Vaccination to Treat Noninfectious Diseases

CHAPTER 21

Vaccination to Treat Noninfectious Diseases: Surveying the Opportunities M.F. Bachmann1, 2, M. Vogel1 1

University Hospital Bern, Bern, Switzerland; 2University of Oxford, Oxford, United Kingdom

INTRODUCTION Vaccination for the treatment and prevention of infectious diseases has been the most successful medical intervention from a public health perspective. The application of vaccination for treating noninfectious diseases is becoming more common, and there are many examples of applying vaccine technology to a diverse range of noninfectious diseases. In this chapter, we attempt to separate the immunological requirements for the treatment of different classes of noninfectious diseases to show the underlying immunological mechanisms that have to be considered in the design of appropriate vaccines. Broadly, this encompasses treatments requiring the strong induction of immune responses, both humoral and cell mediated, or the downmodulation of an existing pathological immune response, either through immune deviation or through suppression. We highlight the desired adjuvant qualities required for each approach and look at some of the potential dangers that may result from using vaccine formulations that push the immune system too far in one particular direction.

THE IMMUNE SYSTEM The immune system is a complicated interconnected network of cells and molecules designed to protect the host from infection. It is clear that there is cross-talk between the various arms of the immune system, with advances focusing on how “‘innate” immune components are required for initiating and directing the quality (and quantity) of the later “adaptive” immune response.65 In the case of infectious diseases mediated by viruses, bacteria, or parasites, there are numerous layers of immunological defense. The innate immune response is alerted rapidly to infection by events such as tissue damage, the binding of natural antibody, complement fixation, and the induction of inflammatory mediators (cytokines, vasoactive compounds), as well as granulocyte and phagocyte recruitment and activation.28,65 The induction of the adaptive immune response critically depends on the

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interactions between T cells and antigen-presenting cells (APCs), of which the major player is the dendritic cell (DC).58 Immature DCs resident in peripheral tissues sample antigen from the environment and, if activated via pattern recognition receptors by pathogen-associated molecular patterns, are induced to migrate to secondary lymphoid tissues where they mature, present pathogen-derived peptides on major histocompatibility complex (MHC) molecules in the context of costimulatory molecules, and become capable of efficiently priming naive CD4þ and CD8þ T cells. T-cell priming requires cell contact between the T cell and the APC, leading to stimulation of the T-cell receptor (TCR) by antigen presented by MHC molecules as well as the reception of costimulatory signals. This induces T-cell proliferation and, under appropriate conditions, differentiation into effector cells. Effector T cells then downregulate lymphoid tissueehoming receptors and migrate to sites of inflammation where effector CD8þ T cells are able to lyse infected target cells or tumor cells and secrete proinflammatory cytokines. The class of T-cell help induced in CD4þ antigen-specific T cells at this stage is critical for fine-tuning the type of response that is mounted, a process known as T-cell polarization. The impact of polarization also feeds back into the innate system, for example, T helper type 1 (Th1) T-cell help is required for optimal macrophage activation and host protection in response to intracellular pathogens,140 and Th17 cells are important for the recruitment and activation of innate cells such as neutrophils.64 CD4þ T-cell help is also pivotal for the humoral response for inducing isotype switching in B cells, as well as supporting germinal center formation, the production of high-affinity long-lived plasma cells, and the formation of memory B cells. Follicular Th cells are particularly important for T/B collaboration, although Toll-like receptor (TLR) ligands may be able to overcome the dependence of IgG responses on this particular Th cell subset.20 Furthermore, CD4þ T helper cells are known to be important for the normal development of memory CD8þ T cells.13,67,110 Thus, T helper cells are key coordinators of the immune response required for the optimal development of antibody and cytotoxic T lymphocyte (CTL) responses. The processes described earlier governing the induction of immune responses are relatively well defined. This contrasts with a lack of detailed understanding of how immune responses are downregulated. The most important mechanism of downmodulating immune responses is probably the successful clearance of the pathogen (essentially the removal of antigen), directly leading to a decline in the response. In contrast, under conditions of persistent infection, when the pathogen cannot be eliminated, additional mechanisms act to minimize damage inflicted onto the host by the immune system. T-cell responses may be exhausted, and specific T cells are either deleted or become nonfunctional.85,139,141,72 Such nonfunctional T cells express inhibitory receptors, such as programmed cell death protein-1 (PD-1), which keep the cells at bay. Indeed, blocking such inhibitory receptors using monoclonal antibodies

Vaccination to Treat Noninfectious Diseases: Surveying the Opportunities

Mode of action Block drug of addiction

Ab

Block endogenous Ligand (e.g. TNF)

Indication Smoking cocaine addiction Rheumatoid Arthritis, Multiple Sclerosis, etc

B

Block allergen effect

Allergy

Block autoimmunity

Rheumatoid Arthritis, Multiple Sclerosis, Diabetes, etc

Kill endogenous cells

Cancer

T reg Th1/Th2

Therapeutic vaccine

T

CTL

Figure 21.1 Mechanism of action of different therapeutic vaccines. Depending on the required vaccine effect, the mechanism of action of different therapeutic vaccines will rely on the type of immune response induced, whether antibody- or cell-mediated immunity [cytotoxic T lymphocytes (CTLs), Th1/Th2, and Treg). Examples of relevant disease indications for each approach are indicated.

(checkpoint inhibitors) is currently revolutionizing cancer treatment. In addition, high levels of persisting antigen may favor the production of antiinflammatory cytokines, such as interleukin (IL)-10, further reducing immune responses. Regulatory T cells, another subset of Th cells, are also pivotal for the downregulation of inflammatory processes, and targeting this cellular subset is another highly attractive way to increase tumor clearance. It is this balance between the induction of effector responses and the exhaustion of T-cell responses and the production of antiinflammatory cytokines that immunologists try to influence to induce protective immunity versus the amelioration of autoimmune diseases (Fig. 21.1).

INDUCTION OF AN IMMUNE RESPONSE BY VACCINATION: GENERAL CONSIDERATIONS Vaccination is a highly successful intervention whereby the immune system is primed by antigen exposure to provide protective immunity upon encounter with the specific pathogen and/or reencounter with its antigens. A key parameter for the success of a vaccine is therefore its immunogenicity. The most immunogenic form of vaccines against pathogens are live but attenuated strains, with killed forms of the pathogen

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and recombinant pathogen subunit vaccines showing reduced immunogenicity. In essence, this reduced immunogenicity is due to the inability of these vaccines to stimulate appropriately the immune system. These vaccines have lost the “flavor” of a pathogen. Current vaccine strategies for inducing an immune response therefore aim at combining safe, but poorly immunogenic, vaccines with additional stimuli that drive an efficient immune response. Essentially three strategies are followed to trick the immune system into viewing forms of the pathogen. The reasons for this high immunogenicity may be listed as follows. (1) Pathogens usually replicate in the host, and pathogen-derived antigens are presented for extended time periods. This is mimicked by giving vaccines in a depot-forming adjuvant, a typical example of which is alum. (2) Pathogens potently activate the innate immune system often through pattern recognition receptors, such as TLRs. This is mimicked by adding TLR ligand to the vaccine, for example, monophosphoryl lipid A (MPL) or CpGs, triggering TLR 4 or TLR 9, respectively or RNA naturally present in a number of viruslike particles (VLPs). (3) Pathogens are macromolecular structures that are efficiently phagocytozed. In addition, many pathogens exhibit highly repetitive surfaces that efficiently cross-link B-cell receptors, leading to potent antibody responses. This is mimicked by increasing the size and organization of the antigen by using VLPs,34 virosomes, or nanoparticles for vaccination.8,51 Currently the development of safe and effective vaccine formulations is a high priority.94 This is especially true if vaccine technology is to be broadened and applied to noninfectious diseases (Table 21.1). Several challenges exist for this approach, which will require potent adjuvants, as it will be especially difficult to manipulate successfully aberrant immune responses (allergy and autoimmunity), ineffective immune responses (cancer immunotherapy), or immune responses against self-antigens.

ADJUVANTS IN IMMUNOTHERAPY BASED ON INDUCTION OF ANTIBODIES Overview The ability of antibodies to bind and neutralize pathogens is critical for the maintenance of vaccine-induced protective immunity against many life-threatening viral and bacterial infections.143 In the field of treatments for chronic noninfectious diseases, such as rheumatoid arthritis or multiple sclerosis, the use of monoclonal antibodies is well established for targeting cells or blocking specific molecular interactions.99 Monoclonal antibodies are very specific and are often effective; however, there are several potential problems with their passive administration as a treatment, including induction of anti-antibody responses, induction reactions, unfavorable pharmacokinetics, and

Table 21.1 An Overview of Possible Vaccination Strategies, Including Some of the Potential Advantages and Disadvantages of Each Approach Aim Vaccination Strategy Advantages Disadvantages

Induction of humoral immunity

Induction of T cell immunity

Removal of tolerance mechanisms SIT for allergy Provide Th1 stimuli with the allergen, either mixed or directly linked Provide Th2 stimuli to treat autoimmunity Enhance Treg suppression to treat autoimmunity

Effective; reversible

Cost; side effects; large and frequent dosing required

Cost-effective; long lasting; with VLP technology humoral immunity is induced without needing adjuvants Cells guaranteed to be specific

Reversibility? Possibility of ADCC/ CDC; T-cell- driven inflammation possible if strong adjuvants are used Cost; labor intensive; low persistence after transfer Therapy requiring ex vivo expansion of T cells or DCs is expensive and labor intensive; responses to antigens in cancer immunotherapy are often observed with little associated clinical benefit

Coadministered adjuvants boost antitumor and antipeptide responses (depot effects, costimulatory and pathogenlike signals, antigen in particulate form); DCs matured ex vivo provide extra adjuvant effects Improves effectiveness of vaccination Effective Decreases time required for desensitization; successful in animal models of autoimmunity Successful in animal models of autoimmunity Successful in animal models of autoimmunity

May increase the risk of autoimmunity Time consuming; risk of anaphylaxis; limited to certain allergens Risk of side effects for some adjuvants (CpG); toxicity associated with direct application of cytokines; risk of inducing autoimmunity? Risk of inducing allergy?

Risk of compromising tumor immunosurveillance?

ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement dependent cytotoxicity; DC, dendritic cells; SIT, specific immunotherapy.

Vaccination to Treat Noninfectious Diseases: Surveying the Opportunities

Deviation or suppression of existing responses

Passive administration of monoclonal antibodies Active vaccination targeting selfantigens Transfer of ex vivoe expanded T cells Improvement of antigen immunogenicity

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expense.10 An alternative for such passive vaccination with monoclonal antibodies would be some form of active vaccination to induce the production of neutralizing antibodies in the host. This approach is envisaged to be more cost-effective and longer lasting; however, the challenge in active vaccination is to find immunogenic formulations of antigen that are sufficient to induce strong antibody responses but are controllable and free from adverse effects such as T-cell-driven inflammation. Given that many active vaccination therapies for chronic noninfectious diseases would target selfantigens, the balance between bypassing self tolerance and avoiding immunopathology becomes critical. The key criterion of safety may in fact prevent the use of strong adjuvants in active vaccination strategies aimed at inducing antibodies against selfantigens (Table 21.1).

Passive Vaccination Passive vaccination using chimeric, humanized, or fully human monoclonal antibodies has become a major success story of modern biotechnology, representing one of the major source of income for the pharmaceutical industry. We will not provide extensive coverage here and suggest that the reader consult one of several reviews on the subject.63,134 We wish only to compare and contrast passive immunotherapy with the active induction of antibodies using therapeutic vaccination for the treatment of noninfectious diseases. Passive immunotherapy using monoclonal antibodies has several attractive features. Monoclonals exhibit generally high target selectivity. For example, Eculizumab,70 a monoclonal specific for complement C5, has a picomolar affinity for its target and blocks complement activation at close to the theoretical 1:2 molar ratio.128 Monoclonal antibodies can also be used as carriers of other bioactive molecules such as toxins or radionuclides, an example being Zevalin, the first radionuclide-containing monoclonal treatment to be approved by the US Food and Drug Administration. Monoclonal antibodies are metabolized with distinct pharmacokinetics, giving potentially full reversibility of their effects. In addition, the engineering of smaller antibody fragments (e.g., single-chain Fv) or designing of new antibody-based molecules (e.g., “diabodies”) may increase the bioavailability of the drug,63 although the half-life of such molecules is usually very short. Despite these qualities, there are several limitations to passive antibody immunotherapy. It is expensive and, due to unfavorable pharmacokinetics, often requires repeated administration at high doses. This can lead to serious side effects such as infusion sickness, risks the induction of inactivating antiantibodies (antiallotypic and anti-idiotypic), and is also inconvenient for patients. In addition, the targeting of cell surface molecules may induce antibody-dependent cell-mediated cytotoxicity (ADCC), a desirable effect in some cases (e.g., Rituxan for the treatment of non-Hodgkin lymphoma) but not appropriate if the target molecule is to be blocked without inducing tissue damage.

Vaccination to Treat Noninfectious Diseases: Surveying the Opportunities

Active Vaccination The alternative to passive antibody immunotherapy is to vaccinate individuals against a variety of foreign and self-antigens to generate neutralizing antibodies. This approach has been proved to be safe and effective in a number of animal models and clinical trial settings in humans. It has the potential advantages that well-established existing vaccine technology and delivery mechanisms can be used to induce long-lived polyclonal neutralizing immune responses against the target of interest, resulting in convenience for the patient and reduced cost of goods. The induction of neutralizing antibodies against a given antigen requires that specific B and T cells of the right specificity are present and able to be activated. For therapeutic vaccines targeting self-antigens, the mechanisms of tolerance may interfere with the induction of an appropriate response. Autoreactive B lymphocytes are in fact present in the periphery, yet they are held in check primarily by lack of T-cell help, as well as by mechanisms of anergy.56 However, self-reactive B cells can be activated under appropriate circumstances allowing the therapeutic induction of antieself antibodies by vaccination. Most therapeutic vaccination strategies for noninfectious diseases target self-antigens. However, there is one notable example of the use of foreign antigens to treat drugs of addiction, including nicotine (Nabi, Xenova, and Cytos) and cocaine (Xenova). The use of these small drug molecules as antigens provides less of a safety concern as it does not require the breaking of selftolerance. Some positive phase II clinical trial results have been reported by Nabi and Cytos for their nicotine vaccines and by Xenova for its cocaine vaccine, but laterphase studies have failed so far.26,36,46,82 A number of strategies have been proposed for inducing neutralizing antibodies against self-antigens, including linking selfantigens to foreign carrier proteins, incorporating foreign T helper epitopes into selfantigens, and using VLPs to display self-antigens in a highly immunogenic form. In foreign carrier protein strategies, vaccination by linking small hormone selfmolecules such as human chorionic gonadotropin (CG),123 gonadotropin-releasing hormone (GnRH),83 gastrin,114,136,137 and angiotensin52 to diphtheria toxoid or tetanus toxoid has been proved to be successful in inducing neutralizing antibodies. Several of these vaccines have been tested in human clinical trials; CG and GnRH vaccines showed promise as both immunocontraceptives83,124 and cancer immunotherapeutics,86,112 and a gastrin vaccine showed efficacy for the treatment of advanced pancreatic cancer.24 A vaccine targeting interferon (IFN)-a has been shown to improve symptoms of systemic lupus erythematosus.77,80 An additional attractive use of active vaccination targeting a small self-molecule is the development of a treatment for Alzheimer disease. Human amyloid beta (Ab) peptides derived from the amyloid precursor protein (APP) accumulate as plaques in the brain of Alzheimer patients. Transgenic mice expressing a plaque-forming variant of human APP can be vaccinated with Ab peptides in strong adjuvant, generating a humoral response that reduces plaque burden105 and improves mental performance in

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the mice.84 In a phase II clinical trial of the vaccine in Alzheimer patients, antibody responses against Ab peptides were associated with a delay in cognitive decline.61 Despite these promising results, the clinical trial was halted after a subset of patients developed aseptic meningoencephalitis.92 This side effect of the vaccine formulation highlights the potential problems of active vaccination in the presence of strong adjuvants and is discussed later with other potential risks. To avid this problem, next-generation Alzheimer vaccines focus on the use of small peptides unable to induce T-cell responses.47 Linking peptides rather than proteins to the self-antigen maybe an additional way to bypass Th cell tolerance.103 Using universal Th cell epitopes, which are recognized in almost all individuals, may allow to avoid B-cell responses restricted by recognition of the introduced Th cell epitopes. It may be possible to genetically engineer Th cell epitopes directly into self-antigens without disturbing the antigen structure.37,38 This approach has been effective in treating disease in several animal models, including arthritis38 and asthma,60 although success in these models requires the coadministration of highly inflammatory adjuvants. Indeed, a tumor necrosis factor (TNF)ebased vaccine incorporating a universal T-cell epitope has not been successful clinically (antieTNF-a therapeutics, Pharmexa), as no strong adjuvants could be used and likely also because the universal T-cell epitope caused changes in the tertiary structure of TNF. The use of VLPs to make antigens more immunogenic by presentation to the immune system as a highly ordered array holds promise as a vaccine delivery system, especially as high neutralizing antibody titers can be obtained even in the absence of adjuvants. The rationale for this vaccine carrier system comes from observations that antibody responses against the glycoprotein of vesicular stomatitis virus could only be elicited in transgenic mice expressing this antigen if the glycoprotein was presented to the immune system as a highly ordered array on the surface of virions, but not in a disorganized soluble or membrane-bound form.12 It may be that only highly repetitive antigens able to efficiently cross-link surface antigen receptors on B cells are able to “rescue” autoreactive B cells from peripheral tolerance mechanisms.9,12 VLP vectors in current use are usually single coat proteins of viruses, which are recombinantly expressed and self-assemble into particles that resemble the live virus but lack viral genetic material and hence infectivity. Antigens are then displayed by these particles as genetic fusions,31 by streptavidinebiotin conjugation,32 by chemical cross-linking,69 or by a SpyeTag, SpyeCatcher system.25 The density of self-antigen on the surface of the particle plays a critical role in the induction of strong neutralizing IgG antibody responses.33,68 VLP-based vaccines have been tested in numerous clinical trials. The current hepatitis B and human papillomavirus (HPV) vaccines are, e.g., based on VLPs.106 Vaccines against influenza virus and Norwalk virus14 and also human immunodeficiency virus18,138 have been tested extensively in the clinic. A vaccine against hypertension based on angiotensin II coupled to bacteriophagederived VLPs (Qb) has also been tested clinically and showed good tolerability and was able to significantly lower blood pressure in moderately hypertensive patients.5,130

Vaccination to Treat Noninfectious Diseases: Surveying the Opportunities

In addition, a next-generation vaccine against Alzheimer disease based on Ab1-6 coupled to Qb (CAD106) is now in phase III trials. Additional vaccines that have reached clinical stage are a vaccine against type II diabetes (targeting IL-1b)30 and allergy (targeting IgE).2,131 In all cases, the vaccines proved to be safe, well tolerated, immunogenic, and inducing neutralizing antibodies. A major advantage of VLPs over other carrier technologies for inducing antibody responses against self antigens is that adjuvants are not required to produce strong neutralizing IgG responses, a point we will return to when we highlight some of the potential problems associated with active vaccination.

POTENTIAL AND ACTUAL PROBLEMS WITH ACTIVE VACCINATION Toxic Effects From Autoantibodies There are several important safety concerns surrounding active vaccination against selfantigens, especially with respect to the possible presence of continual high-titer autoantibodies in the serum. First, autoantibodies binding to cell surface antigens would have the potential to induce ADCC and complement-dependent cytotoxicity. This effect is harnessed, for example, in the action of anti-CD20 monoclonal antibodies for treating non- Hodgkin lymphoma.71,98 Current active vaccination strategies have avoided this issue by immunizing against soluble secreted self-antigens such as growth factors, hormones, and cytokines. As cytokines are present at very low levels in serum immune complex formation may be considered a rather theoretical issue.

Reversibility Unlike passive immunotherapy with monoclonal antibodies, in which the drug is metabolized with given kinetics, active immunotherapy by vaccination relies on the cessation of an ongoing immune response to ensure reversibility. This is potentially problematic, as vaccination of patients who already have immune defects, in particular autoimmunity, may provoke a continuous autoantibody response against the self-antigen. Available reversibility data in animals for self-antigens linked to carrier proteins, genetically fused to foreign T helper epitopes or presented on the surface of VLPs, show that most responses decline over several months. In human trials of the hormone CG conjugated to tetanus toxoid and diphtheria toxoid, antibody titers declined rapidly after each vaccination and this decline was not affected by repeated vaccination.124 Similarly, autoantibodies to TNF-a and ubiquitin induced in mice after immunization with recombinant self-proteins incorporating foreign T helper epitopes showed a 90% reduction 5e6 months after the last immunization.37,38 In papilloma VLP-based immunizations, autoantibody titers against CCR5 declined by two- to eightfold within 6 months of the last immunization.31 Vaccination against TNF-a using the same VLP system led to a reversible autoantibody response with a 60-fold reduction in titers 1 year after the last

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boost.32 Furthermore, endogenous production or exogenous application of TNF or IL1b in immunized mice did not delay the decay of the response.119 These vaccination regimens do not break Th cell tolerance but rather bypass it (by introducing T-cell help from the VLP). Exposure of memory B cells to free cytokine therefore results in B-cell receptor stimulation in the absence of T-cell help, an event that is largely ignored by the memory B cells. Indeed, if a Th cell epitope is linked to the recombinant cytokine, memory B cell may be stimulated.8 Also in humans, induction of self-specific antibody responses have been proved to be reversible for VLP-based vaccines against Ab1-6, IL-1b, and angiotensin II. In summary, all current information suggests that autoantibody titers induced by active vaccination of antigens linked with foreign T helper cell components are reversible; however, this may depend on the vaccine target and the formulation and will have to be carefully investigated for each new vaccine candidate.

T-Cell-Mediated Side Effects The potential dangers of active vaccination were highlighted in a phase IIa clinical trial for the treatment of Alzheimer disease.53,100 Treatment by active vaccination against Ab was halted after some of the patients developed meningoencephalitis. Interestingly, autopsy data from a patient who developed meningoencephalitis showed evidence of T-cell infiltration and an immune response against Ab.89 Vaccine efficacy was observed in a subcohort of patients by the production of high anti-Ab antibody titers, which was associated with delayed cognitive decline,61 but clearly the immunization induced unwanted T-cell-driven inflammatory side effects. This may have been due to immunization with a form of Ab-containing T-cell epitopes in conjunction with the Th1polarizing adjuvant QS-21. At the very least this experience must serve as a cautionary tale for active vaccination strategies and highlight the need for inducing strong antibody responses without inflammatory T cells. This may be possible by removing known T-cell epitopes from antigens53 or using vaccine technologies such as VLPs that induce strong antibody responses without requiring inflammatory adjuvants.

ADJUVANTS TO STIMULATE T-CELL IMMUNITY Outlook The other major arm of the adaptive immune system besides the antibody response is T-cell-mediated immunity. In the field of noninfectious diseases, the boosting of T-cell immunity, particularly CD8þ CTLs, is especially important in the search for an immunotherapy for cancer. Adjuvants will play an important role in the development of any successful cancer vaccine, as methods are clearly required to increase the immunogenicity of tumor antigens, stimulate innate tumor immunity, remove

Vaccination to Treat Noninfectious Diseases: Surveying the Opportunities

immunosuppressive pathways, and deal with the challenge of vaccination in immunocompromised and elderly patients (Table 21.1). Is there hope for the successful treatment of cancer by vaccination? Prophylactic vaccination to prevent infection with the limited number of viral infections directly associated with the development of cancer is clearly feasible as demonstrated by the available hepatitis B and HPV vaccines48,106; however, therapeutic vaccination to treat existing cancers is proving more difficult. Current evidence suggests that the immune system is able to respond to tumors, as tumor-specific T-cell and antibody responses can be detected in patients,17,62 and both immunocompromised humans and mice with defined immunological defects show greater susceptibility to spontaneous and induced tumors.109 Despite this, the poorly immunogenic form in which tumor antigens are usually presented to the immune system means that robust antitumor T-cell responses are not easily induced. Ideally for vaccination, a tumor antigen should be tumor specific, or abundantly expressed by the tumor and essential for the tumor phenotype. The low immunogenicity of tumor antigens can be the result of tumor-derived factors, which can form an immunosuppressive environment by, for example, downmodulating or secreting MHC class I homologs57 or secreting immunosuppressive cytokines such as IL-10 and vascular endothelial growth factor.49 In many cases, specific T cells may have been deleted in the thymus or periphery, rendering the task of inducing protective T-cell responses difficult. In addition, any given cancer immunotherapeutic is initially a “second-line,” treatment and many of the vaccines may therefore be immunosuppressed. Many proposed cancer treatments, for example, those involving the ex vivo culture of DCs, tumor cells, or tumor-reactive T cells, are also very labor intensive and expensive, suggesting that their widespread use may be difficult to achieve.19

ADJUVANTS AND VACCINES TO ENHANCE INNATE IMMUNITY Tumor surveillance by innate immune cells capable of producing IFN-g, such as natural killer T (NKT), and gd T cells is important at least in animal models of tumor immunity.122 Attempts to boost the antitumor activity of this arm of the immune system in humans, however, are in their infancy. For example, although systemic IL-12 administration was shown to be effective in enhancing tumor rejection in experimental animals,88 it resulted in liver toxicity in humans. NKT cells are immune cells expressing ab TCRs that recognize glycolipids presented by the nonclassic MHC molecule CD1d.54 These cells produce large amounts of cytokines (IFN-g, IL-13, IL-4) rapidly upon activation in part due to prestored cytokine messenger RNA. There is some debate about whether NKT cells mediate or hinder antitumor immune reactions. It has been shown that NKT cells are a major source of IL-13, which acts via a myeloid intermediate to generate transforming growth factor (TGF)-b, an immunosuppressive cytokine able to inhibit antitumor activity by CD8þ CTLs in murine cancer models.126,127 From this finding, it may

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be a useful strategy to target IL-13 produced by NKT cells and downstream TGF-b to boost antitumor immunity.1 Alternatively, in cancer patients, the NKT cell cytokine secretion repertoire is reportedly skewed toward T helper type 2 (Th2) (IL-4), producing NKT cells that some have termed “regulatory.”125 The capacity to resecrete IFN-g can be restored by immunization with DCs pulsed with the CD1d ligand a-Gal-Cer,90 and this is actively being pursued as a cancer therapy to boost innate immunity.

ADJUVANTS AND VACCINES BASED ON HUMORAL IMMUNITY Passive monoclonal antibody therapy is used for some tumors, although it is not generally applicable to solid tumors for reasons of bioavailability.63 Active vaccination to induce a humoral antitumor immune response has been described by using the unique variable regions of heavy and light chain immunoglobulin genes as a tumor-specific antigen. There has been a report that DCs pulsed with peptides from specific B-cell lymphoma idiotypes followed by idiotype-keyhole limpet hemocyanin (KLH) vaccination induce both cell-mediated and humoral immunity in B-cell lymphoma patients.129 In general, however, tumor-specific monoclonal antibodies in tumor therapy usually target membrane antigens, which are not the preferred target for B-cell vaccination, as membrane-bound proteins usually cause B-cell anergy and/or deletion11

ADJUVANTS AND VACCINE STRATEGIES TO ENHANCE THE IMMUNOGENICITY OF TUMOR ANTIGENS Vaccination With Modified Tumor Cells The advantage of using tumor cells for vaccination (either autologous cells or cancer cell lines) is that the formulations contain tumor-specific antigens. The major disadvantage is that the production of autologous tumor-derived cell lines is expensive and labor intensive and many more than just tumor-specific antigens will be used for vaccination. The use of cancer cell lines could circumvent this limitation; for example, Melacine and Canvaxin are vaccines derived from melanoma cell lines that have been trialed for the treatment of malignant melanoma. However, clinical trial data from these products are not impressive.116,117 The immunogenicity of killed tumor cells can be improved by transduction with cytokine genes, for example, granulocyte-macrophage colonystimulating factor (GMeCSF), which acts to recruit more DCs to the site of vaccine administration, presumably increasing tumor antigen presentation to the immune system.43 Nevertheless, successes with this approach has remained limited.66,104,113,115

Vaccination With Peptides Vaccination with peptides derived from tumor-specific antigens allows the immune response to be focused to the parts of tumor antigens that are different from normal tissue

Vaccination to Treat Noninfectious Diseases: Surveying the Opportunities

antigens. This may be desirable from a safety point of view, as the risk of inducing autoimmunity is presumably reduced. In addition, peptide antigens are relatively stable, safe, and cost effective. The biggest hurdles for this approach include making the peptide formulation sufficiently immunogenic, defining appropriate peptides, and the limited patient range of a given peptide due to MHC restriction. For increasing immunogenicity, peptides are often administered with adjuvants, including coadministered cytokines, e.g., GM- CSF, CD40L, IL-12, or IL-15.1 In addition, CpG oligonucleotides can be used as an adjuvant to activate numerous immune cells.73,74 Peptides can also be delivered on the surface of mature autologous DCs, an approach that is discussed in more detail later. The problem of identifying “unique” patient-specific tumor antigens may be circumvented by using tumor-derived heat shock proteins as a source of tumor peptides.79 Is peptide-based vaccination successful? In clinical trials of peptide-based cancer vaccines it is often possible to detect immune responses against the peptide in a subset of patients, but this does not necessarily correlate with tumor regression.78,95,101 Using long peptides for vaccination, in combination with cytokines, has demonstrated good efficacy in precancerous lesions of the cervix, and lesion regression could be correlated with the magnitude of the immune response.39

Viral Vectors Expressing Tumor Antigens Viral vectors, including adenoviruses, vaccinia, and avipox vectors, have been used to express tumor antigens and immunostimulatory cytokines.81,142 However, these viral vectors are immunogenic themselves, so two major concerns for this approach are the effect of preexisting neutralizing humoral immunity as well as the problem of the immunodominance of responses against the vector compared with those against the tumor antigen.19 On the other hand, vectored cancer vaccines still hold promise and there is currently phase I/II study ongoing targeting prostate cancer.

Viruslike ParticleeBased Approaches VLPs efficiently enter the MHC class I pathway and cross-prime potent T-cell responses in mice and humans.102 Linking tumor-specific peptides to VLPs may therefore be an attractive way to enhance T-cell responses. Indeed, Melan-A peptide conjugated to VLPs loaded with CpGs as TLR9 ligand induced potent CD8þ and CD4þ T-cell responses in immunized cancer patients. When additionally combined with a ligand for TLR7, responses could be further enhanced.55,23,118

Dendritic CelleBased Vaccines DCs have been used as a kind of vaccine adjuvant for the delivery of tumor antigens to the immune system in an immunogenic form. Although approaches such as direct antigen delivery by targeting DCs with antibodies22 or the use of particulate vaccine

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formulations51 are being pursued, evidence of impaired DC function in animal models of cancer49,50 and cancer patients has led to the ex vivo expansion and maturation of autologous DCs becoming a major focus of cancer immunotherapy.19,21 DCs cultured ex vivo can be either loaded with tumor peptides or tumor lysates,6,50,87,93,144 fused with irradiated tumor cells,111 or transformed with genes encoding tumor antigens by plasmid and viral vectors.4,35,44,135 The major advantage of this method for antigen delivery is that activated DCs are the key APCs involved in priming CTL responses. Increasing the number and quality of these cells that carry tumor-specific antigens should therefore increase the number and quality of tumor-specific CTLs. In clinical trials with cancer patients. there have been encouraging but variable results with DC vaccination to date, which probably reflects the variety of protocols, tumor antigens, and formulations being trialed. For example, Banchereau et al.15 showed clinical responses in 7 of 17 melanoma patients after DC immunization with peptides from four defined melanoma antigens. In another study, however, although DC immunization with undefined tumor antigens from solid tumor lysates elicited DTH responses in several patients, no partial or complete clinical responders were observed.120 One important issue in the field of DC vaccination is the need to ensure that DCs used for clinical trials in humans are reproducibly matured.107 However, very high cost of goods combined with limited efficacy has rendered DC vaccination unattractive. Indeed, Dendreon, a listed company commercializing DC-based vaccination, has closed it’s doors for good.

Approaches to Downmodulate Immunosuppressive Pathways In contrast to the methods outlined earlier, which aim to boost antitumor T-cell immunity by using different type of adjuvants, an alternative possibility is to turn off immunosuppressive pathways that act to limit the T-cell response. Blocking the PD1-PD-L1/2 pathway as well as blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have been proved to be very potent means to enhance tumor immunity. Blocking the PD-1 pathway may allow to activate T cell otherwise blocked by the inhibitory receptor, whereas blocking CTLA-4 may result in reduced Treg activity. A number of such antibodies have been approved for use in humans on their own,7 and a number of studies are ongoing for their combination with vaccination approaches.

VACCINATION AGAINST ALLERGIES Overview Allergy is a rapidly growing disease area, with increasing incidence, severity, and mortality evident in industrialized countries. The well-publicized “hygiene hypothesis” grew out of a proposal to explain the inverse relationship between family size and hay fever incidence.121 This epidemiological hypothesis has found ready support from the

Vaccination to Treat Noninfectious Diseases: Surveying the Opportunities

biological phenomena of Th1/Th2 immune deviation. Children indeed appear to have a more “Th2-like” immune system in early childhood, which becomes more balanced in nonatopic individuals (i.e., not genetically predisposed to allergy) as they age.16,96,97 Most allergies are immediate-type hypersensitivity reactions mediated by IgE and directed against normally innocuous antigens. Allergy is characterized by a sensitization phase that induces allergen-specific IgE, followed by allergic reactions upon reexposure to the allergen. Allergic diseases are driven by an aberrant immune response mediated through CD4þ (Th2) cells and an associated cytokine pattern involving IL-4, IL-5, and IL-13. The Th2 cytokine pattern also promotes isotype switching in allergenspecific B cells to IgE, thereby sustaining the allergic phenotype. Specific immunotherapy (SIT) against allergy was first attempted in 191191 and remains the current treatment for allergy involving the administration of increasing doses of allergen in adjuvant. SIT is not ideal, however, as it requires extensive and long-duration medical interventions for success, it is limited to certain antigens, and involves the risk of inducing anaphylaxis and even promoting allergies to other components of complex allergen mixtures.132 work has focused on improving safety by reducing the anaphylactogenic potential of allergens used in SIT (the so-called “hypoallergenics”) and by using novel adjuvants, including, for example, TLR ligands, to decrease the time required for successful treatment. From a scientific point of view, the mechanism of action of SIT remains unclear. A major hypothesis is that allergen-specific “blocking” antibody induced by SIT (usually IgG1 or IgG4) successfully competes with allergen-specific IgE.133 Furthermore, engaging the inhibitory FcgRIIb by allergeneIgG complexes may inhibit IgE-mediated activation of basophils and mast cells.29,131 Induction of allergen-specific IgG responses may therefore be considered the most important goal of allergen-specific immunotherapy, at least if based on subcutaneous injections of allergen formulations (SCIT).76

Adjuvants Used in SCIT Subcutaneous immunotherapy (SCIT) is based on subcutaneous injection of allergen formulations. Classically, alum has been used as an adjuvant, as it causes a depot effect, enhancing immune responses and presumably reducing side effects caused by the systemic distribution of the allergens.45 However, as SCIT is based on numerous injections (up to 80), exposure to aluminum may become a concern. Crystalline tyrosine may be a valuable alternative, as it has properties similar to those of alum but is biodegradable. If combined with MPL, a ligand for TLR4, it is possible to improve allergic symptoms only for injections, impressively demonstrating the potency of this alternative allergen formulation.40e42 It may be feasible to use even more potent adjuvants; the riskebenefit ratio may, however, become problematic under these conditions, as the allergen alone may already cause rather unpleasant side effects. In a similar way to TLR4 stimuli, DNA containing unmethylated CpG motifs can act as an adjuvant, signaling through

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TLR959 to induce a strong Th1 cytokine response, including the production of IL-12, IL-18, and IFN-g and stimulation of IgG responses.3,75 An interesting and rather novel approach therefore consists of linking the allergen to CpGs, a concept still tested for ragweed allergy.27 In contrast to the MPL mentioned earlier, the CpG is covalently linked to the allergen, presumably enhancing its stimulatory capacities.

Use of Viruslike Particles for the Treatment of Allergies Allergen conjugated to VLPs has proved to be highly effective for the treatment of allergies in preclinical mouse models. Allergens displayed on VLPs exhibited two major advantages over classical formulations, (1) Allergens on VLPs failed to efficiently activate mast cells and basophils. Specifically, the dose response curve was displaced by at least a factor of 100 and no local or systemic reactions were induced in mice. (2) The immunogenicity of allergens was dramatically increased and protective IgG levels were generated after a single injection without measurable side effects. An additional advantage is that the RNA packaged in the Qb-VLPs skews the T-cell response toward Th1, a T-cell subset generally thought to be antiallergic. VLP-based vaccines against allergies are ideal for combination with recombinant allergens, an avenue that is likely followed by a number of large players in the field. It will therefore be interesting to see how such vaccines will perform in the clinic. An alternative approach involving VLPs is their use as adjuvant if loaded with CpGs. Indeed, combining allergen extracts with CpG-loaded VLPs has proved to be very efficient at reducing symptoms in allergic patients. Both open-label and placebo-controlled studies demonstrated good efficacy in a number of different allergen indications.108

SUMMARY AND CONCLUSIONS Therapeutic vaccines for the treatment of noninfectious diseases encompass a wide variety of possible formulations, antigens, and mechanisms of action. Some vaccines aim to stimulate a strong humoral or cell-mediated immune response, whereas others are designed to induce the deviation or suppression of an existing reaction. Adjuvants, as a method of modifying the immune response, have an important part to play in fulfilling the potential of vaccination for noninfectious diseases. Vaccination as a treatment for infectious disease has been hugely successful, but treatments for noninfectious diseases such as the induction of humoral responses against selfantigens, T-cell responses against tumors, or IgG responses against allergens lead to their own special problems. The key will be balancing the competing requirements of treatment of these diseases versus immunopathology by careful appreciation of the underlying disease mechanisms and the consequences of pushing the immune system too far in one direction (Fig. 21.2). For example, humoral immunity sufficient to block the action of a self-antigen may lead to increased susceptibility to certain diseases, and special emphasis

Vaccination to Treat Noninfectious Diseases: Surveying the Opportunities

Transplants accepted Autoimmunity reduced Allergy reduced

Tolerance, Immunosuppression

Tumor immunity compromised Danger bei infectious diseases Protection from intracellular pathogens Less organ-specific autoimmunity

Immunity

Transplant rejection Autoimmunity Allergy

Induction of a strong immune response Antibody-mediated

Cell-mediated

Allergy Systemic autoimmunity Reduced allergy Immunity against intracellular pathogens Increased tumor immunity Helminth immunity decreased Organ-specific autoimmunity

Tumor immunity Protection from infectious diseases

Tumor immunity Protection from intracellular pathogens Less allergy T-cell driven autoimunity

Induction of the right class of response Th2

Th1

Immune deviation of an existing response

Reduced organ-specific autoimmunity Enhanced helminth immunity Reduced immunity against intracellular pathogens Increased allergy Decreased tumor immunity

Figure 21.2 The balancing act of the immune system. Therapeutic vaccinations may conceivably alter the balance of immunosuppression and immunoreactivity, the class of immune response elicited, and the particular pathway of Th differentiation. All these interventions could have positive and negative consequences, which should be considered in vaccine formulation design.

should be placed on the reversibility of the effect. Also, although strong cell-mediated immunity is almost certainly required for successful vaccination against cancer, care should be taken to choose antigens that will not lead to autoimmunity. Interference with the mechanisms of immunosuppression should also be made with care. Does overcoming immunosuppressive mechanisms in cancer therapy predispose to allergy or, more problematic, autoimmunity? Does blocking cytokines cause susceptibility to infection? The answers to these important questions will only become clear with the continued careful development of vaccines and their formulations.

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