Polymeric Particles as Cancer Vaccine Vectors

Vaccines have been successful at preventing a range of diseases including diphtheria, polio, whooping cough, measles and tetanus; whereby incidences of such diseases are now rare in developed countries. In fact, thanks to vaccines, smallpox has been successfully eradicated worldwide whilst polio is on the verge of global eradication. However, the incidence rate of other diseases remains high owing to a lack of efficacious vaccines or therapies to prevent or treat them. This is often because the pathogen or diseased cell, as in cancer, has evolved ways of evading immune detection or suppressing immune-based attack. Despite the substantial progress in cancer care (including early diagnosis), cancer continues to be a challenging and devastating health problem and is still the second leading cause of death in the United States, exceeded only by heart disease. According to the 2018 National Vital Statistics Report issued by Centers for Disease Control and Prevention, nearly 3 million deaths due to cancer were reported in the United States during 2016 with a death rate of approximately 850 per 100,000 population.¹ For many types of cancer, therapies approved by the United States Food and Drug Administration thus far have not significantly reduced mortality among cancer patients but instead, at best, have slowed the progression of the disease and/or extended patient survival.² Chemotherapy, one of the commonly administered conventional cancer therapies, is associated with major limitations since it is a non-specific approach and limited in effectiveness due to a steep dose-response relationship and narrow therapeutic window.³ Therefore, there is a dire demand for more effective therapies to meet the urgent medical needs for cancer patients. Adaptive immune cancer therapy through the administration of vaccine formulations has met with undulating fortunes over the past century, where promising preclinical findings have generally not translated effectively into the clinic.⁴ A major reason for the lack of success in cancer patients is the highly evolved immunosuppressive properties of the tumor, creating a tumor microenvironment inhospitable to antitumor immune effector cells. However, with the recent promising clinical outcomes for cancer patients treated with immune checkpoint inhibitors (ICI), such as pembrolizumab (αPD-1) and ipilimumab (αCTLA-4), there is justified optimism that the cancer patient’s own immune system can play a significant role in combatting cancer; and that an appropriately designed cancer vaccine can act in synergy when combined with ICI.^5-7 Whilst the development of cancer vaccines has progressed promisingly in preclinical settings,^8-10 strategies to further enhance their efficacyare still needed. One strategy that holds promise in the war on cancer involves the employment of technology to fabricate nano- and micro-sized particle-based vectors formulated as cancer vaccines capable of generating robust antitumor immune responses.^11,12 Specifically, polymeric particle- based cancer vaccines have shown immense promise in preclinical studies, possessing the potential to promote appropriate immune responses against tumor cells without damaging healthy tissue.¹² Many of the distinctive traits possessed by polymeric particles make them strong candidates for the vector component of cancer vaccine formulations, and many preclinical studies over recent years have highlighted the advantages of using polymeric particles as cancer vaccine delivery systems.^13,14 In this review, we describe the attributes that polymeric particle-based cancer vaccines possess in terms of improving cancer vaccine efficacy. This review also recapitulates the most recent advances in using polymeric particles in cancer vaccine applications and new approaches to using unique features of polymeric particle-based delivery systems to enhance cancer vaccine efficacy.

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The major fundamental component of most putative cancer vaccine formulations is the tumor antigen which may be provided as a purified protein(s), whole tumor cells (e.g. irradiated tumor cells) or fractions thereof (e.g. tumor cell lysates) or nucleic acids encoding tumor antigen(s).^15-18 There are, however, a number of considerations that need to be taken into account that often delineate from a vaccination approach that is designed to protect against invasion by a highly immunogenic pathogen (e.g. smallpox virus) versus one designed as a therapeutic against tumor cells which are derived from the host and are therefore inherently non-immunogenic; the degree of difficulty is inordinately higher when attempting a therapeutic vaccine as compared to a prophylactic one. The first of these considerations is protection of the antigen from exposure to the harsh degradative extracellular environment upon administration. It is known that the tumor antigen of interest, in order to commence the process of inducing a tumor antigen- specific immune response, ideally needs to be taken up by professional antigen- presenting cells known as dendritic cells. For sufficient quantities of antigen to be taken up by dendritic cells, the residence time of the antigen is of paramount importance. Encapsulation of tumor antigen into particles can improve the stability of the tumor antigen by protecting it from proteases. The notion of protein encapsulation is well-established and various preclinical studies have demonstrated that tumor antigen loaded into polymeric particles promotes stronger antitumor immune responses compared to soluble tumor antigen.^19-21 In addition to susceptibility to premature enzymatic and proteolytic degradation, soluble antigens have low uptake rates by dendritic cells. Polymeric particles can significantly boost the uptake efficiency, and the entrapment of the tumor antigen into particles substantially enhances the phagocytic efficiency by dendritic cells.^22-24 Another advantage of providing antigen in association with particles versus in soluble form is that, upon uptake by dendritic cells, particles will favor the processing and presentation of the tumor antigen in the context of a surface protein (known as MHC class I) that will favor the activation of effector T lymphocytes, commonly referred to as cytotoxic T cells, which upon activation have the potential to specifically kill tumor cells (Figure 1).²⁵ Soluble antigen, on the other hand, will tend to be processed and presented differently; in the form of MHC class II, thus favoring an antibody-mediated response. Generating antigen-specific antibody responses, whilst sufficient for vaccines against many pathogens, is generally insufficient when generating a tumor-specific immune response. This is primarily due to the fact that most tumor antigens are not expressed in their native form on the cell surface and thus cannot be accessed by antibodies.^22,26,27 Also, when considering tumor antigens, due primarily to tolerance mechanisms, most are not sufficiently immunogenic per se to adequately stimulate potent antitumor immune responses. Therefore, cancer vaccines often require an immunostimulatory adjuvant capable of promoting dendritic cell activation and enhancing the ability of the vaccine to promote tumor antigen-specific cytotoxic T lymphocyte responses.^28,29 The most widely investigated adjuvants are Toll-like receptor (TLR) ligands and include; polyinosinic:polycytidylic acid (a TLR3 agonist), monophosphoryl lipid A (a TLR4 agonist), pentaerythritol lipid A (a TLR4 agonist), and CpG oligodeoxynucleotides (CpG ODN: a TLR9 agonist). These ligands, also known as pathogen-associated molecular patterns (PAMPs), are capable of stimulating dendritic cell maturation by binding to TLRs and initiating a signaling cascade resulting in up-regulation of surface antigens (e.g. CD80 and CD86) and cytokines (e.g. interleukin-12) that promote effector T lymphocyte responses. Polymeric particles possess the capability to efficiently encapsulate and deliver the tumor antigen and immunological adjuvant (either co-loaded or separately encapsulated) to dendritic cells.^19-21 Finally, the ability of polymeric particles to be tuned or functionalized provides the opportunity to target the particles to dendritic cells, thereby promoting more efficient uptake and this is discussed in more detail below.

Aside from the many advantages listed above, polymeric delivery systems are considered  to  be   promising   candidates for vaccine delivery because they possess pathogen-mimicking  properties   in   terms of  shape,  size  and   morphology   (Figure   2); and they can deliver the antigen in a similar fashion to how it would be delivered during a natural infection.^30,31 The size of the particles   delivering   vaccine   components is considered to be a determining factor in terms of the endocytic pathway used by dendritic cells for uptake. In general, larger particles are engulfed  by  phagocytosis while smaller particles are taken up by pinocytosis.³² A comparison of antigen- loaded particles of different sizes (300, 1000, 7000, and 17000  nm  diameter)  showed  that smaller-sized particles were readily taken up by bone-marrow derived dendritic cells and consequently they were more efficient at stimulating antigen-specific effector immune responses in vivo in a murine model.³³ Other groups have shown that, while larger particles (> 100-200 nm diameter) generally remain at the site of vaccination and require uptake by migratory dendritic cells in order to be delivered to the local draining lymph node, smaller particles (< 100-200 nm) can potentially traffic independently to the draining lymph node where they can be taken up by the resident dendritic cells, which  are  present  at high densities and may more efficiently process and present antigen than migrating dendritic cells.^34,35 The same researchers also investigated the effect of surface charge and hydrophobicity on the capacity of particles to drain independently to the lymph node and found an inverse correlation between hydrophobicity and lymph node targeting; and a direct relationship between anionic charge density and lymph  node  targeting  of particles.³⁴

Several techniques have been used to fabricate polymeric particles, examples of which include: emulsification, such as single and double emulsion solvent-evaporation methods, and  nanoprecipitation  (also known as solvent displacement method) (Figure  3).  Adjusting  the  parameters  of  the fabrication process can determine the properties of particles, such as size, size distribution, encapsulation efficiency, and the yield. There are a variety of polymers  that can be used to fabricate particles, however those polymers that offer desirable characteristics when considering them for use as cancer vaccine delivery systems are preferred. Specifically, polymers should be biodegradable and biocompatible  where  the degraded by-products are readily metabolized and non-toxic.³⁶ Examples of such polymers are poly(lactic-co-glycolic acid) (PLGA), poly(anhydrides) (PA), poly(sulfenamides) (PSN), and poly(phosphazenes) (PPZ). These polymers have been well-studied and are the most widely explored polymers for particle fabrication and use in vaccine applications. Particle-based formulations fabricated with certain types of polymer can function not only as delivery vehicles, but also as immunological adjuvants. PA and PPZ particles  have  been reported to have an adjuvant effect in that they can stimulate dendritic cells through binding to TLRs.^22,37,38 Another important characteristic of many polymer-based systems is that the degradation rate of the particles can be tailored according to polymer composition. To explain, varying the molar ratio of PA monomers during the copolymerization process can tune the degradation rate and therefore control the release kinetics of the cargo from polymeric particles (Figure 4).^22,38,39 A number of studies have indicated that varying the molar composition of copolymers can also have a significant effect on the properties of particles.³⁸ One major factor is hydrophobicity which plays a key role in the opsonization and cellular uptake of particles. For example, increasing the molar ratio of the carboxyphenoxy hexane (CPH) monomer in a PA  copolymer composition resulted in a significant increase in the hydrophobicity of particles and, in turn, stimulated more potent antitumor immune responses and improved their in vivo performance.³⁸ The effect of hydrophobicity, however, may vary depending on the size of the particles used.³⁴

One of the critical factors affecting cancer vaccine efficacy is the number and timing of vaccinations. Many vaccines are required to be given as a prime-boost involving multiple doses to achieve desirable outcomes. Reducing the number of vaccinations required to achieve an optimal immune response would be desirable from the perspective of patient compliance. Interestingly, preclinical studies showed that vaccination with a single subcutaneous dose of PA-based particles encapsulating a tumor model antigen was found to induce enduring tumor antigen- specific cytotoxic T lymphocytes and generate long-term protection against lethal tumor challenge, and this was as effective as a prime- boost regimen.²² Other novel immunization strategies involving polymeric particles are currently being studied. For example, in situ vaccination, is a promising strategy where particles are injected intratumorally to manipulate the tumor microenvironment. A recently reported example is in situ immunization against B cell lymphoma with PLGA particles co-encapsulating CpG ODN and doxorubicin, a chemotherapeutic compound inducing immunogenic apoptosis. The principle of this strategy is that dying tumor cells provide a source of antigen for dendritic cells in the tumor microenvironment while CpG ODN functions as an immunological adjuvant to enhance dendritic cell maturation and therefore antitumor immune responses.^40,41 Also, heterologous (diversified) prime-boost vaccination strategies where different versions of cancer vaccine formulations are administered hold the promise of inducing more effective cytotoxic T lymphocyte immune responses.⁸ This could be of particular importance for immunogen-encoded viral vectors where homologous prime-boost vaccinations could be problematic due  to  high  immunogenicity  and limited effectiveness owing to the production of viral-specific neutralizing antibodies.⁴² One such example to address this issue is the diversified prime-boost vaccination using antigen-loaded polymeric particles (as a prime vaccine) and attenuated adenoviral vector encoding antigen (as a booster).⁴³

Another attractive characteristic of polymeric particles is that their surface is amenable to chemical modifications, allowing researchers to improve targeting and refine the ability of the delivery system to interact specifically with the host’s immune system, hence, generating robust tumor-specific immune  responses.⁴⁴  The  surface  chemistry  of polymeric particles is of crucial importance in determining their cellular uptake, biodistribution, targeting, and therapeutic effects. Although polymeric particles are generally easily recognized and ingested by dendritic cells (Figure 5), appropriate surface modulation can afford them an enhanced capacity to bind to specific targets or penetrate through biological barriers; therefore, further enhancing the performance of the cancer vaccine formulation.⁴⁵ For example, mannose  and  carbohydrate  grafted  onto   polymeric   particles were found to enhance active targeting to dendritic cells and macrophages.^46,47 In addition, coupling of polymeric particle surfaces to specific proteins such as antibodies offers the opportunity for active immunological targeting.^24,48 As an example, a recent study used a novel targeting approach involving ICI-functionalized particles to target PD-1 on dendritic cells and demonstrated that these polymeric particles could enhance the efficacy of ICI.⁴⁹ The surface charge of particles also plays a crucial role in determining the fate of particles within the cell. Once particles have been taken up, or endocytosed, by dendritic cells, they need to escape the endosome in order to deliver their cargo to the cytoplasm. Switching the surface charge of particles from negative to positive by using cationic polymers or dendrimers such as chitosan, poly(amidoamine), and poly(propyleneimine) can promote endosomal escape through a mechanism known as the proton sponge effect.^36,50 The ease of designing polymeric particles with multifunctional and versatile platforms has made them attractive candidates for cancer vaccine delivery. Collectively, many of the favorable traits of polymeric particle-based platforms discussed above have culminated into the successful implementation preclinically, and many of them are under active and intense investigation for cancer vaccine applications.

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About the Authors

Suhaila O. Suliman is a graduate student in the Ph.D. program in Pharmaceutics at the University of Iowa. As part of her Ph.D. studies, she focuses on enhancing cancer vaccine efficacy and stimulating robust tumor-specific immune responses using particle-based formulations. She is also interested in studying biodistribution and pharmacokinetics of polymeric nanoparticles for drug delivery.

Emad I. Wafa is currently a graduate student in the Ph.D. program at the College of Pharmacy, University of Iowa. Prior to joining the University of Iowa, Emad earned his bachelor’s degree in Pharmaceutical Sciences from Misurata University, Libya. His research primarily deals with designing and developing cancer vaccines using biodegradable polymeric particles. He is also interested in improving transfection of antigen-presenting cells using polymeric nanovectors.

Dr. Sean Geary is an assistant research scientist who obtained his PhD in Tumor Immunology from the University of Adelaide, Australia. For the past decade, he has been intensively involved in the development and testing of a range of particle based and viral cancer vaccines in preclinical settings, resulting in many publications in peer-reviewed journals.

Aliasger K. Salem is the Bighley Chair and Professor of Pharmaceutical Sciences and Head of the Division of Pharmaceutics and Translational Therapeutics at the University of Iowa College of Pharmacy. Aliasger Salem is also currently the leader of  the  Experimental Therapeutics program at the Holden Comprehensive Cancer Center and co-director of the Nanotoxicology Core at the Environmental Health Sciences Research Center. Priortojoiningthe Universityof Iowain 2004, hewasapostdoctoral fellow at the Johns Hopkins School of Medicine and completed his PhD at the School of Pharmacy and Pharmaceutical Sciences at the University of Nottingham in the UK.