-L1, which through its binding to the receptor PD-1 on T cells, suppresses the reactivity of T cells against tumor cells. Checkpoint inhibitors act by blocking this ligand to receptor interaction and thereby maintaining T cell activity. In addition, there are a number of alternative ways to promote the activity of the immune

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system in cancer patients, including isolation and expansion of tumor-infiltrating lymphocytes, gene transfer of the TCR and chimeric antigen receptor-expressing T cells (CAR-T). In addition to the checkpoint inhibitors, various antibodies have been used for immunotherapy including Rituximab, a CD20 antibody, and Trastuzumab (Herceptin), targeting the tyrosine kinase receptor Her2 [32,33].

3.1.5 Nanoparticles as Anticancer Drug-Delivery System Recently, there have been numerous reports of the utilization of nanoparticles as vehicles of drug delivery to tumors. However, the effect on the immune system is often neglected by the use of immune-compromised mouse models. Therefore, in order to truly assess the potential of using various nanoparticle systems for drug delivery, it is of absolute essence to use experimental models with integrated immune system components. Drug delivery to DCs: Zheng et al., who encapsulated the DNA-intercalating drug doxorubicin within silica nanoparticles, demonstrated an interesting example of such. The doxorubicin-formulated nanoparticles were subsequently used for assessment of maturation of DCs, release of cytokines, as well as of target delivery effect on triple-negative breast cancers. Nanoparticle-encapsulated doxorubicin improved delivery to the tumors along with increased cytokine release and elevated DC maturation [34]. An important follow up to this study would be a direct comparison of the antitumor effects comparing nanoparticleencapsulated cytostatic drugs with nanoparticles lacking the anticancer agent, or nanoparticles conjugated with immune cell targeted agents, especially since a variety of recent studies have only looked at the latter. Such studies include the investigation of anticancer effects as well as stimulatory effects on DCs from DC ligand DEC205 tagged polymeric nanoparticles [35], and the stimulatory effects on DCs from coating of CD40-targeting antibodies on nanoparticles [36]. Antigen delivery to DCs: A number of recent reports describe various nanoparticle systems utilized as antigen-delivering systems to immune system components, including DCs. Tu et al. reported on a system where microneedle arrays were coated with ovalbuminencapsulated silica nanoparticles for intradermal delivery [37]. Purwada et al. described a nanogel system able to self-assemble in the presence of protein. Once taken up by DCs, the nanogel released the formulated protein (e.g., ovalbumin, fibronectin, BSA) for DC processing and exhibition to T cells [38]. Other nanoparticle systems tested for DC delivery include aluminum nanoparticles and lipid nanoparticles. In particular when modified with polyethyleneimine, aluminum hydroxide nanoparticles display limited toxicity and high DC cytoplasm delivery efficacy, resulting in substantial tumor growth reduction and prolonged survival when tested in mouse tumor models [39]. An interesting example of a lipid nanoparticle system is the YSK lipid developed by the laboratory of Hideyoshi Harashima. The lipid was first optimized for delivery of different molecules, including cyclic-di-GMP, alpha-galactosylceramide, and siRNAs into various human immune cell lines, where it displayed superiority in comparison to RNAiMAX, mainly due to differences in levels of particle aggregation. The laboratory later tested the system for delivery to DCs in a mouse

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lymphoma model and siRNA-mediated silencing of the suppressor of cytokine signaling 1, resulting in a significant increase in cytokine expression with concomitant reduction of tumor growth [40 42]. Enhance immunity through targeting of TLRs: A more specific antitumor targeted approach to activate the immune system was demonstrated by Ruiz-de-Angulo et al., who trapped an antigen and a TLR9-agonist (CpG) in micelle nanoparticles. Following injection, the CpG-formulated nanoparticles took on a lymph node traveling route [43]. The immune stimulatory effect of CpG-formulated nanoparticles is well documented [44,45]. Other blunt immune stimulatory molecules include the TLR3-agonist polyinosinic polycytidylic acid, a double-stranded RNA (poly I:C) as well as TLR4 and TLR7 agonists. Their formulation into various nanoparticles has demonstrated immune stimulatory effects as well as antitumorigenic effects in both human and murine systems [46,47]. A particular example of a potent TLR4-agonist is lipopolysaccharide (LPS). This TLR4-agonist was formulated into a nanoparticle system for investigation of efficacy and tolerability in a mouse model of colorectal tumors resulting in high deposit of LPS particles to the tumors [48]. T cells: When it comes to activation of T cells, Mueller et al. demonstrated that nanoparticle formulation of tumor antigens resulted in an efficient targeting of B cells with a subsequent activation of CD4 1 T cells [49]. Moreover, Skwarczynski et al. conjugated dendrimer nanoparticles with epitopes of B cells leading to a dramatic antibody production with a subsequent CD4 1 T cell cytokine release [50]. Tang et al. designed cell surface-conjugated nanoparticles with an encapsulated IL-15 agonist. Delivery of this system to mouse tumor models resulted in a rather selective expansion of tumor-infiltrating T cells (up to 16-fold increase in T cell expansion). Further, the increase in T cells enabled a substantially higher tolerability for cytokine administration before any toxicity could be observed and significantly improved clearance of tumors by activated mouse T cells [51]. However, there is a need for a thorough comparison study investigating the antitumorigenic effects, along with the immune stimulatory effects of nanoparticles formulated with specific tumor antigen plus immune component agonist, nanoparticles formulated only with immune component agonist, and nanoparticles formulated with only tumor antigen in order to understand the contribution and impact of each component for immune system-mediated clearance of cancer cells. Adoptive cell transfer: A very elegant example of how to exploit the advantages of nanoparticles as drug-delivery tools was demonstrated by Huang et al. In order to ensure homing to the lymph nodes through preserved CD62L expression, primary T cells were extracted and cultured with supplemented rapamycin (an inhibitor of the mechanistic target of rapamycin and IL-2) followed by membrane coating with SN38 (a topoisomerase I inhibitor)-tagged nanoparticles. The engineered T cells were then implanted into the Eμ-myc Arf2/2 lymphoma mouse model where mouse survival was significantly prolonged compared to unformulated SN38 or SN38-tagged nanoparticles not tethered to the T cell membranes [52]. The depth of this study emphasizes the possible limitations of nanoparticles in anticancer therapeutics and immune system stimulation. In order to substantially halt an advanced cancer disease in its tracks, an ex vivo expanded immune cell component may be required in addition to drugformulated nanoparticles. Further, it would be of great interest to investigate how

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nonengineered ex vivo expanded T cells would perform in comparison to the nanoparticleengineered cells. Influence of nanoparticle size: There are a limited number of studies strictly looking at the influence of nanoparticle size for delivery efficacy and antitumor impact. Also, it should be emphasized that efficiency originating from particle size may look very different depending on other nanoparticle physical properties. Erdogar et al. investigated the antitumorigenic efficiency of cationic chitosan nanoparticles with encapsulated bacillus Calmette Guerin (BCG) in a rat model of bladder cancer. These authors reported on an optimal formulation size of 269 375 nm, resulting in up to 42% efficiency in encapsulating BCG. This nanoparticle size also proved optimal in promoting animal survival and reducing bladder tumor burden [53]. Formulating monoclonal antibodies into nanoparticles: The usage of monoclonal antibodies to specifically target cancer-associated proteins is one of the most sought after current approaches in immunotherapy. One such example is the monoclonal antibody TA99, raised against the gp75 antigen. Chu et al. coformulated TA99 with albumin-loaded nanoparticles followed by administration to mouse tumor models resulting in decreased tumor burden and prolonged mouse survival in comparison to nanoparticles without TA99 or unformulated TA99 [54].

3.2 Nanoparticles as Immunotherapy The notion that the administration of nanoparticles results in modulatory effects on the immune system responses is well established. However, is it always advisable to have an immune system stimulatory effect, and if not, how can you control this through your nanoparticle experimental design? If we start from the cells most likely to take up nanoparticles, DCs, targeting strategies may be tailored depending on the particular disease state where you either want to increase or decrease the maturation of DCs. Multiple studies have shown examples of how to increase DC maturation through different categories of nanoparticles [20,55 57]. In order to decrease DC maturation, it is a necessity to formulate an antiinflammatory compound within the nanoparticle. This could be particularly important when combating an overly active immune system leading to severe inflammation, an outcome often utilized and promoted by highly aggressive tumors. As an example of this, Barbosa et al. formulated the anti-inflammatory agent resveratrol into lipid nanoparticles. Nanoparticle formulated resveratrol blunted tumor necrosis factor potentiated DC activation to a higher degree compared to unformulated resveratrol [58]. When it comes to nondrug-formulated nanoparticles and cancer immunotherapy, there are multiple recent studies claiming antitumorigenic effects by an end output of increased number of CD8 1 T cells in mice, but through completely different nanoparticle structures [59,60]. For example, delivery of PLGA-based biodegradable nanoparticles to DCs blunted angiogenesis and tumor growth correlating with elevated numbers of CD8 1 T cells [61]. Nondrug-formulated nanoparticle targeting is not limited to DCs, but also myeloid cells are

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under investigation as targets in attempts to target tumors through biological components in their environment [62]. This field warrants more studies comparing the immune-stimulatory effects of different types of nanoparticles in the same experimental system in order to determine the optimal nanoparticle structure for tuned DC uptake and maturation.

3.2.1 Complementing Nanoparticle-Based Therapies Except for directly targeting the immune system, nanoparticle-based therapies can also be used as a complement therapy to directed immune system-targeting therapies in cancer. One such field is nanoparticle-based phototherapies, which include photothermal therapy (PTT) and photodynamic therapy, and of which there are numerous preclinical antitumor studies [63 65]. Using gold nanoparticles with a conjugated adaptor for specific targeting of melanomas, Zhang et al. could induce PTT-cell death specific for the tumor cells [66]. Kumar and Srivastava produced biocompatible and biodegradable IR 820-encapsulated polycaprolactone glycol chitosan nanoparticles. In combination with immunotherapy, these nanoparticles proved highly efficient to targeting metastatic breast cancer using a model of MCF-7 cells [67]. Another example of a complementing nanoparticle-based therapy is the utilization of hybrid particles such as the conjugation of nanoparticles to cytotoxic CD8 1 T cells, which were recently demonstrated as therapeutics against cancers related to the Epstein Barr virus [68]. The tLyp1 peptide hybrid nanoparticle displayed targeted efficacy against Treg cells proved by the boosted inhibitory effect of imatinib on Treg cells through blocked phosphorylation of STAT3 and STAT5. In the in vivo setting, administration of this hybrid particle resulted in reduced tumor burden and extended animal survival, correlating with decreased amounts of intratumoral Treg cells and increased numbers of intratumoral CD8 1 T cells [69].

3.3 Nanoparticles as Vaccines Against Cancer Due to the numerous reports demonstrating enhanced immune system function following nanoparticle administration, it is tempting to speculate for a future use of nanoparticles as vaccines against various forms of cancer. But what experimental evidence exists that nanoparticles would fulfill this function at a level which is advancing the field? DC vaccination therapy has been around as a concept for the last couple of decades and hundreds of clinical trials are registered or ongoing for DC vaccination therapy (www.clinicaltrials.gov). The potential benefit of adding nanoparticles to this area would be to further boost the activity of implanted DCs, something that has been suggested in multiple preclinical studies using mouse tumor models [59,70,71]. Further, there are numerous mouse model studies demonstrating a potent activation of the adaptive immune system, including increased antibody production, cytokine production, and activity of T cells, following nanoparticle-mediated vaccination [72,73]. Importantly, Fraser et al. demonstrated the ability of nanoparticles to establish an extended adaptive immunity following the encapsulation of a T cell memory chimeric

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MHC II antigen. Administration of MHC II nanoparticles proved successful all the way to nonhuman primates with immunity recorded during a time lapse of 119 days [74]. The repertoire of other examples of nanoparticle-mediated vaccination covers a variety of formulations, including protein- and DNA-based antigens. All studies report an increased adaptive immunity with activated CD4 1 and CD8 1 T cells, and increased cytokine production including interferon secretion. In addition, for the ability of nanoparticle-mediated vaccinations to block or halt cancer, Wang et al. demonstrated a complete resistance to lung tumor development following the preadministration of silica nanoparticles [75 78]. In particular, many studies have been conducted on the use of nanoparticle vaccines for melanomas. Saluja et al. demonstrated DC stimulation with a subsequent increase in cytostatic CD8 1 T cells following the administration of antigen-formulated nanoparticles with surfaceconjugated ligand targeting DCs [35]. Interestingly, mRNAs have also been tested as antigens in formulation with nanoparticles. Oberli et al. used such an approach resulting in the regression of melanoma tumors and a substantial prolongation of survival in mice. Effects were attributed to substantial increases in CD8 1 T cells [79]. Molino et al. developed a nonviral nanoparticle system for cancer vaccination using a linked pyruvate dehydrogenase E2 peptide. Remarkably, only one immunization with this system expanded the number of CD8 1 T cells reactive to the melanoma epitope by a level of 30 120 in the spleen and draining lymph nodes, respectively, and compared to nonconjugated peptide. When investigated in a mouse melanoma model, B16, E2-nanoparticles extended animal survival rates by 40% compared to control-treated animals [80]. Furthermore, using a similar mouse melanoma tumor model and a nanoparticle-based vaccine containing 500 antigen molecules on each nanoparticle, the majority of mice were protected from tumor initiation. In comparison, all animals in the control-treated group developed tumors. The strong effect on tumor blockage correlated with a substantial induction of CD8 1 T cells [81]. Moreover, in an identical melanoma tumor model, Lu reported biodegradable mesoporous silica nanoparticles as a delivery platform for cancer immunotherapy. In principle, functionalized silica nanoparticles were used as the foundation to deliver the antigen protein ovalbumin in concert with an agonist for TLR 9 to APCs. As with other studies mentioned above, administration of the silica nanoparticles resulted in massive expansion of CD8 1 T cells followed by reduced tumor growth [82]. The future will decide whether this tumor form is particularly suited for nanoparticle-mediated vaccination or whether melanomas are generally more accessible to immune system-enhancing therapeutics. Additional examples of nanoparticle-based vaccines include the surface decoration of attenuated bacteria on synthetic nanoparticles originating from plasmid DNA, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), and cationic polymers. Oral in vivo administration of such nanoparticles resulted in blockage of tumor growth with a substantial activation of T cells and a concomitant increase in cytokine expression. Furthermore, it was evident that administration of VEGFR2 nanoparticles resulted in strong suppression of the tumor vasculature with increased tumor necrosis [83]. The encapsulation of CpG and epitope peptides into layered double hydroxide (LDH) nanoparticles resulted in substantially stronger CD8 1 T cell responses and blunted tumor growth compared with epitope-free

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LDH-based vaccines [84]. Finally, administration of nanoparticles loaded with another TLR agonist, imiquimod (R837), and surface-coated with tumor-specific antigens in therapeutic combination with checkpoint inhibitors displayed superiority in comparison to single-agent treatment [85]. It is currently not clear how all these examples of preclinical nanoparticle studies will add to the current clinical practice of DC vaccination. Furthermore, the broad range of nanoparticle structures and approaches for vaccine formulations makes a clinical transition complicated. There is definitely a need for comparative studies in nonhuman primates comparing multiple nanoparticle classes and formulations to reduce risks of possible complications or setbacks in clinical trials.

3.4 Nanoparticles as Diagnostics Interestingly, recent studies suggest that the applications of nanoparticles may extend beyond that of drug delivery and cancer vaccination. In fact, a few scientific reports propose the use of nanoparticles in diagnostics. So how could we utilize a synthetic particle for diagnostics? The key would be to modify the surface of the nanoparticle in a way that the particle would only react to tumor-specific material. Once a reaction takes place, additional chemical modifications are required to enable detection. This was exactly what Stark and Cheng performed with their nanocapsid platform engineered from a hepatitis E virus. Through chemical modification of the surface of the capsid, a tool was created for both tumor-specific detection and targeting [86]. Another example of nanoparticle-mediated diagnostics relies on the imaging of tumor-associated macrophages. Tumors rich in macrophage infiltration tend to accumulate iron oxide, resulting in a darker contrast in magnetic resonance imaging. A way to exploit this for diagnostics is to utilize administration of iron oxide nanoparticles. Iron oxide nanoparticles represent a noninvasive imaging approach and can be used to stage both primary and metastatic tumors through their inflammatory microenvironment. Furthermore, it is a promising tool for monitoring therapeutic responses to various treatments [87]. Kulkarni et al. developed an elegant reporter system where nanoparticles were engineered to codeliver chemotherapeutic drugs or immunotherapeutic drugs with a responding reporter element to tumors. If tumors were responding to the chemotherapy or immunotherapy in vivo, activation of caspase-3 would cleave a reporter sequence in a way that a fluorescent signal was relieved from its quencher. Utilizing this system, authors could differentiate between chemotherapy-sensitive and chemotherapy-resistant as well as immunotherapy-sensitive and immunotherapy-resistant tumors [88].

3.5 Challenges Although nanoparticle-based treatments have reached clinical trials, there are still a number of different challenges that need to be resolved before nanoparticle-based immunotherapeutics can compete with current FDA-approved immunotherapies [89 91]. In this closing

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section, we are discussing the biology behind these challenges as well as areas of improvement for the design of nanoparticle-based therapies.

3.5.1 Modulating Innate and Adaptive Immunity In this chapter we have described a number of recent studies on how to target the innate and adaptive immunity using nanoparticle-based therapies with the aim of combating cancer. As for the innate immune system, the results of these studies remind us of the efficiency and speed following innate immunity stimulation. Depending on what is targeted in innate immunity, responses can be more or less specific, as seen for TLR-targeting versus general DC activation. There is however still a lot we don’t understand when it comes to targeting innate immunity. The mechanistic outcomes are often unclear, making nanoparticlemediated targeting complicated. One should also remember that the durability of innate immunity is modest compared to adaptive immunity, which will likely dampen the soughtafter clinical effect. While TLR-targeting has shown great promise for clearance of infections, the potential for clinical cancer treatment is less obvious. Also, when it comes to nanoparticle-mediated vaccination of DCs, there is a lack of comprehensive literature. More studies are warranted in order to decipher the potential benefits compared to conventional DC vaccination. Activated T cells belonging to adaptive immunity have spurred an enormous interest as targets of various immune oncology studies. As mentioned earlier in this chapter, activated T cells include CD4 1 and CD8 1 cells, where the CD8 1 cells are also referred to as cytotoxic T cells. Although they hold great promise for the development of vaccines, the complex identity of CD4 1 T cells, where subtypes such as the Treg-cells are immunosuppressive, requires detailed top-quality studies. It is also important to remember that all nanoparticle deliveries to niches of APC residence are very likely to induce CD4 1 T cell responses since APCs will present the engulfed nanoparticle content through MHC-II complexes to CD4 1 T cells. In contrast to the activation of CD4 1 T cells, any cell carrying foreign material triggers CD8 1 T cell responses via exhibition through MHC-I protein complexes. Due to this, it is very challenging to produce a fast and specific CD8 1 T cell response from nanoparticles, although various approaches exist including functionalization of the nanoparticle surface with specific or multiple ligands.

3.5.2 Nanoparticle Characteristics In order for nanoparticles to interact with immune cells following systemic administration, it is essential that they possess a slow turnover time and that they remain in the circulation for an extended amount of time. Steric stabilization can be achieved by poly(ethylene glycol) [92 94]. However, targeting of solid tissues is still far from successful for most nanoparticles, although customized modifications for cell/tissue-specific delivery [95 97] become more common in order to reach a controlled immunity output. Still, our knowledge on nanoparticle surface properties, elasticity, shape, and sizes is immature. We know that all of these

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factors affect the target specificity and efficacy of different tissues [98,99], but due to the broad range of nanoparticle types, it is extremely challenging to define a “gold-standard” of nanoparticle characteristics. The field urgently needs a large comparative study taking into account the targeting effects of both the innate and adaptive immunity from a variety of nanoparticle classes with multiple particle types in each class. Selecting a system for a specific immune system component is currently based on limited literature and therefore in the end down to subjective bias.

3.6 Concluding Remarks The immune system is an immensely complex network where components from different parts communicate with each other. Due to its molecular characteristics, targeting of specific factors will eventually result in broader and less specific outcomes. In order to fully understand the impact of nanoparticle targeting of the immune system, studies need to be conducted in a way that monitoring of a larger panel of components becomes standard practice. For example, subgroups of CD4 1 T cells (e.g., Th1, Th2, and Th17), are rarely investigated in studies describing nanoparticle targeting of the immune system. Furthermore, biological mechanisms are often poorly investigated, relying on cytokine expression instead of modulating various components through genetic knockout systems. Also, the transition from mice to human clinical trials is cumbersome since specific parts of immunity, such as TLR innate immunity, are distinct between mice and humans. Despite all these obstacles, there are numerous nanoparticles currently under clinical investigation [100]. For the FDA-approved nanoparticles specifically, efforts have been focused on target site specificity and particle delivery efficacy [100]. Whether the vast number of studies investigating nanoparticles in various diseases will translate into modified and improved clinical practice in the near future is debatable. However, it is reasonable to believe that approaches combining ex vivo expansion of specific immune system components with drug-formulated nanoparticles could hold the key to success. Such approaches are in some ways similar to CAR-T cell therapy, which has already obtained FDA-approval in non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia (Kymriah—Novartis, Yescarta—Kite Pharma). CAR-T cell therapy has experienced limited efficacy in solid tumors, partly due to challenges to find tumor-specific antigens. Possibly, tethering of drugformulated nanoparticles to ex vivo expanded T cells may provide a specific benefit for solid tumors harboring mutations amenable to small-molecule targeting. Although unformulated small molecules can also target such tumors, the encapsulation into nanoparticles is likely to enhance target delivery.

References [1] O.C. Farokhzad, R. Langer, Nanomedicine: developing smarter therapeutic and diagnostic modalities, Adv. Drug Deliv. Rev. 58 (14) (2006) 1456 1459. [2] O.C. Farokhzad, R. Langer, Impact of nanotechnology on drug delivery, ACS Nano 3 (1) (2009) 16 20.

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