Cytokine-secreting tumor cell vaccines

Modification of the tumor microenvironment with gene transfer techniques stimulates two immune mechanisms that effectuate tumor destruction. One involves improved tumor-antigen presentation for the development of specific cellular and humoral immunity. The second involves compromise of the tumor vasculature by soluble factors and leukocytes.     

树突状细胞与肿瘤疫苗

细胞生物学、分子生物学和免疫学等学科的飞速发展,以及新的实验体系和新的技术方法的不断涌现,促进了肿瘤递呈性免疫治疗的日新月异,树突状细胞作为体内功能最强的抗原递呈细胞在以T细胞识别肿瘤抗原为核心的肿瘤生物治疗研究中展现了良好的应用前景。本文通过对树突状细胞在肿瘤疫苗中设计策略的综述,有助于更加准确地看待当今的肿瘤生物治疗。     

树突状细胞肿瘤疫苗的研究进展

在抗肿瘤免疫应答中,关键的一步是抗原呈递细胞将肿瘤抗原呈递给T淋巴细胞。树突状细胞是专职抗原呈递细胞,它能够有效的将肿瘤抗原呈递给T细胞,引发机体产生抗肿瘤的免疫应答。因此,利用树突状细胞制备肿瘤疫苗可望提供一种有效的肿瘤免疫治疗方法。目前,体外实验、动物实验和初期的临床实验都已经证明了树突状细胞肿瘤疫苗的抗肿瘤作用。本文主要介绍树突状细胞的生物学特征和树突状细胞肿瘤疫苗在肿瘤免疫治疗中的研究进展。     

Dendritic cell-derived exosomes as cell-free peptide-based vaccines

Dendritic cells (DC) are professional antigen-presenting cells and the only ones capable of inducing primary cytotoxic immune responses both in vivo and in vitro. DCs secrete a 60-100 nm membrane vesicle population of endocytic origin, called exosomes. The lipid and protein composition of DC-derived exosomes (DEX) is now well characterized. Besides MHC and costimulatory molecules, DEX bear several adhesion proteins, which are probably involved in their specific targeting. DEX also accumulate several cytosolic factors, most likely involved in exosome's biogenesis in late endosomes. In 1998, we reported that DEX are immunogenic in mice and lead to tumor rejection. These findings have renewed the interest in DEX. The current challenge consists of understanding the mechanisms and the physiological relevance of DEX, which could contribute to the design of the optimal DEX-based vaccination. In this review, we focus on the biological features of DEX and their immunostimulatory functions in mice and humans, and we discuss their potential clinical implementation in the immunotherapy of cancer.     

Dendritic cell discoveries provide new insight into the cellular immunobiology of DNA vaccines.

The evolution of increasingly virulent human pathogens, together with the rapid onset of antimicrobial resistance has created a need for new vaccination strategies. Nucleic acid vaccines, based on recombinant DNA technology are a promising new vaccine formulation capable of eliciting both humoral and cellular immune responses. This technology has been experimentally validated in animal models of pathogen challenge and tumor protection following administration of a DNA vaccine and has led to extensive research into the mechanisms of protective immunity. We focus here on the cellular and molecular mechanisms leading to cell-mediated immune responses to DNA vaccines and discuss these mechanisms in light of recent advances in the field of dendritic cell immunobiology. In particular, the potential involvement of: (i) the CpG pattern-recognition receptor, toll-like receptor-9; (ii) the dendritic cell-specific surface adhesion molecule, DC-SIGN; and (iii) the molecular interactions between CD40 and CD154 in the evolution of protective cell-mediated immunity to DNA vaccines are discussed. An improved understanding of the precise mechanisms leading to protective cellular immunity following DNA vaccination may help in the design of novel DNA constructs containing immunostimulatory features that target one or more of these mechanisms, with the aim of increasing the immunogenic potential and protective efficacy of DNA vaccines.     

Translational mini-review series on vaccines: Dendritic cell-based vaccines in renal cancer

Renal cancer is a relatively uncommon solid tumor, accounting for about 3% of all adult malignancies, however this rate incidence is rising. The most common histological renal cell carcinoma (RCC) subtype is clear cell carcinoma that makes up approximately 70-80% of all renal neoplasms and appears to be the only histological subtype that is responsive to immunotherapeutic approaches with any consistency. Therefore, it has been hypothesized that immune-mediated mechanisms play important roles in limiting tumor growth and that dendritic cells (DC), the most potent APC in the body, and T cells are the dominant effector cells that regulate tumor progression in situ. In this context, the development of clinically effective DC-based vaccines is a major focus for active specific immunotherapy in renal cancer. In the current review we have not focused on the results of recently published RCC clinical trials, as several excellent reviews have already performed this function. Instead, we turned our attention to how the perception and practical application of DC-based vaccinations are evolving.     

树突细胞源肿瘤疫苗

树突细胞(Dc)作为免疫应答的核心环节,具有强大的专职抗原呈递而引起免疫应答的能力,比之传统的直接免疫疗法,将Dc在体外进行制备再回输人体内,能作为最佳的抗原呈递细胞而更好的刺激抗肿瘤免疫应答,是有效的细胞免疫疗法,已被越来越多的应用于肿瘤疫苗的制备.     

DNA tumor vaccines

A new generation of vaccines are being developed to induce immune responses that fight off infectious agents, or erradicate cancerous cells. These new vaccines are based on a plasmid vector, which in transfected mammalian cells cause constitutive high-level expression of the target antigen. Expression of the target antigen, in turn, can induce a full-range of immunologic responses, including cell-mediated killing, cell-mediated cytokine release and the production of antigen-specific antibodies. Through molecular techniques, these nucleic acid vaccines can be enhanced to increase target antigen expression and facilitate antigen presentation. Additionally, genetic adjuvants expressed simultaneously with the target antigens can induce the immune responses to disease-associated antigens. The ease with which these genetic vaccines can be generated and the potency of their ability to generate immune-mediated responses make them highly effective, which creates hope for developing effective treatment and prevention of various diseases, most notably cancer.     

Dendritic cell differentiation and proliferation: enhancement by tumor necrosis factor-alpha

Dendritic cells (DCs) are a diverse group of hematopoietic-derived cells that play a prominent role in initiating the body's immune response. Tumor necrosis factor-alpha (TNFalpha) aids CD34+ hematopoietic stem cells in the development of DCs. In this study, we aimed to further define the relationship between TNFalpha and DC maturation. CD34+ stem cells were isolated from umbilical cord blood and cultured using granulocyte-macrophage colony stimulating factor, stem cell factor, and varying concentrations of TNFalpha. An anti-TNF receptor 1 (anti-TNFR1) antibody was used to show the specificity of TNFalpha. Flow cytometry and light microscopy analyses were performed at days 0, 7, and 14 of culture, revealing mature DCs at all concentrations of TNFalpha by day 14, excluding those with anti-TNFR1 bound to the cell's TNF receptor 1. DCs possessed a characteristic veiled appearance and were consistent with a DC panel of surface markers. TNFalpha was essential to the development of DCs, as those with bound anti-TNFR1 were virtually unable to develop into DCs. Increasing TNFalpha enhanced the survival of culturing stem cells and resulted in a parallel increase in day 14 DCs. Although increases in TNFalpha produced more DCs, these cells were not as phenotypically mature, expressing less CD80 than those receiving only a single initial dosage of TNFalpha. These studies support the prevalence of large numbers of DCs under inflammatory conditions, such as the rheumatoid joint, where local concentrations of TNFalpha are high.     

Dendritic cell as therapeutic vaccines against tumors and its role in therapy for hepatocellular carcinoma

Dendritic cells （DCs） are the most potent professional antigen-presenting cells, and capable of stimulating naive T cells and driving primary immune responses. DCs are poised to capture antigen, migrate to draining lymphoid organs, and after a process of maturation, select antigen-specific lymphocytes to which they present the processed antigen, thereby inducing immune responses. The development of protocols for the ex vivo generation of DCs may provide a rationale for designing and developing DC-based vaccination for the treatment of tumors. There are now several strategies being applied to upload antigens to DCs and manipulate DC vaccines. DC vaccines are able to induce therapeutic and protective antitumor immunity. Numerous studies indicated that hepatocellular carcinoma （HCC） immunotherapies utilizing DC-presenting tumor-associated antigens could stimulate an antitumour T cell response leading to clinical benefit without any significant toxicity. DC-based tumor vaccines have become a novel immunoadjuvant therapy for HCC. Cellular ＆ Molecular Immunology. 2006;3（3）：197-203.     

Adjuvants for enhancing the immunogenicity of whole tumor cell vaccines

Whole tumor cell lysates can serve as excellent multivalent vaccines for priming tumor-specific CD8(+) and CD4(+) T cells. Whole cell vaccines can be prepared with hypochlorous acid oxidation, UVB-irradiation and repeat cycles of freeze and thaw. One major obstacle to successful immunotherapy is breaking self-tolerance to tumor antigens. Clinically approved adjuvants, including Montanide? ISA-51 and 720, and keyhole-limpet proteins can be used to enhance tumor cell immunogenicity by stimulating both humoral and cellular anti-tumor responses. Other potential adjuvants, such as Toll-like receptor agonists (e.g., CpG, MPLA and PolyI:C), and cytokines (e.g., granulocyte-macrophage colony stimulating factor), have also been investigated.     

Dendritic cells and tumor immunity

Researchers and clinicians have tried for decades to use the mechanisms of immunity for the fight against cancer. Early attempts aimed at the instrumentation of soluble immune mediators such as antibodies or cytotoxic proteins for the therapy of malignancies. Major improvements in understanding the induction and regulation of cellular immunity have now made it possible to generate effector cells in cancer patients which are specific for the neoplastic disease. At the beginning of every cellular immune reaction against cancers tumor antigens have to be presented to T cells in order to activate them and drive them into clonal expansion. This is done by antigen presenting cells, the most powerful of which is the dendritic cell (DC). While DC were hard to isolate initially, they can be generated in large numbers in vitro today and manipulated in multiple ways before given back to a patient to induce tumor immunity. Thus, a great amount of hope lies in the use of DC as inducers of tumor immunity. However, the first clinical studies, which have now been completed with only limited success make clear, that still a lot of open questions remain to be answered. This review tries to give an overview of this rapidly developing field, mentioning the major conceptual approaches and techniques, but also discussing important caveats. The next years will show whether we can improve our understanding of DC biology and the mechanisms of immune induction strongly enough to effectively employ DC for immunotherapy of cancer.     

Dendritic cell ontogeny

Abundant evidence indicates that dendritic cells arise from the bone marrow. In vitro, precursors that differ phenotypically from mature dendritic cells divide several times to form functional dendritic cells. A soluble factor(s) produced in the supernatants of ConA-stimulated spleen cells enhances the production of dendritic cells. This factor(s) has not been fully characterized. Further maturation of dendritic cells occurs after they are released from the bone marrow; species differences exist. Interrelationships between various types of dendritic cells need to be elucidated.     

Dendritic cell vaccination

There has been a surge of interest in the use of dendritic cell (DC) vaccination as cellular immunotherapy for numerous cancers. Despite some encouraging results, this therapeutic modality is far from being considered as a therapy for cancer. This review will first discuss preclinical DC vaccination in murine models of cancer, with an emphasis on comparative studies investigating different methods of antigen priming. We will then comment on the various murine DC subsets and how these relate to human DC preparations used for clinical studies. Finally, the methodology used to generate human DCs and some recent clinical trials in several cancers are reviewed.