Preventative and therapeutic vaccines for fungal infections: from concept to implementation

Many challenges confront the development of fungal vaccines for humans including differences in host susceptibility, varied pathogenic mechanisms employed by the different species of fungi and mechanisms of host resistance. Hence, no single antigen can be expected to serve as a pan fungal vaccine. Instead, it is likely that progress for fungal vaccines will have to be made at the level of each individual organism. In recent years, tremendous strides have been made in understanding the immunopathogenesis of medically important fungal infections and identifying putative vaccine candidates. Such discoveries will facilitate the introduction of fungal vaccines into the therapeutic armamentarium of clinicians. The fungi under discussion in this review include Candida spp., Aspergillus spp., Cryptococcus neoformans, Coccidioides spp., Histoplasma capsulatum, Blastomyces dermatitidis, Paracoccidioides brasiliensis and Pneumocystis jirovecii.     

Plant-derived vaccines: An approach for affordable vaccines against cervical cancer

Several types of human papillomavirus (HPV) are causatively associated with cervical cancer, which is the second most common cancer in women worldwide. HPV-16 and 18 are among the high risk types and responsible for HPV infection in more than 70% of the cases. The majority of cervical cancer cases occur in developing countries. Currently available HPV vaccines are expensive and probably unaffordable for most women in low and middle income countries. Therefore, there is a need to develop cost-effective vaccines for these countries. Due to many advantages, plants offer an attractive platform for the development of affordable vaccines. These include low cost of production, scalability, low health risks and the potential ability to be used as unprocessed or partially processed material. Among several techniques, chloroplast transformation is of eminent interest for the production of vaccines because of high yield of foreign protein and lack of transgene transmission through pollen. In this commentary, we focus on the most relevant aspects of plant-derived vaccines that are decisive for the future development of cost-effective HPV vaccines.     

Novel approaches to therapeutic cancer vaccines

Although tumor vaccines have been studied for decades, there is no vaccine approved as a clinical product. Nevertheless, recent advances in immunology and tumor biology justify a renewed interest. First, cancer cells express many antigens that can be recognized by the immune system, some with high tumor selectivity. Second, knowledge about immune regulation, including the importance of costimulatory signals, has been successfully applied to the studies of tumors. Third, mechanisms of how tumors can escape from immunological control have been identified, setting the stage to discover agents to decrease their impact. Rejection of established mouse tumors has been accomplished as a result of therapeutic tumor vaccination and there are encouraging findings from vaccine trials in humans.     

Human papillomavirus vaccines for the treatment of cervical cancer

Human papillomavirus (HPV) infection is a major cause of cervical cancer, the second most common cancer in women worldwide. Currently, a HPV L1-based virus-like particle has been approved as a prophylactic vaccine against HPV infection, which will probably lead to a reduction in cervical cancer incidence within a few decades. Therapeutic vaccines, however, are expected to have an impact on cervical cancer or its precursor lesions, by taking advantage of the fact that the regulatory proteins (E6 and E7) of HPV are expressed constantly in HPV-associated cervical cancer cells. Vaccine types targeting these regulatory proteins include the recombinant protein and DNA vaccines, peptide vaccines, dendritic-cell vaccines, and viral and bacterial vector deliveries of vaccines, and these may provide an opportunity to control cervical cancer. Further approaches incorporating these vaccine types with either conventional therapy modalities or the modulation of CD4(+) regulatory T cells appear to be more promising in achieving increased therapeutic efficacy. In this review, we summarize current and future therapeutic vaccine strategies against HPV-associated malignancies at the animal and clinical levels.     

Clinical development of MVA-based therapeutic cancer vaccines

Tumor-associated antigens (TAAs) have been formulated into vaccines that, combined with adjuvants, cytokines or other strategies to boost the immune response, are now in clinical development. Both humoral and cellular immune responses to TAAs have been generated using these vaccines. This approach relies on the patient's own immune system generating an effective anti-tumor immune response. The advantage of this over therapy with monoclonal antibodies for the treatment of cancer is that multiple antigenic epitopes can be involved and the immune system is able to adapt to the most effective antigenic specificity for tumor growth control and rejection. In this article, we describe the clinical use of vaccinia virus, in particular modified vaccinia virus Ankara (MVA), to express TAAs in vivo and to stimulate an effective immune response to the cancer antigens.     

Discovery and immunologic validation of new antigens for therapeutic cancer vaccines

Immunotherapy using both active and passive approaches is increasingly being used as a modality to treat human cancer. The last decade has seen a tremendous burst of activity in antigen discovery in cancer, and many new targets have now been identified for both monoclonal antibody therapy and active immunization. In addition, advances have been made in our understanding of the immune response against cancer and how new vaccine vectors, such as poxviruses, alphaviruses and bacterial vectors, can be used to overcome some of the traditional hurdles (e.g. self-tolerance and immune suppression in cancer patients) that have hindered the generation of effective antitumor immune responses. Improvements in genomics technology in the area of DNA microarrays and differential display and subtractive hybridization together with a new wave of mass spectrometry-based proteomics tools, as well as more sensitive assays to validate the immunoreactivity of new antigens, have all accelerated the rate of new antigen discovery in cancer. This rapid progress should initiate a major paradigm shift in how we treat cancer within the next 10 years, where, instead of being a novelty, the combination of targeted T cell-based vaccines and antiangiogenesis therapies will be routinely combined with traditional chemotherapy. The successful combination of these approaches will change the face of cancer from a relatively acute, life-threatening disease to a manageable chronic disorder with long survival times.     

宫颈癌疫苗的现状和前景

宫颈癌的发病率和病死率较高,宫颈癌疫苗的应用是一种控制宫颈癌发生的重要的预防手段。目前疫苗存在诸多问题,如预防性疫苗对已经感染HPV的患者或确诊为癌前病变及宫颈癌的患者则无治疗作用,且大部分疫苗都只针对该疫苗所包含的HPV特异型产生保护作用等。因此,本文就有关宫颈癌疫苗的临床前和临床研究现状综述如下,并探讨宫颈癌疫苗的临床应用前景。     

ProtEx technology for the generation of novel therapeutic cancer vaccines

Therapeutic vaccines present an attractive alternative to conventional treatments for cancer. However, tumors have evolved various immune evasion mechanisms to modulate innate, adaptive, and regulatory immunity for survival. Therefore, successful vaccine formulations may require a non-toxic immunomodulator or adjuvant that not only induces/stimulates innate and adaptive tumor-specific immune responses, but also overcomes immune evasion mechanisms. Given the paramount role costimulation plays in modulating innate, adaptive, and regulatory immune responses, costimulatory ligands may serve as effective immunomodulating components of therapeutic cancer vaccines. Our laboratory has developed a novel technology designated as ProtEx^™ that allows for the generation of recombinant costimulatory ligands with potent immunomodulatory activities and the display of these molecules on the cell surface in a rapid and efficient manner as a practical and safe alternative to gene therapy for immunomodulation. Importantly, the costimulatory ligands not only function when displayed on tumor cells, but also as soluble proteins that can be used as immunomodulatory components of conventional vaccine formulations containing tumor-associated antigens (TAAs). We herein discuss the application of the ProtEx^™ technology to the development of effective cell-based as well as cell-free conventional therapeutic cancer vaccines.     

Outlining novel cellular adjuvant products for therapeutic vaccines against cancer

Despite the library of new adjuvants available for use in vaccines, we remain, at present, almost reliant on aluminum-based compounds for clinical use. The increasing use of recombinant subunit vaccines, however, makes the need for improved adjuvant of particular interest. Adjuvants are crucial components of all cancer vaccines whether they are composed of whole cells, proteins or peptides. For the purposes of this article, cellular adjuvant products are defined as adjuvants associated with cellular or T-cell immunity. Several pharmaceutical companies are developing new adjuvants or immune enhancers for the treatment of cancers such as melanoma and non-small-cell lung carcinoma. Several products are being developed and have entered clinical trials either alone or in combination. In this article, we discuss recent adjuvant development and novel cellular adjuvant products for therapeutic cancer vaccines.     

Recombinant vaccines for the prevention of human papillomavirus infection and cervical cancer

Carcinogenic human papillomaviruses (HPVs) that cause cervical cancer preferentially infect basal, metaplastic squamous cells of the transformation zone. If infection persists, and a vegetative infection ensues, a premalignant lesion may develop with the potential to progress into an invasive squamous cell carcinoma. Papillomavirus prophylactic vaccines target the systemic immune system for induction of neutralizing antibodies that protect the basal cells against infection. Because the carcinogenic HPVs are susceptible to neutralization by antibodies for 9–48 h after reaching the basal cells, both low and high titered HPV type-specific antibodies induced by HPV L1 and L2-based vaccines are highly efficacious. The greatest burden of HPV-associated cancers occurs in poor areas of the world where women do not have access to routine gynecological care. The burden of HIV/AIDS in these same regions of the world has added to the burden of HPV-associated disease. There is an urgent need for a cost-effective, broad-spectrum HPV prophylactic vaccine in developing countries, which necessitates substantial cost subsidization of the virus-like particle (VLP) based vaccines licensed in industrialized countries or an alternative approach with second-generation vaccines that are specifically designed for delivery to women in resource-poor communities.     

HPV vaccines: the beginning of the end for cervical cancer

Vaccines prophylactic against infection with human papillomavirus (HPV) are based on alum adjuvanted virus-like particles. Two such vaccines have recently been shown to prevent persistent HPV infection and associated cervical cancer precursor lesions. The genotype-specific neutralising antibody directed at conformational epitopes of the L1 major capsid protein is likely to mediate protection. Vaccines therapeutic for persisting HPV infection can eliminate transplantable tumors in animal models, but are of limited efficacy in mice grafted with skin that expresses HPV antigens or in humans. This paradox has been partially resolved by data clarifying the immunoregulatory role of skin cytokines (e.g. transforming growth factor-beta and interleukin-10) and the consequences of antigen presentation by subsets of skin-associated antigen-presenting cells.     

ISCOMATRIX adjuvant for prophylactic and therapeutic vaccines

The ISCOMATRIX adjuvant has antigen-delivery and -presentation properties, as well as immunomodulatory capabilities that combine to provide enhanced and accelerated immune responses. The responses are broad, including a range of subclasses of antibodies as well as both CD4+ and CD8+ T cells. A range of ISCOMATRIX vaccines (ISCOMATRIX adjuvant combined with antigen) have been evaluated in clinical trials. The results of these completed and ongoing studies indicate that the ISCOMATRIX adjuvant is safe and generally well tolerated and increases the vaccine immune responses.     

Creating therapeutic cancer vaccines: notes from the battlefield

With the identification of tumor antigens and a knowledge of how to vaccinate against them, the field of tumor immunology faces new challenges. In this article, the authors argue that successful immunotherapies of the future will activate anti-tumor T cells without inducing their anergy or apoptotic death.     

Outlining novel scenarios for improved therapeutic cancer vaccines: the PANVAC paradigm

The approval of sipuleucel-T has placed cancer vaccines on the verge of becoming an effective modality. However, there is much to define to understand the intricacies from the multiple confounding factors in vaccine immunotherapy. In this article under review, some patients with metastatic cancer who had limited tumor burden and minimal prior chemotherapy responded immunologically and clinically to PANVAC. This study highlights the need for selecting appropriate patient populations for testing of therapeutic vaccines. The rationale of this study is that patients with a healthier immune system are capable of responding to a vaccine, thus providing long-term tumor control through immune surveillance.     

Tumor antigens for cancer immunotherapy: therapeutic potential of xenogeneic DNA vaccines

Preclinical animal studies have convincingly demonstrated that tumor immunity to self antigens can be actively induced and can translate into an effective anti-tumor response. Several of these observations are being tested in clinical trials. Immunization with xenogeneic DNA is an attractive approach to treat cancer since it generates T cell and antibody responses. When working in concert, these mechanisms may improve the efficacy of vaccines. The use of xenogeneic DNA in overcoming immune tolerance has been promising not only in inbred mice with transplanted tumors but also in outbred canines, which present with spontaneous tumors, as in the case of human. Use of this strategy also overcomes limitations seen in other types of cancer vaccines. Immunization against defined tumor antigens using a xenogeneic DNA vaccine is currently being tested in early phase clinical trials for the treatment of melanoma and prostate cancers, with proposed trials for breast cancer and Non-Hodgkin's Lymphoma.     

Prognostic factors and new therapeutic approaches to cervical cancer

Recent advances in the detection and therapy of carcinoma of the cervix and its squamous intra-epithelial precursor lesions exploit the knowledge that these lesions are a consequence of infection with high risk (HR) human papillomavirus (HPV). HPV infections over-ride cell cycle controls and antibody based immunodetection of proteins that regulate DNA replication may facilitate mass automated cervical smear screening. Detection of HR HPV DNA in smears from selected patient groups will improve detection of high grade precursor lesions and immunodetection of the cell cycle dependent kinase inhibitor p16(INK4a) seems to specifically and sensitively identify HGSIL. Immunisation with HPV early proteins has been shown to have both prophylactic and therapeutic efficacy in animal papillomavirus infections and immunotherapies for low grade intra-epithelial lesions are realistic. Such vaccines are likely to be combined with immunomodulators in order to maximise the response. Immunotherapies for HPV associated high grade pre-cancers and invasive cancers are problematic in view of tumour immune evasion. However, anti-viral chemotherapies may benefit from the neoplastic phenotypic by the induction of: (1) apoptosis as a consequence of small molecule or anti-sense targeting of individual HPV oncoproteins and (2) replicative senescence by down regulation of the early promoter by E2 or small molecule homologues.     

From clinical trials to clinical practice: therapeutic cancer vaccines for the treatment of prostate cancer

Therapeutic options for patients with metastatic castration-resistant prostate cancer are increasing, spurring an urgent need to better understand which treatments are best for individual patients. The recent approval of a first-in-class agent, sipuleucel-T, has intensified this need. This therapeutic cancer vaccine has demonstrated a survival advantage in two Phase III trials, but does not alter progression in the short term. Therefore, a new therapeutic approach for patients with metastatic castration-resistant prostate cancer is taking shape, based on broader understanding of available therapies. This new clinical approach seeks to maximize patient benefit from treatment, minimize associated toxicities, and may have far-reaching implications for other therapeutic cancer vaccines currently in clinical development.     

子宫颈癌治疗性疫苗研究进展

子宫颈癌为妇女最常见的恶性肿瘤之一,其与人乳头瘤病毒(HPV)密切相关.HPV早期基因E6、E7的持续表达是维持癌细胞转化状态所必须的.因此,E6、E7可作为宫颈癌治疗的靶点.目前,针对HPV E66、E7的治疗性疫苗已取得了较大进展.本文就近年来子宫颈癌治疗性疫苗的最新进展进行了综述.     

结核病治疗性疫苗的研究进展

耐药结核分枝杆菌的出现以及由于免疫功能失衡导致的免疫耐受是阻碍结核病有效治疗的两个重要原因.治疗性疫苗能通过对已感染结核分枝杆菌的机体产生二次免疫激发,打破机体的免疫耐受,诱导保护性免疫应答而达到清除结核分枝杆菌的目的.目前,结核病治疗性疫苗研究主要集中在DNA疫苗、亚单位疫苗、减毒活疫苗和死疫苗上.因其可纠正机体失衡的免疫状态,且对耐药性的结核分枝杆菌可产生同样的清除作用,所以,近年来结核病治疗性疫苗逐渐受到人们的关注和重视并取得了较大发展.