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Advanced Drug Delivery Reviews (v.61, #3)

Editorial Board (pp. ii).

CpG oligonucleotides as immunotherapeutic adjuvants: innovative applications and delivery strategies by Aliasger K. Salem (Theme Editor); George J. Weiner (Theme Editor) (pp. 193-194).

Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists by Jörg Vollmer; Arthur M. Krieg (pp. 195-204).

Toll-like receptor 9 (TLR9) agonists have demonstrated substantial potential as vaccine adjuvants, and as mono- or combination therapies for the treatment of cancer and infectious and allergic diseases. Commonly referred to as CpG oligodeoxynucleotides (ODN), TLR9 agonists directly induce the activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. Preclinical and early clinical data support the use of TLR9 agonists as vaccine adjuvants, where they can enhance both the humoral and cellular responses to diverse antigens. In mouse tumor models TLR9 agonists have shown activity not only as monotherapy, but also in combination with multiple other therapies including vaccines, antibodies, cellular therapies, other immunotherapies, antiangiogenic agents, radiotherapy, cryotherapy, and some chemotherapies. Phase I and II clinical trials have indicated that these agents have antitumor activity as single agents and enhance the development of antitumor T-cell responses when used as therapeutic vaccine adjuvants. CpG ODN have shown benefit in multiple rodent and primate models of asthma and other allergic diseases, with encouraging results in some early human clinical trials. Although their potential clinical contributions are enormous, the safety and efficacy of these TLR9 agonists in humans remain to be determined.

Keywords: Toll-like receptor; Oligonucleotide; Innate immunity; Vaccine

Innovative strategies for co-delivering antigens and CpG oligonucleotides by Yogita Krishnamachari; Aliasger K. Salem (pp. 205-217).

Cytosine–phosphorothioate–guanine oligodeoxynucleotides (CpG ODN) is a recent class of immunostimulatory adjuvants that includes unmethylated CpG dinucleotide sequences similar to those commonly found in bacterial DNA. CpG ODN specifically triggers toll like receptor 9 (TLR9), which is found within phagoendosomes of antigen presenting cells (APCs) such as dendritic cells (DCs). CpG ODN triggers activation and maturation of DCs and helps to increase expression of antigens. CpG ODN can be used to induce polarized Th1 type immune responses. Several studies have shown that antigens and CpG ODN must be co-localized in the same APC to generate the most potent therapeutic antigen-specific immune responses. Delivery vehicles can be utilized to ensure co-delivery of antigens and CpG ODN to the same APCs and to significantly increase uptake by APCs. These strategies can result in antigen-specific immune responses that are 5 to 500-fold greater than administration of antigen alone. In this review, we discuss several recent and innovative strategies to co-delivering antigens and CpG ODN adjuvants to APCs. These approaches include the utilization of conjugate molecules, multi-component nanorods, liposomes, biodegradable microparticles, pulsatile release chips and cell-microparticle hybrids.

Keywords: Delivery systems; Antigen; CpG ODN; Adjuvant; Vaccine; Controlled release

Enhancing the therapeutic efficacy of CpG oligonucleotides using biodegradable microparticles by Padma Malyala; Derek T. O'Hagan; Manmohan Singh (pp. 218-225).

Oligonucleotides, with specific sequence surrounding CpG motifs, appear to be very effective for the induction of a potent Th1 responses. This molecule represents pathogen-associated molecular patterns (PAMPs) that allows the pathogen recognition receptors (PRRs) present on innate immune cells to recognize them and become activated. PAMPs and related compounds are often labelled as immunopotentiators, allowing a clear distinction between them and particulate delivery systems such as emulsions, liposomes, virus-like particles and microparticles.Microparticles prepared from biodegradable, biocompatible polyesters, and poly (lactide co-glycolide) (PLG). They have been proven to be a good particulate delivery system for the co-delivery of antigens and adjuvants. PLG has been used in humans for many years as a resorbable suture material and controlled-release drug delivery systems. It has been demonstrated that antigen presenting cells (APCs) efficiently uptake the PLG microparticles (∼1 μm) both in vivo and in vitro. After uptake, the PLG subsequently induces an antigen specific CTL response in rodents.Several groups, including our group, have evaluated CpG as an immunopotentiator in various formulations and delivery systems (i.e. emulsions and particulate systems). This review will discuss in detail the work conducted so far with CpG using PLG microparticles as a delivery system. We will also discuss the advantages and enhancement of immune properties of formulating CpG (soluble, adsorbed, and encapsulated forms) with PLG microparticles along with future directions for these microparticles with CpG.

Keywords: Immunopotentiator; Antigen; Polylactide-co-glycolide; CpG; Charged particles

Approaches to enhancing immune responses stimulated by CpG oligodeoxynucleotides by George Mutwiri; Sylvia van Drunen Littel-van den Hurk; Lorne A. Babiuk (pp. 226-232).

CpG oligodeoxynucleotides (ODN) activate the immune system and are promising immunotherapeutic agents against infectious diseases, allergy/asthma and cancer. It has become apparent that while CpG ODN are potent immune activators in mice, their immune stimulatory effects are often less dramatic in humans and large animals. This disparity between rodents and mammals has been attributed to the differences in TLR9 expression in different species. This along with the sometimes transient activity of ODN may limit its potential immunotherapeutic applications. Several approaches to enhance the activity of CpG ODN have been explored including formulation of ODN in depot-forming adjuvants, and more recently, coadministration with polyphosphazenes, inhibitors of cytokines that downregulate TLR9 activation, and simultaneous activation with multiple TLR agonists. We will discuss these approaches and the mechanisms involved, with emphasis on what we have learned from large animal models.

Keywords: CpG DNA; Oligodeoxynucleotides; Toll-like receptors; Polyphosphazenes; Formulation; Delivery

Lipid-based delivery of CpG oligonucleotides enhances immunotherapeutic efficacy by Kaley D. Wilson; Susan D. de Jong; Ying K. Tam (pp. 233-242).

There has been significant interest in the potential of cytosine–guanine (CpG) containing oligodeoxynucleotides (ODN) as an immunotherapy for malignant, infectious and allergic diseases. While human trials have yielded promising results, clinical use of free CpG ODN still faces several challenges which limit their effectiveness. These include suboptimal in vivo stability, toxicity, unfavorable pharmacokinetic/biodistribution characteristics, lack of specificity for target cells and the requirement for intracellular uptake. To overcome these challenges, optimized lipid-based delivery systems have been developed to protect the CpG ODN payload, modify their circulation/distribution so as to enhance immune cell targeting and facilitate intracellular uptake. Ultimately, lipid-mediated delivery has the capacity to increase the immunopotency of CpG ODN and enhance their prophylactic or therapeutic efficacy in a range of diseases. Lipid-encapsulation provides a feasible strategy to optimize the immunostimulatory activity and immunotherapeutic efficacy of CpG ODN, thereby allowing their full clinical potential to be realized.

Keywords: CpG; Lipid nanoparticle; Encapsulation; Immunotherapy; Adjuvant; Vaccine; Innate; Adaptive

The immunogenicity of CpG-antigen conjugates by Hermann Wagner (pp. 243-247).

Compared to “live” vaccines the immunogenicity of “split” vaccines is notably poor, because exogeneous antigens (Ag) insufficiently access the MHC class I processing pathway needed for cross-presentation. Here we review our evidence that targeting ligands of endosomally expressed Toll-like Receptors (TLRs), together with exogeneous Ag to endosomes of dendritic cells (DCs) conveys immunogenicity to Ag similar in magnitude as “live” vaccines that produce Ag. We explored the consequences of enforced endocytosis of “Ag plus TLR ligands” either by crosslinking Ag and CpG-Oligonucleotides (CpG-Ag conjugates) or by co-encapsulating Ag plus endosomally expressed TLR ligands in biodegradable microspheres (MP). While both approaches equally well yielded in effective cross-priming of MHC class I restricted CD8 T effector cells, our data recommend MP as a generally applicable endosomal delivery device to vaccinate for protective and therapeutic CD4 and CD8 T cell immunity. Furthermore, our data suggest that functional inactivation of Foxp3⁺ regulatory T cells further enhances the immunogenicity of “split vaccines”.

Keywords: Split vaccination; Cross-priming; Toll-like Receptor (TLR); Endosomal translocation of rec. Ag plus TLR ligands; Immunogenicity; Protective CD8 T cell immunity

CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases by Dennis M. Klinman; Sven Klaschik; Takashi Sato; Debbie Tross (pp. 248-255).

Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs act as immune adjuvants, accelerating and boosting antigen-specific immune responses. CpG motifs promote the induction of Th1 and pro-inflammatory cytokines and support the maturation/activation of professional antigen presenting cells (particularly plasmacytoid dendritic cells). These effects are optimized by maintaining close physical contact between the CpG ODN and the immunogen. Co-administering CpG ODN with a variety of vaccines has improved the resultant humoral and/or cellular immune responses, culminating in enhanced protective immunity in rodent and primate challenge models. Ongoing clinical studies indicate that CpG ODN are safe and well-tolerated when administered as adjuvants to humans, and that they can support increased vaccine-specific immune responses.

Keywords: CpG; Adjuvant; Vaccine; Immunogenicity; Antibody; IFNg; Protection

Use of CpG oligonucleotides in treatment of asthma and allergic disease by David E. Fonseca; Joel N. Kline (pp. 256-262).

In the last several decades, there has been a marked increase in the prevalence of atopic disorders including asthma in “Western” societies; a relationship has been identified between lack of early-life exposure to microbes or microbial products and increased susceptibility to atopic disorders. The innate immune system is activated by early microbial exposures, many of which utilize one of the Toll-like receptors, and there has been significant interest in studying how ligation of TLRs may be therapeutically useful. CpG oligonucleotides (CpG–ODN, resembling bacterial DNA) engage TLR-9 on B-cells, dendritic cells and other cell types, resulting in a cascade that includes induction of Th1-type and T-regulatory-type immune responses. Preclinical models of asthma have demonstrated that CpG–ODN are potent inhibitors of atopic responses, suppressing Th2 cytokine and, reducing airway eosinophilia, systemic levels of IgE, and bronchial hyperreactivity-in short the critical attributes of the asthmatic phenotype. In models of chronic allergen exposure, CpG–ODN are also effective at preventing the development of airway remodeling. In established asthma, CpG–ODN can reverse manifestations of disease, both when used alone or in combination with allergen immunotherapy. Early clinical trials have had mixed results, including a significant benefit when CpG–ODN were conjugated to ragweed allergen in an allergic rhinitis immunotherapy study, but only limited efficacy seen when administered prior to allergen challenge in asthmatics. Further study of CpG–ODNs for the treatment of asthma and other atopic disorders is warranted by existing data.

Keywords: Asthma; Atopy; Inflammation; CpG oligonucleotides; Immunotherapy

CpG oligodeoxynucleotide-based therapy of lymphoid malignancies by George J. Weiner (pp. 263-267).

Preclinical and early clinical trials indicate synthetic oligodeoxynucleotides containing unmethylated CG dinucleotides (CpG ODN) have potent immunostimulatory effects. CpG ODN are being explored as immune adjuvants in vaccination strategies and as potential treatments for a wide variety of disorders including cancer and asthma. Therapeutic approaches designed to take advantage of this potent class of agents are based largely on the ability of CpG ODN to activate professional antigen presenting cells (APCs) that express the target receptor — Toll-Like Receptor 9 (TLR9). B-cell malignancies are unique in that the malignant cells themselves express TLR9. CpG ODN can have a direct effect on the malignant B cells and lead to activation induced cell death. CpG ODN also alter the phenotype of target malignant B cells as indicated by upregulation of MHC, immunostimulatory molecules, and antigens that serve as targets for other approaches to lymphoma immunotherapy such as CD20. B cell malignancies are also relatively sensitive to the cytokines that are produced by dendritic cells in response to CpG ODN. Thus, B cell malignancies appear to be uniquely sensitive to CpG ODN because of both the direct and indirect effects the CpG ODN on target cells and the sensitivity of B cell malignancies to an immune response. Preclinical studies support further exploration of the potential of CpG ODN as a component of therapy for lymphoid malignancies. Ongoing clinical trials are exploring the potential of CpG ODN, both alone and in combination with other agents.

Keywords: CpG ODN; B cell; Lymphoid malignancies; TLR 9

CpG oligonucleotide as an adjuvant for the treatment of prostate cancer by David M. Lubaroff; Dev Karan (pp. 268-274).

The use of an adenovirus transduced to express a prostate cancer antigen (PSA) as a vaccine for the treatment of prostate cancer has been shown to be active in the destruction of antigen-expressing prostate tumor cells in a pre-clinical model, using Balb/C or PSA transgenic mice. The destruction of PSA-secreting mouse prostate tumors was observed in Ad/PSA immunized mice in a prophylaxis study with 70% of the mice surviving long term tumor free. This successful immunotherapy was not observed in therapeutic studies in which tumors were established before vaccination and the development of anti-PSA immune response was not as easily generated in PSA transgenic mice. Immunization of conventional and transgenic animals was enhanced by incorporating a collagen matrix into the immunizing injection. Therefore the need to strengthen anti-PSA and anti-prostate cancer immunity was an obvious next step in developing a successful prostate cancer immunotherapy. Because the use of immunostimulatory CpG motifs was shown to enhance immune responses to a wide variety of antigens, our studies incorporated CpG into the Ad/PSA vaccine experimental plans. The results of the subsequent studies demonstrated a dichotomy where Ad/PSA plus CpG enhanced the in vivo destruction of PSA-secreting tumors and the survival of experimental animals, but revealed that the number and in vitro activities of antigen specific CD8+ T cells was decreased as compared to the values observed when the vaccine alone was used for immunization. The dichotomous observations were confirmed using another antigen system, OVA also incorporated into a replication defective adenovirus. Despite the reduction in antigen-specific CD8+ cells after vaccine plus CpG immunization the enhanced destruction of sc and systemic tumors was shown to be mediated entirely by CD8+ T cells. Finally, the reduction of the CD8+ T cells was the result of an observed decrease in the proliferation of the antigen specific cell population.

Keywords: Vaccine; Prostate cancer; CpG; Immunotherapy

CpG oligonucleotides for immunotherapeutic treatment of neuroblastoma by Suzanne A. Miles; Anthony D. Sandler (pp. 275-282).

Neuroblastoma is the most common extracranial solid tumor malignancy of childhood. Although it is generally responsive to treatment, high risk cases of neuroblastoma frequently recur. The prognosis for relapsed cases is extremely poor despite aggressive therapy. The frequency of relapse and subsequent failure of further treatment has spurred the need to develop non toxic and more effective treatments for targeting residual tumor cells during the phase of minimal residual disease. Traditional cancer therapies are non-specific, leading to the destruction of normal, healthy tissues. Failure to induce specific tumor immunity may be due to several immunosuppressive factors. Primary amongst these factors are: lack of co-stimulatory molecules on the surface of tumor cells, the ability of the tumor to modulate immunity in a suppressive manner and the presence of an immunosuppressive microenvironment at the location of the tumor. Unfortunately, tumor tolerance impedes the ability to establish immunity to tumor antigens and overcoming this tolerance is essential to developing effective tumor immunity. Vaccine strategies that target host immune effector cells with synthetic oligodeoxynucleotides (ODNs) that contain unmethylated CpG motifs (CpG-ODNs) represent a novel approach to overcoming tolerance in cancer therapy. This approach enables biasing of host immunity toward a proinflammatory Th1 and thus anti-tumor response. The addition of immunogenic tumor specific antigen to the CpG-ODN vaccine may allow for specific targeting and killing of established tumors.

Keywords: Cancer; Neuroblastoma; Toll-like receptor; Vaccine; Immunotherapy; Th1 response

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Advanced Drug Delivery Reviews (v.61, #3)