Human tumor antigens for cancer vaccine development

Summary: The adoptive transfer of tumor-infiltrating lymphocytes (TH.) along with interleukin (H.)-2 into autologous patients with cancer resulted in the objective regression of tumor, indicating that T cells play an important role in tumor regression. In the last few years, efforts have been made towards understanding the molecular basis of T-cell-mediated antitumor immunity and elucidating the molecular nature of tumor antigens recognized by T cells. Tumor antigens identified thus far could be classified into several catagories: tissue-specific differentiation antigens, tumor-specific shared antigens and tumor-specific unique antigens, CD4 T cells play a central role in orchestrating the host immune response against cancer, infections diseases, and autoimmune deseases, and we thus have attempted to identify major histocompatibility complex (MHC) class II-restricted tumor antigens as well. The identification of tumor rejection antigens provides new opportunities for the development of therapeutic strategies against cancer. This review will summarize the current status of MHC class I- and class II-restricted human tumor antigens, and their potential application to cancer treatment.     

Mucosal immunity: implications for vaccine development.

The mucosal surfaces in e.g. the gastrointestinal, respiratory and urogenital tracts represent a very large exposure area to exogenous agents including microorganisms. Not surprising, therefore, those mucosal tissues are defended by a local immune system with properties and functions that in many respects are separate from the systemic immune system. The intestine is the largest immunological organ in the body. It comprises 70-80% of all immunoglobulin-producing cells and produces more secretory IgA (SIgA) (50-100 mg/kg body weight/day) than the total production of IgG in the body (ca. 30 mg/kg/day). The local immune system of the gut has two main functions: to protect against enteric infections, and to protect against uptake of and/or harmful immune response to undergraded food antigens. The best known entity providing specific immune protection for the gut is the SIgA system. The resistance of SIgA against normal intestinal proteases makes antibodies of this isotype uniquely well suited to protect the intestinal mucosal surface. The main protective function of SIgA antibodies is the "immune exclusion" of bacterial and viral pathogens, bacterial toxins and other potentially harmful molecules. SIgA has also been described to mediate antibody-dependent T cell-mediated cytotoxicity (ADCC), and to interfere with the utilization of necessary growth factors for bacterial pathogens in the intestinal environment, such as iron. It is now almost axiomatic that in order to be efficacious, vaccines against enteric infection must be able to stimulate the local gut mucosal immune system, and that this goal is usually better achieved by administering the vaccines by the oral route rather than parenterally. Based on the concept of a common mucosal immune system through which activated lymphocytes from the gut can disseminate immunity also to other mucosal and glandular tissues there is currently also much interest in the possibility to develop oral vaccines against e.g. infections in the respiratory and urogenital tracts. It has previously been widely assumed that only live vaccines would efficiently stimulate a gut mucosal immune response. However, an oral cholera vaccine, composed of the nontoxic B subunit of cholera toxin in combination with killed whole cell (WC) cholera vibrios has been shown to stimulate a strong intestinal SIgA antibody response associated with long-lasting protection against cholera. We have used this new cholera subunit vaccine and developed ELISPOT methods for examining at the clonal B and T cell level the dynamics of intestinal and extra-intestinal immune responses in humans after enteric immunizations.(ABSTRACT TRUNCATED AT 400 WORDS)     

Human tumor antigens, immunosurveillance, and cancer vaccines

Cancer is a serious health problem as a scientific challenge. A lot has been learned about the process of transformation of a normal cell into a tumor cell by studying genes and proteins that regulate this process either in cis or in trans. However, whether these molecular mechanisms succeed in fulfilling their potential to give a clinically evident disease depends in great measure on the host response to those molecular changes. The work of my laboratory aims to provide evidence in animal models as well as in cancer patients that immune system can control cancer growth and that this important function can be improved through vaccination with welldefined tumor antigens.     

Th1 memory: implications for vaccine development

Summary: T‐helper 1 (Th1) cells play a critical role, via interferon‐γ (IFN‐γ) production, in mediating intracellular killing against a variety of infectious pathogens. Thus, understanding the regulation of Th1 responses could provide better insight into vaccine design for infections requiring Th1 immunity. The cellular and molecular mechanisms that control the induction of Th1 effector cells have been well characterized. More recently, there has been substantial progress in furthering our understanding of the factors that regulate the development of Th1 memory cells. It is clear that Th1 responses are functionally heterogeneous, as defined by their ability to produce IFN‐γ. Furthermore, this heterogeneity has profound implications for the capacity of distinct lineages of Th1 cells to develop into memory cells. This review emphasizes the mechanisms controlling the differentiation of naïve CD4⁺ T cells into effector and then memory cells in a progressive manner. It highlights the importance of IFN‐γ as a positive regulator for inducing Th1 responses but a negative regulator for sustaining Th1 effector cells. In conclusion, we discuss how this current understanding of Th1 differentiation will inform vaccine design and better define immune correlates of protection.     

MHC antigens and cancer: implications for T-cell surveillance.

Evidence for a direct involvement of cell-mediated immune mechanisms in the control of human tumours remains sketchy. The past year, however, has seen advances in our understanding of the relationship between the immune system and tumour cells, and has given rise to new prospects for immunological treatment and the prevention of cancers.     

Human tumor antigens recognized by T-cells

T-cells play an important role in in vivo tumor rejection in many animal tumor models and in human melanoma. Many human tumor antigens recognized by autologous T-cells have now been identified. These are found to be nonmutated and mutated peptides derived from various self proteins as well as viral proteins. A variety of mechanisms involved in generating these T-cell epitopes on growing cancers have also been identified. However, the role of these identified antigens remains to be evaluated. Passive or active immunotherapies using these identified tumor antigens are being conducted in many institutions. The results obtained from these clinical trials may give us better insight into the role of T-cell responses to each antigen in tumor rejection as well as the development of new antigen-specific immunotherapies for patients with cancer.     

The implications of antigenic diversity for vaccine development

The reactivity of human monoclonal and polyclonal anti-HIV-1 antibodies demonstrates that shared epitopes, including those that induce neutralizing antibodies, exist and are recognized by the human immune system. A priori, there is no reason why cross-clade neutralizing antibodies could not be induced by an appropriately constructed HIV vaccine. But to construct such a vaccine, it is critical to understand, as completely as possible, the antigenic structure of HIV, to establish and identify immunologic classifications for HIV, and to choose rationally the minimum number and types of viruses from these immunologic groupings that will induce the broadest protective responses.     

Pressure-inactivated yellow fever 17DD virus: implications for vaccine development

The successful Yellow Fever (YF) vaccine consists of the live attenuated 17D-204 or 17DD viruses. Despite its excellent record of efficacy and safety, serious adverse events have been recorded and influenced extensive vaccination in endemic areas. Therefore, alternative strategies should be considered, which may include inactivated whole virus. High hydrostatic pressure has been described as a method for viral inactivation and vaccine development. The present study evaluated whether high hydrostatic pressure would inactivate the YF 17DD virus. YF 17DD virus was grown in Vero cells in roller bottle cultures and subjected to 310 MPa for 3 h at 4 °C. This treatment abolished YF infectivity and eliminated the ability of the virus to cause disease in mice. Pressure-inactivated virus elicited low level of neutralizing antibody titers although exhibited complete protection against an otherwise lethal challenge with 17DD virus in the murine model. The data warrant further development of pressure-inactivated vaccine against YF.     

Antibody and cell-mediated immunity to Streptococcus pneumoniae: implications for vaccine development

It has long been assumed that children develop natural immunity to pneumococci via the acquisition of anticapsular antibodies, which confers serotype-specific immunity to the organism. This view has been further reinforced by the recent success of capsular polysaccharide conjugate vaccines in children in reducing colonization and disease caused by vaccine-type strains. Less clear, however, is whether this mechanism is responsible for the age-related gradual increased resistance to pneumococcal carriage and disease. Recent epidemiologic and experimental evidence point to the possibility that another mechanism may be involved. Here, an alternative possibility is presented, whereby it is proposed that acquired immunity to this common human pathogen is derived not only from natural acquisition of antibodies (capsular and noncapsular) that provides protection against invasive disease but also from the development of pneumococcus-specific CD4+ T_H17 cells that reduces the duration of carriage and may also impact mucosal disease. This review focuses on the experimental and clinical evidence in support of this hypothesis. The implications for future vaccine development against Streptococcus pneumoniae are also discussed.     

Yersinia enterocolitica: subversion of adaptive immunity and implications for vaccine development

Enteric Yersinia spp. invade Peyer's patches, disseminate to lymphoid tissues, and induce mucosal and systemic immune responses. Many virulence factors of Yersinia enterocolitica have been investigated in detail and were found to act on host cells involved in innate and adaptive immunity. Recent work explored as to whether attenuated Y. enterocolitica or recombinant components of Y. enterocolitica can be used as tools for vaccination. We and others have tested whether by means of the type three secretion system in attenuated Y. enterocolitica strains antigens might be delivered to antigen-presenting cells in order to induce CD8 and CD4 T cell responses. Alternatively, recombinant components of Y. enterocolitica such as invasin protein which binds to β1 integrins of host cells have been tested for their ability to target antigen along with microparticles (fused to invasin) to antigen-presenting cells and to act as adjuvant. The work summarized in this article demonstrates that Y. enterocolitica and its components might be useful tools for novel vaccination strategies; in fact, invasin when fused to antigen and coated to microparticles might induce both CD4 and CD8 T cell responses. Likewise, attenuated Y. enterocolitica live carrier strains were reported to induce both CD8 and some CD4 T cell responses. However, we need to know more about how Y. enterocolitica subverts functions of antigen-presenting cells in order to design mutants with optimized antigen delivery features and deletion in those virulence factor that contribute to subversion of innate or adaptive immune responses.     

肿瘤疫苗治疗膀胱癌进展

肿瘤疫苗免疫治疗是利用肿瘤抗原进行主动免疫来激发、增强机体的主动特异性免疫反应.肿瘤疫苗的设计,首先是基于对肿瘤发生免疫逃逸机理的认识.肿瘤免疫逃逸机制十分复杂,缺乏抗原表位、MHC表达下调以及共刺激分子或某些粘附分子的缺乏等可能是其重要的机理.肿瘤疫苗策略包括基因疫苗、肽和蛋白疫苗、基因修饰的肿瘤细胞疫苗以及抗独特型抗体疫苗等.利用DC细胞荷载抗原肽或者基因修饰的肿瘤细胞等建立膀胱癌细胞疫苗,在体内、外实验中已证实对膀胱癌的治疗有一定的效果.     

Staphylococcus aureus antigens and challenges in vaccine development

Staphylococcus aureus is an important cause of nosocomial and community-acquired infections in humans and animals, as well as mastitis in dairy cattle. Methicillin-resistant S. aureus is increasingly recognized as a cause of staphylococcal infection and, therefore, immunotherapeutics have received new interest in both human and veterinary medicine. Vaccines aimed at preventing S. aureus infection in humans and mastitis in dairy cattle have been studied for many years. While some formulations have shown promise in ameliorating clinical disease, few, if any, of the S. aureus vaccines developed have adequately prevented new infection. The antigens targeted by S. aureus vaccines and potential reasons for the lack of success of vaccination against S. aureus are reviewed in this article.     

Human immune responses to Schistosoma mansoni vaccine candidate antigens

To determine the naturally occurring immunological responses to the Schistosoma mansoni antigens paramyosin, IrV-5, Sm-23 (MAP-3), and triose phosphate isomerase (MAP-4), a total of 119 subjects from an area of endemicity for schistosomiasis, including "resistant" subjects (n = 17) were evaluated. Specific immunoglobulin G1 (IgG1), IgG2, IgG3, IgG4, and IgA levels for each of the antigens and the cytokine profile in culture supernatants from antigen-stimulated peripheral blood mononuclear cells (PBMC) were determined. Although all the subjects had a high degree of contaminated water exposure, their infection levels were variable (0 to 1,128 eggs/g of stool). There were direct correlations between infection levels and levels of SWAP- and paramyosin-specific IgG1 and IgG4 (P < 0.05). However, an inverse correlation between infection levels and specific IgG2 to IrV-5 (P < 0.01) was observed. The evaluation of the cytokine profile (interleukin 5 [IL-5], IL-10, gamma interferon [IFN-gamma], and tumor necrosis factor alpha) in response to these antigens showed inverse correlations between the degree of infection and IFN-gamma levels in PBMC supernatants stimulated with paramyosin (P < 0.05) and IrV-5 (P < 0.01). Additionally, inverse correlations between the degree of infection and IL-5 levels in MAP-3- and MAP-4-stimulated PBMC supernatants (P < 0.01) were found. Logistic regression analysis was performed to adjust the results of cytokine profile by age. IL-5 production in MAP-3-stimulated PBMC supernatants was associated with lower infection levels (odds ratio = 11.2 [95% confidence interval, 2.7 to 45.8]).     

From cancer genomics to cancer immunotherapy: toward second-generation tumor antigens

Clinically successful specific cancer immunotherapy depends on the identification of tumor-rejection antigens (Ags). Historically, tumor Ags have been identified by analyzing either T-cell or antibody responses of cancer patients against the autologous cancer cells. The unveiling of the sequence of the human genome, improved bioinformatics tools and optimized immunological analytical tools have made it possible to screen any given protein for immunogenic epitopes. Overexpressed genes in cancer can be identified by gene-expression profiling; immunogenic epitopes can be predicted based on HLA-binding motifs; candidate peptides can be identified by mass spectrometry of tumor-cell-derived HLA molecules; and peptide-specific T cells can be qualitatively and quantitatively analyzed at the single-cell level using ELISPOT and tetramer technologies. Here, we suggest that, based on these advancements, a new class of tumor Ags can be identified by directly linking cancer genomics to cancer immunology and immunotherapy.     

Translating tumor antigens into cancer vaccines

Vaccines represent a strategic successful tool used to prevent or contain diseases with high morbidity and/or mortality. However, while vaccines have proven to be effective in combating pathogenic microorganisms, based on the immune recognition of these foreign antigens, vaccines aimed at inducing effective antitumor activity are still unsatisfactory. Nevertheless, the effectiveness of the two licensed cancer-preventive vaccines targeting tumor-associated viral agents (anti-HBV [hepatitis B virus], to prevent HBV-associated hepatocellular carcinoma, and anti-HPV [human papillomavirus], to prevent HPV-associated cervical carcinoma), along with the recent FDA approval of sipuleucel-T (for the therapeutic treatment of prostate cancer), represents a significant advancement in the field of cancer vaccines and a boost for new studies in the field. Specific active immunotherapies based on anticancer vaccines represent, indeed, a field in continuous evolution and expansion. Significant improvements may result from the selection of the appropriate tumor-specific target antigen (to overcome the peripheral immune tolerance) and/or the development of immunization strategies effective at inducing a protective immune response. This review aims to describe the vast spectrum of tumor antigens and strategies to develop cancer vaccines.     

Human challenge trials in vaccine development

The increasing recent interest in human challenge studies or controlled human infection model studies for accelerating vaccine development has been driven by the recognition of the unique ability of these studies to contribute to the understanding of response to infection and the performance of vaccines. With streamlining of ethical processes, conduct and supervision and the availability of new investigative tools from immunophenotyping to glycobiology, the potential to derive valuable data to inform vaccine testing and development has never been greater. However, issues of availability and standardization of challenge strains, conduct of studies in disease endemic locations and the iteration between clinical and laboratory studies still need to be addressed to gain maximal value for vaccine development.