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The Revised Authoritative Guide To Vaccine Legal Exemptions

Comprehensive, authoritative information about vaccine exemptions you can trust, from Alan Phillips, J.D., a leading vaccine rights attorney with years of experience helping clients throughout the U.S. legally avoid vaccines in a wide variety of vaccine-refusal settings. Critical details for parents, students, immigrants, healthcare employees, military personnel and contractors, agencies, attorneys and clientsvirtually anyone concerned with legally avoiding vaccines in the United States. This Guide provides and explains: Important background information about the legal system; How state and federal statutes, regulations, constitutions and legal precedent interact to define the boundaries of your legal exemption rights; How to deal with local authorities and to avoid mistakes that cost others their exemption; Where legal technicalities and practical reality differand what to do about it; Continue reading...

The Revised Authoritative Guide To Vaccine Legal Exemptions Summary

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Cellbased Cancer Vaccines

However, as the science of determining how an effective APC initiates an immune response advance, these strategies are being used to alter tumor cells and render them as loci of immune stimulation. The most general method for cell-based immunotherapy is to use a single representative cancer cell as a universal vaccine for all patients with that same type of cancer. Some investigators consider this approach as suboptimal as it is allogeneic, where the MHC type of the vaccine and the patient do not match, and the immune system may be distracted from generating a tumor-antigen-specific to an allospecific response. Others argue that an allogeneic vaccine will be effective for just this reason, and that the alloimmune response will serve to amplify the cancer-antigen-specific response. This issue will be addressed in Chapter 10, where Copier and Dalgleish discuss the use of whole tumor cells as vaccines in this unique approach to cancer therapy, as tumor-specific...

Carbohydrate Antigens and Vaccines

As early as 1918, Landsteiner and Lampl (147) observed that nonimmuno-genic small molecules (haptens) could be rendered immunogenic by covalent coupling to proteins. The pneumococcal capsular polysaccharides by themselves are relatively weak stimulators of the immune system in producing antibodies, but when conjugated to a protein carrier they can serve as effective vaccines for targeting virulent strains of pathogenic bacteria. The validity of this concept was demonstrated in 1931 by Goebel and Avery (148), who coupled the type 3 pneumococcal polysaccharide to horse-serum globulin to produce a conjugate that induced specific antibody to the polysaccharide antigen in experimental animals. The success of this approach is amply demonstrated in the development of effective vaccines for clinical use, with the notable example of antibacterial prophylaxis against childhood meningitis using a conjugate vaccine prepared by coupling the capsular material of the Gram-negative bacterium...

Synthetic Carbohydratebased Vaccines

Unimolecular Monovalent Vaccines Our first vaccine constructs were monovalent in nature, composed of a single antigen conjugated to an immunogenic carrier molecule, such as KLH. In order to achieve appreciable levels of immunogenicity in mouse or human settings, these vaccine conjugates must be coadministered with an immunoadjuvant, in our case, QS21 7 . One of the original constructs to be synthesized in our laboratory was the Globo-H-KLH conjugate 8 . Globo-H, a hexasaccharide, was first isolated from the human breast cancer cell line (MCF-7) and later found to be overexpressed in a variety of other cancer cell lines, including colon, lung, ovarian, and prostate 9 . At the time, the synthesis of the Globo-H antigen was a significant undertaking, and provided an important platform for the evaluation of our glycal assembly protocol, outlined above (see Scheme 2.1). The Globo-H-KLH vaccine performed well in immunologic investigations 10 . Preliminary studies conducted on mice revealed...

Selection Of Vaccines

The primary aim of developing antitumor T-cell vaccines is to induce effective cytolytic T-cell response against tumor cells. This section will focus on the contributions of antigen processing in the selection of effective T-cell vaccines, i.e., vaccines that induce tumor-reactive CD8+ T cells. It will not discuss the impact of antigen processing on production of CD4+ helper T-cell epitopes, mainly because of insufficient characterization of this process. As described above, several intracellular factors can influence the processing of the target epitopes. These factors should naturally be reckoned with during the development of T-cell vaccines. However, vaccines themselves can also be administered in different forms (peptides, proteins, immune complexes, DNA, RNA, etc.), which may or may not be influenced by intracellular processing and impact on their efficacies.

With Bcrablderived Peptide Vaccines

As discussed above, many clinicians still consider allo-geneic stem cell transplantation to be the gold standard for curative therapy in CML by virtue of the long-term survival achieved and the ability of this modality to render the patient BCR ABL negative using PCR-based assays. The importance of the immunologic properties of the graft has received a great amount of attention, with attempts to recapitulate a GvL effect while separating it from the side effects of conventional transplantation regimens undertaken by a number of investigators. The potential to induce and then employ specific antileukemic immune effectors is attractive and has seen realization in the formulation of a vaccine strategy for this disease. Based on the immunogenic evidence of b3a2 peptides-derived translocation, the Memorial Sloan-Kettering Cancer Center (MSKCC) Group initiated studies to evaluate the safety and immunogenicity of a multidose, multivalent BCR ABL breakpoint peptide vaccine in CML patients,...

Research into a DNA Vaccine for HIV

As of 2006, there was no vaccine to prevent infection by the human immunodeficiency virus (HIV), the virus that causes AIDS. It is important to develop an effective and safe vaccine, since over 25 million people died from AIDS-related causes between 1981 and 2005. Consequently, scientists around the world are working intensively to develop a DNA vaccine and have tested many of these vaccines. Such vaccines are made artificially, so they do not contain any actual HIV viruses. As a result, DNA vaccines cannot infect anyone with HIV. So far, the only side effects associated with experimental HIV DNA vaccines have been minor irritation around the injection area, a low fever, and minor body aches that quickly go away. As with other experimental DNA vaccines, a future HIV vaccine should be safe, inexpensive to make, and not need refrigeration, so that it will be easy to store and give to those who need it.

Vehicles For Delivery Of Peptidebased Vaccines

The recent elucidation of the requirements associated with CTL activation, such as the maturation of antigen-presenting cells (APCs) and the production of proinflammatory cytokines, has led to the generation of more effective peptide-based vaccine strategies aimed at eliciting the signals required to generate CTLs. These include recombinant bacterial and viral vectors recombinant DNA-based delivery systems and lipid-based delivery systems, such as immunostimulatory complexes (ISCOMs), lipopeptides, and liposomes 4-8 . The most successful of these delivery vehicles are self-adjuvanting, having the capacity to target pattern recognition receptors on the surface of APCs in order to provide the necessary signaling required for maturation of the APC, in addition to the capacity to deliver antigens into the MHC class I pathway. A number of these delivery vehicles, including viral, DNA, and lipid-based vectors, have been shown to be safe for use in humans.

Vaccine development and licensing

Vaccine and manufacturing process design Early attention to regulatory requirements for characterization and sourcing of strains, raw materials and appropriate quality systems can reduce the need to repeat work at a later stage. The choice of an appropriate glycan and carrier protein will be made early in product development, and should include consideration of manufacturing and testing requirements of these components. For example, batches of chemically or genetically toxoided toxins should be assessed for reversion to toxicity (6-9), or may be subject to existing pharmacopoeial monographs. The disease target will define the appropriate glycan chain and hence influence the preferred manufacturing method and conjugation chemistry to be used (I). When glycans are prepared from bacterial sources, the strain should be from a reliable source or well characterized in-house, and animal-derived culture components should be avoided (23). Experience indicates that a wide variety of structural...

Peptidebased Vaccines For Treatment Of Human Diseases

Animal models have thus far provided a platform to model and optimize peptide-based vaccine strategies, typically by analysis of CTL responses of a single specificity presented by a single MHC molecule. Similarly, single-peptide-based vaccines have also been employed in a number of clinical trials to treat human malignancies 9 . However, the development of effective peptide-based vaccines for use in humans will likely be more complex, requiring the presence of pep-tides presented across a broad range of human HLA types. Although vaccination with full-length antigens offers an alternative to defining CTL epitopes across all HLA types, the nature of the antigen in question can significantly impact on its suitability as a vaccine candidate. Antigens may be toxic or oncogenic 10 , and therefore inappropriate for use as full-length antigens in vaccines. Some antigens are known to be immunosuppressive or nonimmunogenic 11 , and vaccination with the full-length antigen may not result in...

Table 230 Key steps in the planning of an vaccination campaign

Plan vaccination strategies mass vaccination campaigns vs. routine vaccination selective vs. non-selective vaccination. 4. Define needs number of vaccine doses cold chain equipment other supplies (auto-destruct syringes, safety boxes, monitoring forms, vaccination cards, tally sheets) staff. 5. Implement vaccination campaign safety of injection safe disposal of injection material record keeping individual vaccination cards other activities (e.g. nutritional supplementation and vitamin A, treatment of complications) health education and social promotion materials. 6. Evaluate coverage percentage vaccinated among estimated target population) incidence of side-effects (post-vaccination surveillance).

Mass vaccination strategies

To implement a mass vaccination campaign in emergencies, there are two main strategies. 1. Vaccination can be carried out at the screening centre on arrival at a camp. This is possible when the screening facility has been set up and the influx of refugees is steady and moderate. 2. Vaccination sites can be set up in different sections of the target area and mass vaccination carried out by outreach teams. This is necessary when the population has already settled at a site or the influx has been too rapid to organize a screening facility.

Routine vaccination strategies

In the case of measles, once the target population has been immunized in the mass campaign, measles vaccination must become part of health care activities. Ongoing vaccination is required to cover children who might have missed the initial vaccination campaign, children vaccinated at the age of 6-9 months who must receive a second dose of the vaccine at 9 months, Vaccination may be selective, whereby the vaccination status of the child is checked on the basis of a vaccination card and the vaccine is given if there is no evidence of previous vaccination. In non-selective vaccination, vaccination status is not checked and all children are immunized regardless of their immune status. A second dose of measles vaccine has no adverse effect. Non- selective vaccination is preferred in a mass campaign, as it is quicker and leaves little chance for error. The first activity is to assess the need for an vaccination campaign by Data on background vaccination coverage in the emergency-affected...

Strategies To Enhance Dna Vaccine Potency

One method for boosting antigen-expressing DC populations is to find the most effective routes for the delivery of DNA vaccines. Among the different routes of DNA administration, we have concluded that vaccination via gene gun is one of the most potent methods for the delivery of genes of interest into DCs 2 . The gene gun is used to fire DNA-coated gold particles into the epidermis and efficiently transfect intradermal DCs that can mature and migrate to the lymphoid organs for T cell priming. Thus, gene gun delivery of DNA represents a convenient and effective method for the in vivo introduction of naked DNA into DCs. Another strategy for increasing the number of antigen-expressing DCs is to promote the spread of an encoded antigen between DCs by linking the antigen with proteins capable of intercellular transport. We have investigated the use of DNA encoding HPV-16 E7 fused to herpes simplex virus type 1 VP22 (HSV-1 VP22), a viral protein with intercellular trafficking properties,...

Oral cholera vaccines

New generation orally administered cholera vaccines (OCV) have passed the stage of research and development and two formulas are commercially available. Currently, the main users of marketed OCV have been individual travelers from industrialized countries who expect to be exposed temporarily to the risk of cholera while traveling in endemic areas. Recently, there has been renewed interest in using oral cholera vaccines in mass vaccination campaigns, in conjunction with traditionally recommended control measures such as provision of safe water and improved sanitation. Several mass-vaccination campaigns using OCV have been performed with the support of WHO. In 2000, the Federated States of Micronesia exposed to an ongoing outbreak in Pohnpei Island decided on using the live-attenuated oral cholera vaccine CVD 103-HgR to limit the spread of the outbreak. A retrospective analysis suggested that mass vaccination with OCVs can be a useful adjunct tool for controlling outbreaks, particularly...

Anti Hib conjugate vaccines

Actual anti-Hib vaccines are composed of either the capsular polysaccharide or its oligosaccharide fragments isolated from bacterial growth. Hence, the molecular weights of effective commercial vaccines cover a wide range of sizes, ranging from the intact capsular polysaccharide to relatively small oligosaccharide fragments (7) containing 5-15 ribosyl-ribitol-phosphate repeating units. Despite the enormous differences in composition, the mechanism of action is quite similar and therefore no major differences were found in clinical trials that could be associated to the size of the polysaccharide (8).

Therapeutic Vaccines and Toleragens

While vaccines have traditionally been used as prophylactics, they are increasingly being used as therapies for already established chronic disease.31 For autoimmune disease therapy, a peptide similar to that causing the disease is administered to the patient in theory, the vaccine then stimulates an immune response to the T cells reacting in the disease. This presumes that the autoantigen(s) is known, and that the disease is caused by one or a few antigens. An advantage to this hypothetical mechanism is that the anti-Tcell response should, in theory, be specific for the T cells contributing to disease pathogenesis. Glatiramer acetate is the first vaccine that has been used to treat an autoimmune disease - in this case RRMS32 it was approved by the US FDA in 1996. It is a mixture of many synthetic peptides - random polymers - that mimic the antigenic portion of MBP. It reduces the relapse rate in RRMS, impacts MRI markers of disease activity, is well tolerated, and does not appear to...

Cytokine Modified Tumor Vaccine

Several cytokines such as IFN-a, IFN-g, IL-12, and IL-2 have been used to enhance an antitumor CD8+ response (32-35), of which one of the most effective cytokines used as an immune adjuvant is GM-CSF (36). GM-CSF is a powerful immune adjuvant, and attracts and activates DCs at a site of vaccination (37). Transducing polyvalent tumor cells with GM-CSF has the advantage of recruiting DCs to the vaccine where it encounters a multitude of potential tumor antigens to provide a wide-ranging and durable response. Preclinical studies in a B16 mouse-melanoma model have demonstrated that GM-CSF transduced tumor cells, in comparison to other cytokines such as IL-4 and IL-6, and induced the most potent systemic antitumor effect (36). Many subsequent studies in other murine tumor models have validated the potent systemic immunity induced by GM-CSF-transduced tumor-cell immunotherapies (38-40). The above-mentioned approach is currently followed in clinical trials for treatment of several types of...

Infectious Disease Vaccines

Generation of vaccines for infectious diseases has been more successful for obvious reasons in that the antigen is foreign and the immune system can therefore mount a robust response. This vital observation by Edward Jenner in 1796 revolutionized this discipline when he inoculated people with the related cowpox virus to build immunity against the deadly smallpox virus, leading to the global eradication of the disease by 1980. Prophylactic cancer vaccines that prevent the onset of cancer have shown success in a preventative setting through neutralizing antibodies against the virus that is the causative agent for some cancers. The recently approved vaccine Gardasil is of prominence for cervical cancer in young women 9 to 26 years of age who are protected from the onset of infection to the HPV (1). This VLP vaccine is effective against HPV types 16 and 18, responsible for approximately 70 of cervical cancers, and against HPV types 6 and 11, which cause approximately 90 of genital warts....

Vaccine for Alzheimers

Alzheimer's disease is a condition where the nerve cells of the brains of elderly people slowly stop working, leading to memory loss, madness, and death. Some scientists think that Alzheimer's is caused by the buildup in the brain of chemicals called amyloid-beta peptides. They are trying to make a vaccine using a kind of vaccine called a DNA vaccine. In this kind of vaccination, DNA is put into body cells. This DNA acts like a recipe for an antibody, which is a substance that helps the body's immune system recognize germs. The antibody made by cells that have received the DNA vaccine are for amyloid-beta peptides. That is, these antibodies cause the body's lymphocytes to attack amyloid-beta peptides and destroy them. Researchers have had good success in mice with DNA vaccine, but are quick to point out that human beings are not simply large mice. What works in mice often does not work in people. It will be years before we can know whether an Alzheimer's vaccine for humans is...

Lessons Learned From Traditional Cancer Vaccine Trials And Infectious Disease Vaccine Models

Over the past two decades, cancer vaccines as a possible treatment modality have seen much promise. While a variety of approaches in preclinical studies have induced a cure for mouse cancers, several of these approaches have been tried in human with limited success. The only approved therapeutic cancer vaccine, a xenogeneic DNA vaccine, was for the treatment of canine melanoma (74). However, the field has substantially matured, with information from a host of clinical trials now available to help in the understanding of major aspects of preclinical and clinical vaccine development. In contrast, infectious disease vaccines target an invading pathogen, and the success in developing this type of vaccine is inherently straightforward. Taken collectively, there are some elements from these studies that may be useful in developing therapeutic cancer vaccines regardless of whether the cancer arises from self-tissue or is induced by a pathogen. There are several factors in the preclinical...

The L12R4 Vaccination Model

Vaccination of syngeneic mice (i.p.) with mitomycin C-treated L12R4 (L12R4M) lymphoma cells induces a tumor-specific immune response with life-long specific memory the mice are resistant to further inoculation with live tumor cells even in high quantities (Rubin 2009 Gonthier et al. 2004). In this model, CD4+ Th1 cells are activated by L12R4-processed material associated with MHCII molecules on mature DCs (Corthay et al. 2005), and the activated Th1 cells help the activation and differentiation of CD8+ L12R4-specific CTL and memory cells (Denizot and Rubin 1985). These CTLs are specific for variable region epitope(s) on the TCR expressed by the L12R4 cells (Va10 Vp12), or for unknown household protein epitope(s). Thus, this is an example of a tumor-specific antigen which is normally present in the antigenic repertoire of self however, a special Va Vp combination with multiple CDR3 variations may be present in such low concentrations that the negative selection in the thymus neglects...

The conjugate vaccine

Several proteins from bacterial origin were tested as carrier candidates. Finally, tetanus toxoid was selected because of its many advantages a) wide experience of its use alone or as a carrier for Hib conjugate vaccines b) it is probably the cheapest bacterial protein available c) it can be produced with an acceptable degree of purity d) its solubility and the availability of its amino groups for conjugation are ideal. Several years ago (24) we adapted a procedure from peptide-protein chemistry for the conjugation of oligosaccharides to proteins. This process is distinguished by its simplicity and the high conjugation yield of the oligosaccharides. Tetanus toxoid (TT) was initially thiolated with N-hydroxysuccimide dithioproprionate to provide -30 lysine amino groups Compound 22 was further developed as a vaccine candidate. In a series of experiments (25), immunization of laboratory animals with 22 elicited antibodies similar to those elicited by commercially available vaccines in...

Therapeutic Cancer Vaccines Vs Traditional Cancer Treatment

Therapeutic cancer vaccines belong to a newer class of targeted cancer therapies. Like innovative treatments such as Gleevec (imatinib mesylate Novartis, New Jersey, U.S.) and Herceptin (trastuzumab Genentech, California, U.S.), most cancer vaccines in development are designed to attack only malignant cells. By targeting tumor cells with high specificity, this new class of treatments tends to be associated with fewer toxicities compared with traditional cancer drugs. The increased risk of cancers in patients with medically induced primary or acquired immunosuppression has firmly established a role for the immune system in the control of cancer (11). The tumors observed in medically immuno-suppressed organ transplant patients are similar to cancers seen in individuals infected with human immunodeficiency virus (HIV). HIV patients have a 10,000-fold increased risk of developing blood cancers as well as a significantly higher incidence of other cancers (11,12). However, similar to...

Live Recombinant Vaccine Vectors

Intracellular bacteria have attracted special interest as vaccine delivery vectors because of their ability to target antigen presenting cells (APCs) directly. While Salmonella and Mycobacteria remain in the phagosome, which they are able to modify in order to escape lysis, Listeria and Shigella avoid the antimicrobial environment of the phagolysosome by escaping into the cytosol (Fig. 8.1). This has important consequences on antigen presentation as peptides from the phagolyso-some usually are presented in the context of MHC class II, whereas antigens derived from the cytosol are processed in the ER and loaded on MHC class I 4 . Listeria monocytogenes as a Vaccine Vector

Personalized Cancer Vaccines

Despite the varied approaches employed by the many therapeutic cancer vaccines in development, they all share one fundamental goal to program a patient's immune system to attack the patient's cancer. Some vaccines utilize antigens (any substance capable of stimulating an immune response) that are known to be associated with certain types of tumors. In recent years, there was an increased interest on so-called unique antigens that are products of random mutations arising in the course of tumor cells' uncontrolled cell divisions. This led researchers' interest and work on personalized (autologous) cancer vaccines that use the patients' own tumor cells to generate immune response specific to the The personalized vaccines have the opportunity to present to the host immune system the entire repertoire of the mutated peptides (antigens capable of triggering immune system response) resulted from the degradation of encoded proteins. The vaccines prepared from patient's own tumor have the...

Immunology of Experimental Synthetic Carbohydrate Protein Conjugate Vaccines against Streptococcus pneumoniae Serotypes

ijkman-Winkler Institute for Microbiology, Infectious Diseases and Inflammation, Vaccines Section, University Medical Center Utrecht, Heidelberglaan 100,3584 CX Utrecht, The Netherlands 2Bijvoet Center, Department of Bio-Organic Chemistry, Utrecht University, Padualaan 8,3S84 CH Utrecht, The Netherlands 23-valent PS vaccine The capsular PS of the 23 most prevalent serotypes have been included in the licenced 23-valent PS vaccine (34, 35). This vaccine provides protection against 73 of the strains and reduces the risk of systemic infection in the adult population by 83 (36). The efficacy of the vaccine, however, is debatable in groups at risk of pneumococcal infections (37, 38). For example, ineffective antibody responses after vaccination have been reported in the elderly (39) and the poor immunogenicity of the PS vaccine has been shown beyond doubt in infants (40). Polysaccharide-protein conjugate vaccines As noted above, the conventional 23-valent PS vaccine provides insufficient...

How Wholecell Vaccines Elicit Effective T Cell Responses

Preclinical studies in mice have demonstrated robust antitumor responses to whole-cell vaccines that are dependent on a variety of immunologic mechanisms, including T cell (both CD4+ and CD8+) and NK responses, and the presence of macrophages and eosinophils depending on the formulation of the vaccine 3-10 . How these vaccines work is poorly defined and remains an area of controversy. The majority of studies indicate a substantial requirement for cytotoxic T cell responses that are elicited through one or both of the following mechanisms either (1) the vaccine cells directly prime T cells or (2) vaccine antigens are taken up by professional antigen-presenting cells (APCs), which then stimulate a T cell response, an effect known as cross-priming. Evidence for direct priming is scant, but a few studies have indicated that access of tumor cells to the T cell areas of the lymph node are a requirement for tumor rejection, indicating the likelihood of a direct interaction between the...

Challenges In Clinical Development Of Cancer Vaccines Longer Trials to Reach Evaluable Clinical End Points

There are several differences between traditional cancer treatments and therapeutic cancer vaccines, which largely stem from the differences in the action of newer targeted treatments such as cancer vaccines compared with the classical, cytotoxic (cell-killing) that characterize most of the current cancer treatments. Supported by numerous animal studies, these differences are consistent with basic principles of tumor immunology, and include The action of cancer vaccines is primarily cytostatic rather than cytotoxic therefore, treatment effect typically includes slowing tumor growth instead of reducing tumor burden. Cancer vaccines are most effective when tumor burden is low and thus function well in the earlier-stage disease or adjuvant treatment settings. There appears to be a latent period before cancer vaccines exert a treatment effect. This is likely due to the time required for adequate tumor-targeting immune mechanisms to maximally expand. Collectively, these differences...

Advantages Of Wholecell Vaccines

There are a number of advantages to using whole-cell vaccines. As mentioned above, there is no specific requirement for knowledge of the nature of the target antigen. In addition, cellular vaccines can be modified in ways that modulate immune responses (see discussion below). The polyvalent approach assumes that vaccine cells have an antigenic profile identical to, or overlapping with, the patient's tumor. In the case of autologous tumor cell vaccines, prepared directly from resected tumor tissue, this is probably the case, and clinical benefit has been shown using such vaccines in randomized trials of colorectal and renal cancers 20,21 . However, autologous vaccines have a number of disadvantages when translated to the clinic. Resected autologous tumor's must provide enough cells for a vaccine schedule, and where this is not possible, they must be amenable to culture, which is often not the case. Moreover, lengthy culture periods can allow sufficient time for a patient's disease to...

Effectiveness Of Allogeneic Wholecell Vaccination

Proof of principle for the effectiveness of allogeneic whole-cell vaccination has been established in mouse tumor models where both prophylactic protection against tumor challenge and the presence of tumor-specific CTLs was demonstrated 22,26,27 . In a rat Lobund-Wistar model of prostate cancer, prophylactic vaccination with an allogeneic cell vaccine was effective in protecting 80 of the treatment group against challenge with a PAIII tumor 28 . When this was repeated in a Copenhagen rat model (where the cancer was poorly immunogenic and more aggressive), no protection was elicited by treatment with allogeneic vaccine. However, this and other studies have shown that addition of adjuvant to ineffective allogeneic vaccines leads to protection against tumor challenge 27,28 . Clinical trials have been quick to follow, and while encouraging clinical results have been shown in melanoma and prostate cancer, there remain difficulties in monitoring immunologic responses to such vaccines....

Modification Of Allogeneic Cell Vaccines With Costimulatory Molecules

Tumor cells are generally thought to be poorly immunogenic, although immuno-genicity varies considerably between tumors of different backgrounds. A variety of strategies have arisen that are aimed at improving the immunogenicity of the vaccine including modification of vaccine cells to express costimulatory molecules or cytokines. Modification of allogeneic cell lines is often difficult as transfection often fails and it is necessary to use viral vectors to introduce the relevant cDNA, which itself carries certain implied health risks to patients. Nevertheless, a certain degree of success has been obtained in preclinical and clinical studies using modified allogeneic cells as cancer vaccines. Poor immunogenicity is due at least partly to the heterogeneous expression of MHC and costimulatory molecules 33,34 . The absence of costimulation raised concerns that vaccine cells might induce tolerance, and consequently the introduction of B7.1 CD80 costimulatory molecules into vaccine cells...

Modification Of Allogeneic Vaccines To Secrete Cytokines

Recombinant cytokines expressed by modified tumor cells can be used to target the cytokine to tumor or vaccination sites where they can induce a proinflammatory environment, with the additional benefit of lowering the levels of circulating cytokine and therefore circumventing the toxicity related to high systemic doses. Cytokine-secreting tumor cells have been tested extensively in mouse models for their efficacy in reducing tumorigenicity, protecting against tumor challenge and raising immune responses. To date a range of cytokines, including IL-2 6,47,48 , IL-4 8,49,50 , IFNy 51,52 , GM-CSF 53 , IL-12 54,55 , IL-15 56 , IL-21 57-60 , IL-23 61-63 , and IL-27 64-66 , have been investigated in models of autologous tumor cell vaccination with a considerable degree of success. Of these only IL-2 and GM-CSF have been shown to have potential in allogeneic tumor cell vaccination models. Interleukin 2 is produced by CD4+ T cells of the TH1 type. It...

New Therapies 41 Anti Idiotypic Vaccines

Since all major chemotherapeutic treatments in CLL induce good responses but are unable to effect a cure, one of the major questions that needs to be answered is whether there is a place for immunotherapeutic approaches like anti-idiotypic vaccines. Since each B-cell undergoes a unique, characteristic, rearrangement and since malignant B-cell hemopathies are characterized by clonal expansion of a clone displaying a unique rearrangement, idiotype constitutes a privileged tumor antigen. One of the aims of tumor immunotherapy is the induction of CD8 cytotoxic T-lympho-cytes. Although, trials of idiotype vaccination have not been reported in CLL, interesting results were reported in the case of lymphoma patients (93).

Active Specific Immunotherapy Vaccines

As a general concept a therapeutic antitumor vaccine refers to the subcutaneous administration of a tumor-specific antigen with the intent to induce an active and possibly long-lasting humoral and or cellular immune response able to eliminate tumor cells harboring the putative antigen. Many years of disappointing clinical results with antitumor vaccines against different types of advanced solid tumors has taught tumor immunologists that the best setting for effective immunotherapy is the situation of MRD (10). In CML, like in other tumors, the ideal vaccine candidate would be an antigen expressed only in tumor cells, but common to all patients. It should be highly immunogenic and should be essential for tumor cell survival, and thus not susceptible to mutation or deletion. Several CML antigens have been identified as potential targets for an anti-CML vaccine strategy (Fig. 1), and different approaches at different stages of development are now under evaluation for CML patients (Table...

True Chronic Myeloid Leukemia Specific Antigen Vaccines

The BCR-ABL-derived p210 protein and particularly the alternative b3a2 or b2a2 peptide epitope at its fusion point is the most obvious CML-specific target, and thus was first explored for a vaccine strategy. p210 is exclusive to the CML clone, and the sequences of amino acids contained in the b3a2 and b2a2 junctional regions represent unique tumor-specific determinants, which can be exploited for an immunological attack against the tumor cell (11). Recent data support the hypothesis that peptides binding HLA with moderate-to-high affinity are capable of stimulating T-cells after natural processing and cell surface presentation within the cleft of the appropriate HLA molecule. Within the p210 b3a2 breakpoint sequence, five junctional peptides were found to be capable of binding to certain HLA class I and class II molecules and were shown to elicit in vitro a specific T-cell response both in normal donors (12) and in CML patients (13). After these initial observations, p210 b3a2...

Development of a Carbohydratebased Vaccine against Malaria

Anti-Malarial Carbohydrate-Based Vaccines In contrast to other diseases, humans are only able to develop partial immunity to malaria (31). In areas of high transmission, immunity to malaria is acquired in two stages an initial phase of clinical immunity occurs despite persistent high parasitemias, followed some years later by an antiparasite immunity which limits parasite numbers, replication and burden within the host. Vaccines designed to provide protective immunity against malaria by lowering the parasite burden have several disadvantages. Evidence for considerable redundancy in invasion pathways, immune evasion strategies, and problems of major histocompatibility complex (MHC)-linked genetic restrictions in the immune response to the parasiticidal antigens, complicate vaccine development (30). Antigenic diversity and variation may also enhance evasion of immunity and breakthrough parasites. For these reasons, multi-component vaccines are desirable, and a great deal of effort is...

Tregulatory Cells And Tumor Vaccines

Tumor vaccines have enjoyed some limited successes, but their utility remains modest. Although some vaccines induce TAA-specific immunity, significant, lon-glasting clinical benefits from these vaccines have seldom been observed. The prior discussions of tumor-associated Tregs now help provide mechanisms for the failure of at least some vaccines. Effective cancer vaccines must overcome the immunosuppressive tumor microenvironment to help stimulate a potent antitumor immune response. However, more recent data suggest that cancer vaccines may contribute to immunosuppres-sion by expanding tumor microenvironmental Tregs 7 . These data are consistent with other recent data showing that certain subsets of dendritic cells can also expand various Treg subsets 8,9 . Taken together, these data imply that the capacity of cancer vaccines to induce effective antitumor immunity may be impaired by the simultaneous expansion of vaccine-induced Tregs. As we begin to combine Treg depletion with active...

Shared Tumor Antigen Peptide Vaccines

Another active-specific immunotherapy with potential antitumor effect in CML relies on the use of intracellular proteins other than p210. In fact a number of self proteins are aberrantly overexpressed in CML and other tumor cells while being expressed at low levels in normal lineages and thus may function as targets for directed immunotherapy of residual disease. As in the case of p210, despite the intracellular location of these proteins, short peptides produced by their cellular processing can be presented on the cell surface within the cleft of HLA molecules and in this form they can be recognized by T cells. Several peptide vaccines derived from such proteins have reached the stage of clinical development in CML patients. Proteinase-3-Derived Peptide Vaccines been detected in CML patients and have been implicated in the clearance of malignant cells in patients treated with IFN-a or stem cell transplantation (SCT) (24). Vaccinations of PR1 peptide in Montanide were administered...

Malignant Glioma Responsiveness To Chemotherapy Postdc Vaccination

The processes that can explain a reason why tumor recurs despite CTL induction by DC vaccination are immunoselection and immunoediting. These processes allow tumor cells to escape from CTLs by antigen loss (65,66). The potential synergies between immunotherapy and other therapies must therefore be investigated due to the clinical inconsistency of cancer vaccines and the effects of immunoselection on tumor evolution (67-69). Cedars-Sinai Medical Center (68) and Brigham and Women's Hospital have conducted clinical trials to examine the synergy of vaccines with chemotherapy treatment (70). A retrospective analysis of clinical outcomes (survival and progression times) in 25 vaccinated (13 with and 12 without subsequent chemotherapy) and 13 non-vaccinated de novo GBM patients receiving chemotherapy was performed. Patients who received post-vaccine chemotherapy demonstrated longer survival times and significantly longer times to tumor recurrence after chemotherapy relative to their own...

Which vaccines are effective in COPD

Polyvalent pneumococcal vaccine is used in many countries to protect against the development of pneumococcal lung infections 15 , but there is little evidence that it is specifically beneficial in patients with COPD, and it therefore cannot be routinely recommended. Influenza vaccine is usually recommended, as patients with COPD are subject to severe exacerbations with this infection. Neuraminidase inhibitors, such as inhaled zanamivir or oral oseltamivir, are now becoming available for the treatment and prevention of influenza A and B infections 16 . However, it has not yet been shown that they specifically reduce the duration of exacerbations in patients with COPD, and they would only be of value during an influenza epidemic.

Chronic Myeloid Leukemia Cell Derived Multi Antigen Vaccines

Heat Shock Protein Vaccines Heat shock proteins (HSPs) are ubiquitous protective intracellular molecules induced by cellular stress, which act as chaperones for peptides. HSPs isolated from tumor cells carry an array of tumor-specific peptides capable of inducing immune responses. In fact, purified HSP-peptide complexes have been demonstrated to activate CD8+ and CD4+ lymphocytes to induce innate immune responses, including natural killer (NK) cell activation, cytokine secretion, and induce maturation of DCs (33). In a phase I trial, vaccinations with patient-specific autologous leukocyte-derived HSP70 peptide complexes were given to 20 CML patients who had cytogenetic or molecular evidence of disease despite ongoing treatment with imatinib (34). In each patient entering this study, HSP70 was purified from the leukapheresed peripheral blood mononuclear cells and administered in eight-week intervals as intradermal injections without immunological adjuvant. The vaccine produced no...

Future Strategies For Dc Vaccines

The success of vaccines depends on the identification of appropriate tumor antigens, establishment of effective immunization strategies, and their ability to circumvent inhibitory immune mechanisms. The challenge for scientists in the future will be to further extend our fundamental knowledge of DC immunobi-ology, tumor immunology, and cancer biology, and to implement these findings in the rational design of DC immunotherapy for the treatment of cancer patients. The challenge with vaccination strategies is to break tolerance so that the patient's immune system recognizes cancer cells. Several aspects involving DC vaccines need to be optimized to include the protocol of DC generation, DC subtype, dose and timing interval of vaccination, route of administration, approaches of antigen loading, and especially DC maturation (71). Recently, a group of researchers has identified a small population of cancer stem cells in adult and pediatric brain tumors (72). These cancer stem cells form...

Strategies For Vaccine Development

The birth of immunology as a science dates from Edward Jenner's successful vaccination against smallpox in 1796. The importance of prophylactic immunization against infectious diseases is best illustrated by the fact that worldwide programs of vaccination have led to the complete or nearly complete eradication of many of these diseases in developed countries (see Chapter 1, Table 1-1). The fundamental principle of vaccination is to administer a killed or attenuated form of an infectious agent, or a component of a microbe, that does not cause disease but elicits an immune response that provides protection against infection by the live, pathogenic microbe. The success of vaccination in eradicating infectious disease is dependent on several properties of the microbes. Vaccines are effective if the infectious agent does not establish latency, if it does not undergo much or any antigenic variation, and if it does not interfere with the host immune response. It is difficult to effectively...

Attenuated and Inactivated Bacterial and Viral Vaccines

Vaccines composed of intact nonpathogenic microbes are made by treating the microbes in such a way that they can no longer cause disease (i.e., their virulence is attenuated) or by killing the microbes while retaining their immunogenicity. The great advantage of attenuated microbial vaccines is that they elicit all the innate and TABLE 15-6 Vaccine Approaches Type of Vaccine Subunit (antigen) vaccines Conjugate vaccines Synthetic vaccines DNA vaccines adaptive immune responses (both humoral and cell mediated) that the pathogenic microbe would, and they are therefore the ideal way of inducing protective immunity. Live, attenuated bacteria were first shown by Louis Pasteur to confer specific immunity. The attenuated or killed bacterial vaccines in use today generally induce limited protection and are effective for only short periods. Live, attenuated viral vaccines are usually more effective polio, measles, and yellow fever are three good examples. The most frequently used approach for...

Synthetic Antigen Vaccines

A goal of vaccine research has been to identify the most immunogenic microbial antigens or epitopes, to synthesize these in the laboratory, and to use the synthetic antigens as vaccines. It is possible to deduce the protein sequences of microbial antigens from nucleotide sequence data and to prepare large quantities of proteins by recombinant DNA technology. Vaccines made of recombinant DNA-derived antigens are now in use for hepatitis virus, herpes simplex virus, foot-and-mouth disease virus (a major pathogen for livestock), human papillomavirus, and rotavirus. In the case of the most widely used human papillomavirus vaccine, recombinant viral proteins from four viral strains (HPV 6, 11, 16, and 18) are made in yeast and combined with an adjuvant. HPV 6 and 11 are common causes of warts, and HPV 16 and 18 are the most common HPV strains linked to cervical cancer. This antiviral vaccine is therefore also a preventive cancer vaccine.

Live Viral Vaccines Involving Recombinant Viruses

Another approach for vaccine development is to introduce genes encoding microbial antigens into a noncyto-pathic virus and to infect individuals with this virus. Thus, the virus serves as a source of the antigen in an inoculated individual. The great advantage of viral vectors is that they, like other live viruses, induce the full complement of immune responses, including strong CTL responses. This technique has been used most commonly with vaccinia virus vectors. Inoculation of such recombinant viruses into many species of animals induces both humoral and cell-mediated immunity against the antigen produced by the foreign gene (and, of course, against vaccinia virus antigens as well). A potential problem with recombinant viruses is that the viruses may infect host cells, and even though they are not pathogenic, they may produce antigens that stimulate CTL responses that kill the infected host cells. These and other safety concerns have limited widespread use of viral vectors for...

SV40 Virus in Early Polio Vaccines

Polio vaccines have been blamed for everything from initiating the AIDS epidemic to being a Western plot to subvert the developing world. Poliovirus vaccines that were used during the late 1950s and early 1960s were contaminated with simian virus 40 (SV40), a monkey virus that came from the monkey cells in which early batches of the vaccine were grown. A survey done in 1961 indicated that about 90 of U.S. citizens younger than 20 years of age (those born between 1941 and 1961) had received at least one immunization with poliovirus vaccine that may have contained SV40 virus.189 It is difficult to determine the average exposure because the titers of live SV40 in different vaccine lots varied from undetectable to high. Most epidemiological studies of populations who were immunized with polio vaccine potentially containing live SV40 during early childhood, which is presumed to be the highest at-risk age group for a lifetime risk of developing an exogenous agent-induced cancer, have failed...

Optimizing Peptidebased Vaccines

Several strategies for modifying peptides have been attempted to improve their efficiency as cancer vaccines. The clinical use of peptides is limited by their rapid proteolytic digestion. To overcome this limitation, Celis et al. designed a peptide construct containing a pan-reactive DR epitope, a CTL epitope, and a fatty-acid moiety (58). A lipopeptide-based therapeutic vaccine was able to induce strong CTL responses both in humans and in animals (59). Several studies demonstrated a correlation between MHC binding affinity and peptide immu-nogenicity (60). Peptides derived from gp100, whose anchor residues were modified to fit the optimal HLA-A2 binding motif, stimulated tumor-reactive CTL more efficiently than the natural epitopes (61). An unmodified, gp100-derived peptide failed to elicit peptide-specific CTL in melanoma patients after subcutaneous administration with IFA. In contrast, vaccination with the modified peptide induced CTL responses in 91 of cases (13). None of the 11...

Uniquely Small Protective Carbohydrate Epitope May Yield a Conjugate Vaccine for Candida albicans

The cell wall phosphomannan of C. albicans is a promising target for the induction of immunity by development of a conjugate vaccine. It contains a unique antigen, a (31,2-mannan that affords active protection to mice following immunization and subsequent challenge with live organisms. Disaccharide and trisaccharide fragments of the (31,2-mannan antigen optimally inhibit two murine monoclonal antibodies that confer protection in a mouse model of candidiasis implying that epitopes of this size might constitute viable vaccine components. Short oligosaccharides conjugated to suitable immunogenic proteins have been synthesized by two distinct approaches one of which is well suited to multigram synthesis. Tetanus toxoid was chosen as a carrier protein for its ability to induce a vigorous hapten specific IgG response and for compatibility with human vaccine applications. Preliminary data show that rabbits immunized three times with a trisaccharide glycoconjugate produce sera with ELISA...

Considerations On Peptide Vaccine Design And Application

A difficulty with the use of peptide vaccines is the fact that the T-cell responses usually do not last long enough to have a significant effect on the tumor. To address this issue, Davila et al. examined the role of synthetic oligodeox-ynucleotide (ODN) adjuvants containing unmethylated cytosine-guanine motifs (CpG-ODN) and CTLA-4 blockade in enhancing the antitumor effectiveness of peptide vaccines intended to elicit CTL responses (86). This study found that combination immunotherapy consisting of vaccination with a synthetic peptide corresponding to an immunodominant CTL epitope derived from tyrosinase-related protein-2 administered with CpG-ODN adjuvant and followed by systemic injection of anti-CTLA-4 antibodies increased the survival of mice against the poorly immunogenic B16 melanoma. These findings suggest that peptide vaccination applied in combination with a strong adjuvant and CTLA-4 blockade is capable of eliciting durable antitumor T-cell responses that provide survival...

Studies toward the Development of Anti Tuberculosis Vaccines Based on Mycobacterial Lipoarabinomannan

Recent investigations suggest that oligosaccharide-based conjugate vaccines containing fragments of a mycobacterial polysaccharide, lipoarabinomannan (LAM), have potential utility in the prevention of tuberculosis. We report here work towards the synthesis of oligosaccharide fragments of LAM and studies directed towards identifying the minimum epitopes required for vaccine generation. Tuberculosis is the world's most lethal bacterial disease, killing more than 2 million people each year (7). The impact of tuberculosis on world health has been the source of increased concern due to the emergence of multi-drug resistant strains of the organism that causes the disease, Mycobacterium tuberculosis, and problems in treating tuberculosis in HIV-positive patients. (2,3) As a consequence, there has been renewed interest both in the identification of new antibiotics for the treatment of tuberculosis (4,5), as well as in the development of novel vaccines that protect against the disease (6). The...

Advantages Of Plasmid Vectors As Therapeutic Vaccines For Cancer

Among different vaccine forms for treating cancer, DNA vaccine has several advantages such as immunogenicity, intrinsic adjuvant effect, capacity for harboring larger or multiple antigens and ease to manipulate, preferred safety profile, excellent stability, and inexpensive manufacturing cost. The cellular arm of the immune response, the focus of active immuno-therapy employing DNA vaccination, results from uptake of plasmids into cells (DCs, Langerhans cells, and muscle cells) (30,31), where the encoding target For therapeutic vaccine against cancer, targeting multiple CD8-specific epitopes derived from different tumor antigens (as opposed to monovalent approaches) is believed to be more effective, considering the heterogeneity and genetic instability of tumor cells (39). Plasmid can naturally harbor larger DNA fragments of coding sequences, thus making it possible to express in vivo engineered synthetic tumor antigen. Prophylactic and therapeutic vaccines expressing polyepitope...

Strategies To Imrpove Efficacy Of Dna Vaccine

Clinical trials with DNA vaccines expressing microbial antigens showed a favorable safety profile, but a relatively modest immune response, and thus moderated the initial enthusiasm in regard to this new approach for immunization (45). Various factors may have contributed in concert, to the apparent discrepancy between the generally exciting preclinical results and the modest clinical data (1) predominant use of the intramuscular administration route, relying on cross-processing as a main mechanism of action (MOA) (2) relatively diminished inoculation volumes and amounts relative to the body mass Based on these observations, many strategies have been and are currently being tested at various stages of research and development, aimed at troubleshooting the limitations of naked plasmids as vaccines The simplest ones were the complementation of DNA vaccines via prime-boost approaches or the use of synthetic CpG motifs as adjuvants, the utilization of electroporation or...

Ctl In Vaccine Development

It is widely believed that the only way to slow down the HIV epidemic is through the use of an effective vaccine. This view is bolstered by the findings showing a possible role being played by HIV-specific CTL in slowing down the progression to HIV in several studies. Several candidate vaccines have been developed and more are in development (Girard et al., 1999 Gorse et al., 1999). Most of the initial candidate vaccines were based on recombinant envelop proteins and were targeted at obtaining neutralizing antibodies to HIV (Johnston, 1997). The frequent mutations involving the env gene segment and the several findings that CTL might play a role in control of HIV lead many to conclude that an effective vaccine must have the capability of eliciting both humoral and cellular immunity (Kourilsky et al., 1998). There is a lot of skepticism regarding the finding of an effective HIV vaccine because of the high genetic variation of HIV quasi-species, even within the same individual. It is...

Whole Cell Vaccines with Capacity to Stimulate CD137

Introduction of costimulatory molecules into tumor cells to improve its ability as better APCs has become a common therapeutic vaccine in tumor immunotherapy. Transfection of tumor cells to express CD137L showed to enhance immunogenicity of murine P815 mastocytoma or AG104A sarcoma lines by developing a strong CTL response, which rejected these tumors (Melero et al. 1998b). Although CD137 is an independent costimulator, optimal effect of CD137L in CTL stimulation may require B7-CD28 interaction since blockade of this interaction by antibodies down-regulated the expression of CD137 on T cells and decreased CTL activity. Furthermore, co-expression of CD137L and B7-1 in the poorly immunogenic AG104A sarcoma enhanced the induction of effector CTL and the rejection of the wild-type tumor while neither CD137L nor B7-1 single transfectants were effective (Melero et al. 1998b). In a later study using the A20, a B-cell lymphoma cell line, a similar result was obtained (Guinn et al. 1999)....

Cancer Vaccines Key Elements And Challenges

Cancer vaccines or active immunotherapeutics encompass defined antigens, analogues, or fragments, which are in fact molecular targeted agents. Immune cells such as Th or Tc cells or antibodies elicited by the vaccine are aimed to recognize specific molecules expressed by cancer cells or within the tumor environment. The indirect mechanism of action (MOA) is a distinctive property of cancer vaccines compared to other molecular targeted therapies. Particularly, while monoclonal antibodies or tyrosine kinase inhibitors act directly on receptors and affect cell viability or signal transduction pathways, vaccines relay on their capability to induce immune mediators that in turn act on the target (Fig. 1). This has far-reaching implications in the R& D of such investigational agents and presents a set of unique challenges that distinguish this class of drug candidates from all others. In addition, there is no current benchmark in terms of approved cancer vaccine in the United States,...

Case Study Translational Approach Applied To An Investigational Cancer Vaccine

Herein, we illustrate the translational concept applied to a new cancer vaccination approach encompassing recombinant DNA vectors (Table 1). The overarching aim, resulting from the prior evidence in animal and man, was to develop a cell-free immunization approach that does not encompass replicating or integrating microbial vectors, yet has a chance to elicit potent antitumor responses. Recombinant DNA vectors in the form of plasmids expressing antigen fragments were an appealing strategy since the potential to elicit a broader range of immune responses encompassing MHC class I-restricted T-cell immunity (6) does not replicate in mammalian cells and does not significantly integrate into the host's genome (7). There are, however, several pitfalls associated with plasmid vectors when used as vaccines first and foremost, the low magnitude of immune response achieved particularly in humans but also in the preclinical models (the data in preclinical models were overestimated primarily...

Vaccine and Peptide Delivery by Carbon Nanotubes

Basic concept for utilizing CNTs in vaccine delivery is to link the antigen to CNTs, while retaining its conformation and thereby inducing specific antibody response. In addition, the CNTs themselves should not trigger any response by the immune system. In a study by Pantarotto et al. 301 , CNTs functionalized with a pyrrolidine ring through the 1,3-dipolar cycloaddition of azomethine ylides were covalently linked to a peptide sequence derived from the foot-and-mouth disease virus (FMDV), generating mono- and bisconjugated peptide CNTs. Their results demonstrated that both the mono- and bispeptide-derivatized CNTs elicited strong antibody response in BALC c mice, thereby indicating that the antigen conformation was retained during the delivery, which is essential for the induction of antibody responses with the right specificity. In addition, the authors determined that the CNTs did not have any detectable immunogenicity. These findings suggested the potential of CNTs to present...

Synthetic Carbohydrate Based Antitumor Vaccines

Our laboratory has a longstanding program devoted to the preparation and immunological evaluation of fully synthetic carbohydrate-based antitumor vaccine constructs. We present herein a brief historical account of the evolution of this research program, and describe key achievements, including the synthesis of the Globo-H-KLH construct, which is currently in clinical trials. Remarkable advances in carbohydrate and glycopeptide assembly techniques have allowed for the synthesis of increasingly sophisticated, structurally complex vaccine constructs. In this setting, we have successfully accomplished the synthesis of a highly complex unimolecular pentavalent vaccine construct, in which five prostate and breast cancer-associated carbohydrate antigens are displayed on a single polypeptide backbone.

Tools Necessary For Support Of Vaccination Therapies

To be able to initiate and conduct vaccine-based therapeutic trials, a specialized laboratory, equipped and prepared to support vaccine production and postvaccine monitoring, is necessary. Services required of such a laboratory are extensive and varied (Table 18.1). The process of experimental vaccine introduction to the clinic begins with extensive preclinical evaluations. The laboratory responsible for vaccine production plays a critical role at this stage. In the case of investigator-initiated clinical trials, preclinical studies that lead to vaccine development are often done in experimental animals. The process of translating the concept and methods used in animal vaccination studies to the clinical arena may require extensive adaptation. In general, this involves reproducing vaccine generation under cGMP conditions TAB LE 18.1. Laboratory Services Necessary for Support of Cancer Vaccine Trials Adapt and translate research findings to humans Establish vaccine composition and...

Objectives Of Therapeutic Cancer Vaccines

Anticancer vaccines are designed to induce generation and activation of immune effector cells able to interact with tumor cells and eliminate them. In addition, anticancer vaccines should aim at establishing tumor-specific longlasting immunologic memory to prevent tumor recurrence or its metastasis. Still another desirable effect would be to induce alterations in the tumor microenvironment to enhance infiltrations with immune cells and impede tumor growth 8 . Once generated or activated in response to the vaccine, immune cells need to be sustained and protected from functional impairments or death, which is their fate in patients with cancer 9 . These objectives may not be easily achievable in view of immune suppression often associated with cancer 5,9 . While tumor-reactive antibodies and T cells specific for tumor epitopes are detectable in many patients with cancer 10,11 , immune responses directed at the tumor are weak and, obviously, not effective in most cases. This is because...

Evaluation Of Immune Competence Prior To Vaccination

Patients recruited to clinical vaccination protocols should be evaluated for the integrity of their immune system. For example, an immune screen before entry on the protocol could be performed. Such a screen could perhaps be used to define the eligibility criteria for the protocol, and could provide investigators with valuable insights about potential effectiveness of vaccination therapies in individual patients. However, the problem arises as to which immune assays to select for this immune screen and how to interpret the generated data in the context of a subsequent immunologic response to the vaccine. This is a dilemma, because no single immune marker associated with cancer progression has emerged so far. Consequently, a broad immune screen may not be relevant, as patients with cancer are immunologically incompetent with respect to their tumor but may have normal responses to mitogens or nontumor bacterial or viral antigens. A DTH response to the autologous tumor, when available,...

Selection Of Assays For Monitoring Of Cancer Vaccines

Immune monitoring of vaccination protocols requires assays that can accurately measure vaccine-induced changes in the frequency and function of antitumor effector cells. These assays have to be adaptable to serial monitoring with a minimal loss of accuracy and to a high-volume testing. In all cases, it is important to select an assay that can accurately measure therapy-induced changes in an immune response relative to that measured at baseline. It is, therefore, not surprising that selection of a right assay for evaluation of responses to the vaccine is an important decision. An assay that accurately reflects vaccine-induced changes in the phenotype or function of immune cells may require adaptation to serial monitoring necessary for evaluation of cryopre-served batched specimens. Such specimen batching is routine and is done in order to test all serial samples collected from a patient in the course of therapy in the same assay. This practice avoids interassay variability and...

CD137CD137 Ligand in the Antiviral Immune Response and in Viral Vaccination

Immunotherapy has potential for chronic and latent viral infections. Therapeutic vaccination and adoptive T-cell transfer are the strategies that are being explored for HIV and chronic viral hepatitis. Mice lacking CD137 or CD137 ligand show defects in CD8 T cell responses against viruses (DeBenedette et al., A pioneering study (Halstead et al., 2002) demonstrated increased CTL responses against experimental influenza. In vivo CD137 stimulation with an agonistic monoclonal antibody enhanced the primary CD8+ T cell response to influenza type A viral infection in mice. Stimulation of CD137 increased the absolute number of CD8+ T cells to influenza epitopes in the lungs of infected animals, preferentially expanding CD8+ T cells that recognized nondominant epitopes and greatly enhancing direct ex vivo cytotoxicity. The studies confirmed that the CD137 costimulatory pathway could operate independently from CD28 (Halstead et al., 2002). The effects enhancing memory to a broadened series of...

Tumor Vaccines and Active Specific Immunotherapy ASI

All forms of vaccination rely on the immune system's active cooperation and support in order to provoke a targeted immune response. This is true also for tumor vaccination, which is therefore referred to as active specific immunotherapy (ASI). If a tumor cell is supposed to induce a T-cell-me-diated immune reaction, a professional antigen-presenting cell (e. g., a dendritic cell) must phagocytose tumor proteins and, subsequently, present peptide fragments of the tumor antigens on its surface together with genetically determined major histocompatibility complex (MHC) molecules (55). The complex of MHC molecule and tumor peptide is then recognized by cytotoxic (CD8+) or helper (CD4+) T lymphocytes. T-cell activation can only occur when, in addition to antigen recognition, activation signals are mediated to the T cells. This activation includes their proliferation and maturation into effector cells, which are either cytotoxic or release cytokines, such as IFN-y. Cytotoxic T cells can...

Treatment and Prevention of AIDS and Vaccine Development

The development of an effective vaccine against HIV is a priority for biomedical research institutions worldwide. The task has been complicated by the ability of the virus to mutate and vary many of its immunogenic antigens. It is likely that an effective vaccine will have to stimulate both humoral and cell-mediated responses to viral antigens that are critical for the viral life cycle. To achieve this goal, several approaches are being tried for HIV vaccine development. Much of the preliminary work has involved simian immunodeficiency virus (SIV) infection of macaques, and effective vaccines against SIV have already been developed. This success is encouraging because SIV is molecularly closely related to HIV and causes a disease in macaques that is similar to AIDS in humans. Various live virus vaccines have been tested in the hope that they will induce strong CTL responses. Such vaccines include nonvirulent recombinant hybrid viruses composed of part SIV and part HIV sequences or...

Factors affecting the efficacy of glycoconjugate vaccines

For the glycan in the polysaccharide vaccine are often used. Assessment of the degree of substitution of high molecular weight polysaccharides randomly activated is required (33). Molecular size of the final conjugate, as a marker of the integrity of the complex. Whilst the molecular size of a glycoconjugate vaccine has not been shown to modulate immunogenicity, molecular sizing by HPSEC is a simple method to ensure consistency in the manufacturing process and that degradation has not occurred (61). Saccharide content of the vial. Glycoconjugate vaccines are dosed by mass, not potency-related units. Whilst monovalent Hib and Men C conjugates typically contain 10 jig of saccharide per dose, multi-valent vaccines are formulated with less of each serotype. The sugar content of the vial can be measured chemically, but immunochemical methods may have advantages for multivalent products. Chemical approaches may be problematic for some vaccines. Identity of saccharide and protein components...

Development of a Carbohydratebased Vaccine against Leishmaniasis

Vaccine Design Considerations Lipophosphoglycans (LPGs) are the ubiquitous epitopes found on the surface of Leishmania parasites (Fig. 4) (57). The LPG contains three constituents a glycosylphosphatidylinositol (GPI) anchor, a repeating phosphorylated disaccharide, and a tetrasaccharide cap. Different leishmania species are distinguished by minor modifications in their backbone and by the number of repeating units. The phosphoglycan portion of the LPG has been shown to be a disease-promoting antigen (58-63) sparking much interest in the LPGs. However the size (MW ca. 1200) and the heterogeneity of the LPG precludes its use as a vaccine candidate. Consequently, several fragments of the Leishmania LPG have been investigated for their antigenicity including Carbohydrate-Based Vaccine Constructs against Leishmaniasis Two Leishmania immunogens were then prepared by joining the tetrasaccharide antigen 20 with the immmunostimulator tripalmitoyl-S'-glycerylcysteine (Pam3Cys) and with the...

Clinical Data In Personalized Cancer Vaccines That Reached Phase 3 Clinical Trials

One of the shared and clear advantages to cancer vaccines is the excellent safety profile, which makes their use in the adjuvant or earlier-stage disease setting more suitable than more conventional treatments such as chemotherapy. Choudhury et al. note that collectively the data indicate that vaccine therapy is safe, and no significant autoimmune reactions are observed even on long-term follow-up (18). Such a safety profile would indicate the potential for a high quality of life index, which is a unique feature when measured against the adverse effects associated with traditional cancer treatments. Despite a general consensus that cancer vaccines appear to be safe and well tolerated, it is more difficult to draw conclusions regarding their efficacy. To date, there have only been approximately 25 randomized phase 2 or 3 trials conducted with cancer vaccines. However, there are several examples that indicate treatment activity is present in subsets of cancer patients and, as predicted...

Vaccination with Tumor Antigens

Immunization of tumor-bearing individuals with tumor antigens may result in enhanced immune responses against the tumor (Table 17-2 and Fig. 17-6). The identification of peptides recognized by tumor-specific CTLs and the cloning of genes that encode tumor-specific antigens recognized by CTLs have provided many candidates for tumor vaccines we have mentioned several examples earlier in the chapter. One of the earliest vaccine approaches, immunization with purified tumor antigens plus adjuvants, is still being tried. More recently, therapeutic dendritic cell vaccines have been used to immunize cancer patients against their own tumors. In this approach, dendritic cells that are purified from patients are either incubated with tumor antigens or transfected with genes encoding these antigens and then injected back into the patient. For example, a cell-based vaccine is now approved to treat advanced prostate cancer. This vaccine is composed of a preparation of a patient's peripheral blood...

Purified Antigen Subunit Vaccines

Subunit vaccines are composed of antigens purified from microbes or inactivated toxins and are usually administered with an adjuvant. One effective use of purified antigens as vaccines is for the prevention of diseases caused by bacterial toxins. Toxins can be rendered harmless without loss of immunogenicity, and such toxoids induce strong antibody responses. Diphtheria and tetanus are two infections whose life-threatening consequences have been largely controlled because of immunization of children with toxoid preparations. Vaccines composed of bacterial polysaccharide antigens are used against pneumococcus and H. influenzae. Because polysaccharides are T-independent antigens, they tend to elicit low-affinity antibody responses and may be poorly immunogenic in infants (who do not mount strong T cell-independent antibody responses). High-affinity antibody responses may be generated against polysaccharide antigens even in infants by coupling the polysaccharides to proteins to form...

Vaccination

The major vaccines used in emergency situations are those against measles, meningococcal meningitis and yellow fever. Measles vaccination is one of the highest priorities in the acute phase of an emergency if vaccine coverage rates in the affected population are below 90 . The main objective of a measles vaccination programme is to prevent an outbreak of measles with the high mortality rates often associated with this disease in emergency situations. In this way, the measles vaccine provides one of the most cost-effective public health tools. The use of cholera vaccine is recommended only in stable post-emergency situations. Once the acute phase of the emergency is over, plans should also begin to re-establish the Expanded Programme on Immunization (EPI) to routinely immunize children against tetanus, diphtheria, polio and tuberculosis. This should be integrated with the national EPI programme using national vaccination policies, and it is important to involve the national EPI...

Protein Vaccine

Delivery of the various forms of vaccines into APCs. Nucleic acid vaccines can be delivered via gene gun directly into the nucleus of APCs. The DNA or RNA is expressed, and the cytosolic protein product is degraded into peptides that are presented via the MHC class I pathway. Live viral vectors, such as adenoviruses, can infect the cell and deliver nucleic acid into the nucleus the antigen is then processed and presented like a nucleic acid vaccine. Antigenic peptides can either enter the cell in vesicles and be presented via the MHC class II pathway or be targeted for immediate presentation on the cell surface. Protein antigens, which can be encapsulated in liposome delivery systems, enter the cell in vesicles and are degraded into their constituent peptides. These peptides are then presented in association with MHC class II molecules. In the context of DNA vaccines, delivery of DNA-encoding tumor antigens to DCs allows for the stimulation of tumor antigen-specific T...

Measles vaccination

Prevention of measles in emergency situations has two major components routine vaccination and measles outbreak response. The disease can be prevented by the administration of measles vaccine. Some 95 of individuals vaccinated when over 9 months old gain lifelong immunity. Mass vaccination is a priority in emergency situations where people are displaced, there is disruption of normal services, there are crowded or insanitary conditions and or where there is widespread malnutrition, regardless of whether a single case of measles has been reported or not. A measles vaccination campaign should begin as soon as the necessary human resources, vaccine, cold chain equipment and other supplies are available. Measles vaccination should not be delayed until other vaccines become available or until cases of measles have been reported (if cases are reported the campaign should begin within 72 hours of the first report). Vaccination is also a priority in refugee populations from countries with...

Meningitis vaccine

Meningococcal meningitis A and C can be prevented by vaccination. The vaccine is effective within 8-14 days. Some 90 of recipients over 18-24 months of age seroconvert and are protected against the disease. Vaccine-induced immunity lasts about 5 years in adults and older children, while younger children are protected for approximately 2 years. A quadrivalent vaccine is also available for combined vaccination against serogroups A, C, Y and W135. Vaccination recommendations for meningococcal meningitis are summarized in Table 2.32. Table 2.32 Meningococcal meningitis vaccination recommendations Table 2.32 Meningococcal meningitis vaccination recommendations The group at highest risk of meningococcal meningitis is children aged 2-10 years this should be the priority group during vaccination campaigns Deep subcutaneous or deep intramuscular, using a new sterile disposable needle and syringe for each individual mixing the meningitis vaccine in the same vial or syringe as live virus...

Yellow fever vaccine

Vaccination is the primary means of preventing yellow fever. The yellow fever vaccine offers a high level of protection, with seroconversion rates of 95 or higher for both adults and children. The duration of immunity is at least 10 years and probably lifelong. The serological response to yellow fever vaccine is not inhibited by simultaneous administration of BCG, diphtheria, pertussis, tetanus, measles and poliomyelitis vaccines. Reactions to yellow fever vaccine are generally mild. It can be given to asymptomatic patients infected with HIV, but should not be given to symptomatic HIV-infected persons or other immuno-suppressed individuals. For theoretical reasons, yellow fever vaccine is not routinely recommended for pregnant women however, there is no evidence that vaccination of a pregnant woman is associated with abnormal effects on the fetus. In an outbreak, the risk of disease would outweigh the small theoretical risk to the fetus from vaccination. Recommendations regarding...

Allogeneic Vaccines

There is growing evidence that a variety of cancers can be clinically treated by vaccines. This was seen in two randomized phase 3 studies where an autologous tumor-cell-vaccine approach as an adjuvant for the treatment of colorectal and renal cancers provided clinical benefit (7,8). Several vaccine strategies (DC peptide or RNA, protein or DNA) have employed a single-antigen approach in which either an overexpressed or uniquely expressed tumor antigen or epitope that is identified on tumor tissue is targeted. The limitation of this approach lies in both the chosen antigen as well as the major histocompatibility complex type of the patient (in the case of peptide immunization). Polyvalent tumor vaccines that are allogeneic or autologous should, at least in theory, overcome these limitations. Tumor cells as polyvalent vaccines have been attractive as they are the richest source of antigens. With a wide array of potential tumor antigens (some or possibly most of them unknown), they...

Genes and vaccines

To take another example, vaccines against disease are traditionally prepared from killed or disarmed pathogens (disease-causing microbes). They are effective in the vast majority of people, but a small percentage of the population have allergic reactions to vaccines. There is also a very small risk of vaccine organisms reactivating to their former pathogenic state. Genetically engineered vaccines are safer because they contain no living organisms, only the proteins that stimulate the body to develop immunity (Figure 3.3). Engineered vaccine A safe vaccine against viral disease can be produced by engineering the gene for the viruses' protein coat into bacteria. The bacteria manufacture the viral coat protein, which is then injected to stimulate the body to make antibodies against the virus. vaccine vaccine Vaccines are the second-largest category of over 200 drugs now being produced by American pharmaceutical companies using biotechnology. Other products include hormones, interferons,...

Vaccines

Several vaccines are currently in clinical trials for follicular NHL. Most of these are directed against the idio-type of the hypervariable region of the immunoglobu-lin light chain. Interest in this approach has been stimulated by a number of nonrandomized studies, such as one from Stanford in which 49 of patients with follicular NHL reacted to their own idiotype conjugated to keyhole limpet hemocyanin (KLH) by exhibiting a cellular and humoral immune response. Those patients capable of mounting such a response had a time to tumor progression of 7.9 years compared to 1.3 years for those who could not.95 The results of the three randomized trials will determine if there is clinical benefit from this approach.

Gp120 Vaccines

The most eagerly awaited new development in the HIV community is the HIV vaccine. Because of the rapid spread of disease worldwide and, in many countries, limited resources to effectively treat the infection, a vaccine to prevent HIV infection is highly desirable. Moreover, a vaccine that would prime the host immune system to recognize and kill infected host-immune cells in an already infected individual would also be helpful, given the current issues of drug resistance and intolerance. Because the HIV envelope gp120 makes up most of the exposed portions of the HIV virus, it was one of the early focuses for HIV vaccine design. Ideally, a vaccine would provide the following four important functions elicit neutralizing antibodies, stimulate a T cell immune response, stimulate mucosal immunity, and stimulate the innate immune system.89 In order to effectively achieve all four of these immune functions, a live-attenuated virus vaccine would be necessary. In the macaque model, a...

Tumor Vaccines

Tumor vaccines are an active immunotherapy in which the host is induced to generate an immune response against autologous tumor cells. The different types of vaccines are quite variable and include those directed at known tumor-specific antigens, such as the idiotype vaccines and modified tumor cellular vaccines that attempt to enhance immunogenicity by introducing granuloctye macrophage colony-stimulating factor or other ligands, which improve or induce tumor antigen presentation into tumor cells. In addition, the use of primed antigen presenting cells, such as dendritic cells, to improve the immune response to the desired tumor antigens is also being explored. target for immunotherapy. The first clinical trial of idiotype vaccines in patients with follicular lymphoma was conducted by Dr. Levy's group at Stanford.7778 Thirty-two patients with follicular lymphoma in first remission were treated with autologous purified Id protein chemically linked to kehale impel (KLH) as an...

DNA Vaccines

An interesting method of vaccination was developed on the basis of an unexpected observation. Inoculation of a plasmid containing complementary DNA (cDNA) encoding a protein antigen leads to strong and long-lived humoral and cell-mediated immune responses to the antigen. It is likely that APCs, such as dendritic cells, are transfected by the plasmid and the cDNA is transcribed and translated into immunogenic protein that elicits specific responses. The unique feature of DNA vaccines is that they provide the only approach, other than live viruses, for eliciting strong CTL responses because the DNA-encoded proteins are synthesized in the cytosol of transfected cells. Furthermore, bacterial plasmids are rich in unmethylated CpG nucleotides and are recognized by a TLR (TLR9) on dendritic cells and other cells, thereby eliciting an innate immune response that enhances adaptive immunity (see Chapter 4). Therefore, plasmid DNA vaccines could be effective even when administered without...

DNA Vaccination

This technique is currently being explored as a potential strategy for treating CLL and other B-cell malignancies. For patients with B-cell tumors, the immunoglobulin idiotype expressed by the neoplastic clone provides a defined tumor-specific target antigen. However, the immunoglobulin idiotype is poorly immunogenic, especially in patients with CLL. Fusion of a gene encoding a fragment of tetanus toxin with the gene encoding the idiotype can enhance the immune response to such weak tumor-specific antigens. DNA fusion vaccines containing genes that encode immune-enhancing factors can also augment the immune response to such antigens (38-40).

Autovaccines

Autovaccines are autogenous vaccines prepared from the endogenous, inactivated (dead) bacteria isolated from a patient they are used as individualized medicine for this patient only and are opti Autovaccines prepared from intestinal bacteria are of special importance because of the prominent role that the intestine-associated immune system and the intestinal microflora play in influencing the immune system. Nonpathogenic, inactivated E. coli is used for this purpose, and the autogenous vaccines are referred to as intestinal tract autovaccines. Other autovaccines are also a possibility (16).

Defining Effective Clinical Responses

The development and use of cancer vaccines has a long history in experimental medicine. However, to gauge the effectiveness of a cancer vaccine, standard ways to evaluate the immune response must be formulated. Chapter 17, from Dr. Kaufman's laboratory, introduces the various immune assays that are currently being used to monitor responses in clinical cancer vaccine trials. In Chapter 18, the final contribution in this volume, Dr. Whiteside discusses in detail the laboratory services necessary to support a cancer vaccine trial, the assays and limitations of immune monitoring for the detection of tumor-specific T cells after cancer vaccine administration, and the advantages of having a central laboratory operated as a good laboratory practice (GLP) facility to produce the vaccine and perform the immune monitoring assays. In this volume we have attempted to present some of the best current research on cancer vaccines. We did not include sections devoted to adoptive immunotherapy or...

Carbohydrate Synthesis

In short, since the mid-1980s, we have continued to develop techniques that allow us to efficiently and selectively synthesize increasingly complex carbohydrate sectors. These major advances in the synthetic chemistry of oligosaccharides, taken as a whole, have provided us with freedom to operate in designing and implementing the syntheses of a number of very complex carbohydrate-based vaccine

Processing of MHC Class IRestricted Peptide Antigens

Several tumor cell lines have been shown to transcribe the genes encoding the immunoproteasome subunits constitutively. It is not clear whether this transcription results from in vitro culture conditions and if these subunits are incorporated into functional proteasomes. Most interestingly, several human cancer cells have been found to express preferentially the LMP7-E1 isoform (19). Thus, despite apparent transcription of the p5i LMP7 subunit in tumor cells, mature proteasomes may not contain that subunit and the processing of tumor-associated antigens may be affected. Altogether, detailed knowledge of the proteasome composition of the intended target cells is important in selecting appropriate T-cell vaccines. In conclusion, antigen processing is prone to large modulation by intra-cellular proteases and peptidases. It has been estimated that only 1 peptide in 2000 synthesized proteins will eventually be presented by MHC class I molecules at the cell surface (53). Moreover, the...

Processing of MHC Class IIRestricted Peptide Antigens

Will relax the conformation of the protein and will probably render it more sensitive to proteolytic attack or will allow some part of it to associate with MHC class II molecules. A specialized thiol reductase, IFN-g-inducible lysosomal thiol reductase (GILT), has been identified. GILT is constitutively expressed in MHC class II-positive cells, typically DCs, B cells, and macrophages, and has the particularity of operating at acidic pH, typical of the endo lysosomes. In other cells, its expression is induced by IFN-g. The relevance of GILT for the processing of some MHC class II-restricted peptide antigens, in particular those derived from peptide precursors containing disulphide bridges, was demonstrated by showing that the CD4+ T-cell response against these antigens was reduced in GILT-deficient mice or cell lines (78,79). Even though tumors such as melanomas frequently express MHC class II molecules, they do not express GILT, unless treated with IFN-g, and do not present...

Impact of Adjuvants and Carriers on Antigen Processing

T-cell vaccines are generally administered in combination with so-called adjuvants, which stimulate the antigen-specific immune response. Most adjuvants activate the innate and adaptive arms of the immune system, the latter through the induction of DC maturation. Even though the key cellular receptors the Toll-like receptors (TLR) that bind these adjuvants have been reasonably well described (85), little is known about the processing (if any) of these adjuvants and its influence on the efficacy of T-cell vaccines. Aside from adjuvants, vaccines also frequently contain nonpeptidic carriers. The function of these carriers is both to protect the antigen from premature degradation and to serve as depot. Several studies have demonstrated that long-lived and acid-resistant carriers ameliorate antigen-specific responses (91-93). Newer generations of carriers aim at combining the carrier function with the adjuvant effect by decorating antigen-containing liposomes with antibodies specific for...

Selection Of Target Antigens

Given that the aim of antitumor T-cell vaccines is to induce effector CD8+ T cells capable of eliminating tumor cells via the recognition of peptide-MHC class I complexes, the focus of this section will be on MHC class I ligands. Ideally, target antigens of T-cell vaccines should be derived from gene products that directly participate in tumorigenesis or that are essential for tumor survival, so as to minimize the selection of antigen-negative mutant cells. However, the most reliable technique currently used to identify potential targets of cancer vaccines does not particularly select for such gene products (Table 1). This technique, pioneered by Boon and colleagues (95), relies on the capacity of T-cell clones to recognize autologous tumor cells specifically, irrespective of the biological role of the gene product from which the MHC class I-restricted peptide is derived. Importantly, because this technique is based on the recognition

Minimal TCell Epitope

Many vaccines are based on peptides of the optimal size for binding MHC class I molecules. These peptides are generally 9 to 10 amino acids and may contain amino acid substitutions that increase binding affinities to MHC class I molecules without affecting T-cell recognition. The main advantage of this type of vaccines is that they can be immediately loaded onto MHC class I molecules expressed at the surface of DC without any processing. However, the efficacy of these vaccines may be limited by the presence of highly active proteolytic enzymes in the serum and at the surface of DC (106,107). The removal of a single amino acid at the N- or C-terminus of the peptide will immediately produce an inactive product since it will be too short to bind MHC class I molecules. Minigenes encoding minimal T-cell epitopes are also widely used. Contrary to peptidic vaccines, minigene-based vaccines necessitate the transfer of the nucleic acids into target cells and the synthesis of the peptide....

Altered Peptide Ligands

Second, the T-cell repertoire against the peptide antigens may be partially tolerized or have low-intermediate avidity. Third, the peptide may be rapidly modified or degraded. To circumvent these limitations, altered peptide ligands have been developed. However, careful biochemical analyses of the impact of such modification on processing are rarely performed. All too often, it is assumed that the processing of antigens containing modified amino acids will be similar to those containing the natural sequences. One category of altered antigens includes peptides with modified anchor residues to increase affinity to MHC molecules. The natural sequence of these peptides is characterized by the presence of suboptimal anchor residues. Substitution of these residues by canonical MHC class I anchor residues dramatically increases the stability of the peptide-MHC complexes and converts most of these peptide antigens into highly immunogenic peptides. Typical...

Impact of Processing on TCell Development and Repertoire

This process eliminates most potentially autoreactive T cells and is of central importance for the development of tolerance to self-antigens, including those expressed by tumor cells. Analyses of the T cells of p1i LMP2 mice indicated a 50 reduction in the frequency of CD8+ T cells in the periphery (147). Also, the T-cell repertoire against several epitopes was drastically altered (52). Thus, the processing of antigens by immunoproteasomes in the thymus shapes the peripheral T-cell repertoire that can be mobilized by T-cell vaccines.

Impact of Processing on TCell Responses

It is accepted that CD8+ T-cell priming and cross-priming are primarily mediated by DCs. Both priming and cross-priming of CD8+ T cells depend on the processing of MHC class I-restricted antigens by the proteasomes of DCs (122). DCs exist in at least two states the immature and mature states. Immature DCs reside in tissues, have the capacity of capturing antigens, and express both standard and immunoproteasomes. Upon stimulation, tissue-resident DCs mature and migrate to the draining lymph node. Mature DCs lose endocytic capacity, upregulate co-stimulatory molecules, process antigens efficiently, and express only immunoproteasomes. Given that some tumor-associated peptide antigens (but not all) are produced by standard proteasomes of tumors but not by immunoproteasomes of DCs, vaccines exploiting the recipients' DCs to elicit T-cell responses should primarily incorporate target antigens that are efficiently processed by both types of proteasomes. In the context of the...

Conclusion And Prospects

Anticancer T-cell vaccines have to fulfill at least two conditions First, they have to stimulate cytolytic CD8+ T cells and, second, they have to activate CD8+ T cells capable of recognizing tumor cells. These two conditions are constrained by the available T-cell repertoire into which the vaccines will have to tap, by the efficacy of the vaccine at mobilizing this repertoire and by factors influencing antigen processing and presentation. As discussed in this chapter, antigen processing regulates the selection of thymocytes in the thymus and the T-cell repertoire in the periphery. It also controls the presentation of tumor-associated peptides by MHC molecules and, consequently, regulates both CD4+ and CD8+ T-cell responses. Antigen processing may produce largely different peptides depending on the environment of the tumor. Finally, induction of effective T-cell responses against peptide tumor antigens may favor the selection of antigen-negative tumor cell populations. On the basis of...

Corey Smith and Rajiv Khanna

Cytotoxic T lymphocytes (CTLs) play an important role in the immunosurveillance and clearance of both intracellular pathogens and malignant cells 1,2 . Following T cell receptor engagement of the peptide-major histocompatibility (MHC) class I complex, CTLs function by inducing lysis of the target cell 3 . The capacity to isolate the peptide determinants presented by MHC class I molecules, typically 8-10 amino acids in length, has resulted in the development of vaccine strategies that employ minimal CTL determinants to target the induction of CTL. 5.2 PEPTIDE-BASED VACCINES AND IDENTIFICATION OF CTL PEPTIDE TARGETS Cancer Vaccines and Tumor Immunity of immunization strategies targeting minimal CTL determinants, thus limiting side effects that may be associated with more complex vaccines. The ability to correctly define the appropriate peptide targets, particularly with regard to antigens expressed by malignant cells, is essential in order to generate effective peptide-based vaccines. A...

Polyepitope Technology

There is evidence from animal models that the processing and presentation of CTL epitopes from native antigen can be significantly influenced by the flanking amino acid sequences 12,13 . Modification of these flanking sequences has been shown to completely abrogate the induction of a CTL response. It would therefore seem likely that the generation of effective polypeptide-based vaccines would depend on the presence of appropriate flanking amino acid residues. However, it has become evident from numerous studies that polyepitope-based vaccines can be produced against a range of diseases by simply linking CTL epitopes end-to-end in the absence of appropriate flanking sequences (Fig. 5.1). However, it is as yet not clear why flanking sequences are not required for processing of epitopes from a polyepitope. The first study to demonstrate that a polyepitope without flanking sequences could be used effectively employed a polypeptide encoded by a recombinant vaccinia virus (VV) vector and...

Predictive Value Of Preclinical Models

Cancer vaccines have been extensively characterized in the preclinical setting, providing a strong foundation and supporting rationale for studies in humans. Several approaches are described in this section (non-exhaustive list) Two key points emerge from these studies. First, therapeutic vaccination against cancer results in benefit to the host, as measured by complete tumor rejection, prolonged stabilization of tumor growth, and or improved survival time. The evidence for this point is extensive and based on a large variety of tumor models (described below). Second, where examined, efficacy has been observed to be greater in the minimal disease setting compared with the setting of more advanced disease. This second point echoes the case of successful early intervention against established smallpox infection If smallpox vaccine is administered within one to four days of exposure to the disease, it may prevent or lessen the degree of illness however, the effect of vaccination is...

Tumor Derived Heat Shock Protein Peptide Complexes

Table 1 Examples of Preclinical Activity in Rodents Treated with Autologous Cancer Vaccines Effect of Tumor Burden on Outcome Cancer type Vaccine type Fibrosarcoma HSPPC-96 100 of mice alive at day 33 in vaccine group in early setting compared with 4 in control group (P < .04) vs. 60 survival in advanced disease (9) 40 of mice alive at day 60 (end of study) in vaccine group in early setting compared with 0 in control group (P < .04) vs. no difference in survival in advanced disease (11) Significant reduction in rate of tumor growth in minimal disease setting vs. no effect of vaccination in bulky disease setting (16) Minimal disease primary tumor surgically removed prior to start of vaccination, yet still bore second tumor at distal site Bulky disease no surgical resection and thus bore primary and secondary tumor at time of vaccination Table 1 Examples of Preclinical Activity in Rodents Treated with Autologous Cancer Vaccines Effect of Tumor Burden on Outcome (Continued ) Cancer...

Polyepitopebased Treatment Of Ebvassociated Malignancies

Hodgkin's lymphoma and NPC do not express the full array of latent antigens, as typically occurs in PTLD, and are limited to the expression of EBNA1, LMP1, and LMP2. LCL-mediated T cell expansion predominantly leads to the induction of T cells that are specific for epitopes found in EBNA3 and in most instances generate only a small percentage of cells specific for the LMP antigens or EBNA1. Therefore strategies aimed at using CTL-based adoptive immunotherapy or vaccination to treat EBV-associated HL and NPC need to capable of generating T cells that are primarily specific for the LMP antigens. Latent membrane proteins 1 and 2 play a significant role in activating and transforming B cells following infection, allowing proliferation and survival of latently infected cells. The LMP antigens are thus oncogenic by nature the sequences that encode this oncogenic phenotype have been identified. Furthermore, both LMP1 and LMP2 are poorly immunogenic, presumably because of poor processing and...

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