Applying Biodegradable Particles to Enhance Cancer Vaccine Efficacy
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Immunol Res DOI 10.1007/s12026-014-8537-9 IMMUNOLOGY AT THE UNIVERSITY OF IOWA Applying biodegradable particles to enhance cancer vaccine efficacy Kawther K. Ahmed • Sean M. Geary • Aliasger K. Salem Aliasger Salem Ó Springer Science+Business Media New York 2014 Abstract One of the primary goals of our group and our collaborators here at the University of Iowa is to develop therapeutic cancer vaccines using biodegradable and biocompatible polymer-based vectors. A major advantage of using discretely packaged immunogenic cargo over non-encapsulated vaccines is that they promote enhanced cellular immunity, a key requirement in achieving antitumor activity. We discuss the importance of co-encapsulation of tumor antigen and adjuvant, with specific focus on the synthetic oligonucleotide adjuvant, cytosine–phosphate–guanine oligodeoxynucleo- tides. We also discuss our research using a variety of polymers including poly(a-hydroxy acids) and polyanhydrides, with the aim of determining the effect that parameters, such as size and polymer type, can have on prophylactic and therapeutic tumor vaccine formulation efficacy. Aside from their role as vaccine vectors per se, we also address the research currently underway in our group that utilizes more novel applications of biodegradable polymer-based particles in facilitating other types of immune-based therapies. Keywords Cancer vaccine Á Biodegradable polymer Á Poly(a-hydroxy acids) Á CpG Á PLGA Introduction metastases, and chemotherapy is often limited by its highly toxic side effects and the capacity of tumor cells to develop Cancer remains a challenging health problem and is the multidrug resistance [4]. Therefore, improved therapies are second leading cause of death in the USA [1]. Although required that reduce morbidity for cancer patients during incidence and mortality rates have marginally declined for treatment while ultimately extending their survival. Cancer many cancer types over the past decade, this is speculated vaccines are a promising therapy in this regard in that they to be primarily due to a combination of preventative have been shown to be well tolerated by patients, as they measures (i.e. reducing risk factors) and enhanced early rarely cause serious side effects, along with being capable detection, rather than a significant increase in the effec- of promoting tumor-specific immune responses entailing tiveness of treatment modalities per se [2, 3]. Conventional the activation of CD8? T cells [also referred to as cyto- treatments involve surgery and radiotherapy, to remove the toxic T lymphocytes (CTLs)] [5–7]. These CTLs are not main tumor bulk (usually the primary tumor), along with only potentially capable of eradicating existing tumor cells chemotherapy to ensure complete elimination of tumor but can also provide the host with immune memory such cells in order to prevent or combat metastases. However, that tumor recurrence can be prevented. surgery and radiotherapy cannot address the problem of The fact that the immune system can be instrumental in the fight against cancer was recognized more than a century ago through the work of William Coley [8, 9]. At the time K. K. Ahmed Á S. M. Geary Á A. K. Salem (&) there was little understanding of the immune system and its Division of Pharmaceutics and Translational Therapeutics, components, however, many advances in our understand- College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA ing have been made since that have resulted in significant e-mail: [email protected] developments in the field of oncoimmunology. These 123 University of Iowa Immunology 2014 include the findings that tumors express tumor antigens; addition, the use of biodegradable over non-biodegradable that the host possesses tumor antigen-specific T cells particles offers another advantage of eliminating the need capable of being activated; that immunosuppression, par- for carrier removal [30]. It is also generally the case that ticularly within the tumor microenvironment, plays a key biodegradable particles are less toxic than non-biodegrad- role in abrogating antitumor immunity; and that the innate able particles and can be readily studied for their effects on immune system and various adjuvants play an important dendritic cells (e.g. maturation and particle uptake) in vitro role in determining the nature and efficacy of immune prior to progression to in vivo studies [31, 32]. Biode- responses [6, 10–14]. The primary aim of any cancer gradable polymeric particles are versatile delivery systems vaccine is to alert the patient’s immune system to the that can be fabricated using different polymers such as presence of the cancer and to activate an effective T cell- poly(lactic-co-glycolic) acid (PLGA), poly(lactic acid) mediated tumor-specific attack. For a cancer vaccine to be (PLA), polyanhydrides, chitosan, or other types of polymer effective, it is important that the antigenic material [tumor (Fig. 1)[33, 34]. Different methods can be employed for antigen(s)] be delivered in a particulated rather than soluble their synthesis, and the choice of the method would pri- form as this promotes uptake and cross-presentation of marily be governed by the property of the cargo (hydro- antigen (i.e. presentation of antigen such that CTL philic/hydrophobic) and desired particle size [35, 36]. responses are favored) by professional antigen presenting Particle size is a flexible parameter, and depending on the cells known as dendritic cells [15, 16]. It is also important intended use can vary from less than a 100 nm to more than for the particulated antigen to be co-delivered with an 10 lm. adjuvant capable of promoting dendritic cell maturation The literature is rich with preclinical studies using a and TH1-type immune responses, as this will result in more wide diversity of biodegradable particle-based formula- potent T cell activation and IFN-c production [17–19]. tions as cancer vaccines. The type of polymers used to Many different approaches and formulations have been fabricate particles for cancer vaccines have included well- investigated as potential cancer vaccines and include whole established poly(a-hydroxy acid)-based polymers, such as tumor cells, tumor cell lysates, dendritic cells pulsed PLA and PLGA, as well as more novel polymers such as ex vivo with tumor antigen, as well as the use of biode- polyanhydrides. Microparticles based on the polyanhy- gradable particles as vaccine delivery vehicles co-encap- drides 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane sulating antigen and adjuvant [20–22]. Biodegradable (CPTEG) and 1,6-bis(p-carboxyphenoxy) hexane (CPH) particles, aside from their potential as vaccine carriers, may have been reported to have inherent immune adjuvant also have the potential to improve upon other vaccine properties [37, 38]. Polyanhydride particles (1–3 lmin strategies. For instance, they could be used to deliver tumor diameter) co-loaded with ovalbumin (OVA) and the syn- lysates in particulated rather than soluble form, to form thetic adjuvant, CpG, were fabricated using a double- cell–particle hybrid structures where the particle may carry emulsion solvent evaporation method [35] and tested as a a range of immune stimulatory agents and thereby enhance vaccine in a murine study [39]. Vaccination with these the antitumor potential of whole-cell tumor vaccines [23], microparticles resulted in higher levels of OVA-specific or to improve delivery of tumor antigen to dendritic cells CD8? T cells and provided superior prophylactic protec- pulsed ex vivo. Many of these possibilities are being tion against an OVA-expressing tumor challenge, as dem- investigated by various groups within the University of onstrated by slower tumor progression and enhanced Iowa and are mentioned below. survival of mice, compared to mice vaccinated with soluble OVA and CpG [39]. In a separate study, various poly(a-hydroxy acid)-based Biodegradable polymeric particles as cancer particles were investigated as priming agents in a heterol- vaccine vectors ogous prime/boost cancer vaccine strategy where the ade- novirus (encoding OVA) was used as the boost [40]. This Biodegradable particles, such as polymeric particles, lipo- study involved the comparison of particles (1–3 lm somes, and virus-like particles have shown potential as diameter) fabricated from PLA, PLGA, or PLGA-COOH vectors for cancer vaccines in both clinical and preclinical polymers and coated with OVA by passive adsorption. All settings [24]. The use of particles as delivery vehicles three particle types demonstrated the ability to stimulate offers many potential advantages over non-particulated similar levels of murine dendritic cell maturation in vitro as vaccine systems that include protection of the payload from defined by CD86 upregulation. Using mice, it was estab- premature degradation, enhancing intracellular delivery of lished that all three particle types were also capable of cargo [25, 26], providing sustained release of contents [27– generating long-term immune memory responses in vivo as 29], and enabling co-delivery (to dendritic cells) of mul- determined by the sustained presence of OVA-specific tiple components [e.g. immunogen(s) and adjuvant(s)]. In CD8? T cells in the blood and the ability to resist 123 University of Iowa Immunology 2014 Fig. 1 Scanning electron microscope image showing a, b blank PLGA particles of different sizes. Particles are spherical with smooth surfaces. Scale bar = 5 lm, c blank polyanhydride particles prepared using 50:50 CPTEG/ CPH, d OVA-loaded polyanhydride