Therapeutic potential of dendritic cell vaccines in sarcoma of the extremities

Sarcomas of the extremities are challenging to treat. They are divided into soft-tissue and bone sarcomas in general, which also have many subtypes, based on their different mesenchymal origins and anatomical locations, respectively. Each of these sarcomas present in different ways, exhibit different behaviors and prognoses, and present unique therapeutic challenges. Dendritic cells (DCs) are the best professional antigen-presenting cells that can induce both the generation and proliferation of specific cytotoxic T lymphocytes and helper T lymphocytes through antigen presentation by MHC class I and class II molecules, respectively. In this review, a series of recently conducted immunotherapy for extremital sarcomas based on DCs are summarized and the potential for therapeutic DC vaccination targeted against these tumors is assessed.     

Tocotrienol as a potential anticancer agent

Vitamin E is composed of two structurally similar compounds: tocopherols (TPs) and tocotrienols (T3). Despite being overshadowed by TP over the past few decades, T3 is now considered to be a promising anticancer agent due to its potent effects against a wide range of cancers. A growing body of evidence suggests that in addition to its antioxidative and pro-apoptotic functions, T3 possesses a number of anticancer properties that make it superior to TP. These include the inhibition of epithelial-to-mesenchymal transitions, the suppression of vascular endothelial growth factor tumor angiogenic pathway and the induction of antitumor immunity. More recently, T3, but not TP, has been shown to have chemosensitization and anti-cancer stem cell effects, further demonstrating the potential of T3 as an effective anticancer therapeutic agent. With most of the previous clinical studies on TP producing disappointing results, research has now focused on testing T3 as the next generation vitamin E for chemoprevention and cancer treatment. This review will summarize recent developments in the understanding of the anticancer effects of T3. We will also discuss current progress in clinical trials involving T3 as an adjuvant to conventional cancer therapy.     

以端粒为靶的肿瘤治疗研究进展

端粒自身的鸟嘌呤四联体(guanine-quadruplex)和一些端粒特异性结合蛋白对端粒长度、端粒稳定甚至对端粒酶活性都有调节作用，在肿瘤形成和生长中发挥重要作用。以此为靶点抑制肿瘤，直接作用于端粒，不依赖端粒酶的存在，对端粒酶阴性肿瘤亦有作用。因此，端粒可能成为新的肿瘤抑制靶点。     

miR-181b as a potential molecular target for anticancer therapy of gastric neoplasms

Objective: MicroRNAs (miRNAs) play important roles in carcinogenesis. The aim of the present study wasto explore the effects of miR-181b on gastric cancer. Methods: The expression level of miR-181b was quantifiedby qRT-PCR. MTT, flow cytometry and matrigel invasion assays were used to test proliferation, apoptosis andinvasion of miR-181b stable transfected gastric cancer cells. Results: miR-181b was aberrantly overexpressed ingastric cancer cells and primary gastric cancer tissues. Further experiments demonstrated inducible expression ofmiR-181b by Helicobacter pylori treatment. Cell proliferation, migration and invasion in the gastric cancer cellswere significantly increased after miR-181b transfection and apoptotic cells were also increased. Furthermore,overexpression of miR-181b downregulated the protein level of tissue inhibitor of metalloproteinase 3 (TIMP3).Conclusion: The upregulation of miR-181b may play an important role in the progress of gastric cancer andmiR-181b maybe a potential molecular target for anticancer therapeutics of gastric cancer.     

A new era in anticancer peptide vaccines

The use of synthetic peptides as vaccines aimed at the induction of therapeutic CD8‐positive T‐cell responses against tumor cells initially experienced great enthusiasm, mostly because of advances in vaccine technology, including design, synthesis, and delivery. However, despite impressive results in animal models, the application of such vaccines in humans has met with only limited success. The therapeutic activity of vaccine‐stimulated, tumor‐specific, CD8‐positive T cells can be hampered through the physical burden of the tumor, tolerance mechanisms, and local factors within the tumor microenvironment. Recently, accumulating evidence has suggested that combining a peptide‐based therapeutic vaccination with conventional chemotherapy can uncover the full potential of the antitumor immune response, increasing the success of immunotherapy. In addition, therapeutic vaccination in the preventive setting has been extremely effective in eliciting antitumor responses in preclinical tumor models and has demonstrated good promise clinically in patients with minimal residual disease. The rationale behind preventive vaccination is that patients with minimal tumor burden still have a fully competent immune system capable of developing robust antitumor responses. Finally, therapeutic CD8‐positive T‐cell peptide vaccines have been improved by coimmunization with T‐helper epitopes expressed on long peptides. Cancer 2010. © 2010 American Cancer Society.     

Carcinoembryonic antigen as a target for therapeutic anticancer vaccines: a review.

PURPOSE: To describe the features of carcinoembryonic antigen (CEA) that are important for its use in vaccination approaches and review the clinical experience with therapeutic vaccines targeting CEA. METHODS: A PubMed search was performed on CEA, along with various qualifiers such as cancer vaccines, epitopes, and function. Relevant articles were reviewed. RESULTS: CEA is a member of the immunoglobulin supergene family and may play a role in tumorigenesis. CEA protein is processed and presented on major histocompatibility complex (MHC) proteins for multiple alleles, including HLA A2, A3, and A24. T lymphocytes from healthy volunteers and cancer patients can recognize the processed epitopes of CEA and can become activated to lyse CEA-expressing tumors. Therapeutic vaccination approaches that have targeted CEA include vaccination with recombinant CEA protein, CEA anti-idiotype antibodies, and dendritic cells pulsed with agonist epitopes of CEA. Humoral responses have predominantly been induced with the first two approaches, whereas CD4 and CD8 responses, disease stabilization, and even objective clinical responses have been seen with the dendritic cell approach. Recently, CEA-poxvirus vectors encoding CEA and costimulatory molecules such as B7.1 have been shown to be safe and to induce increases in the frequency of T-cell precursors that recognize processed epitopes of CEA presented on MHC class 1 molecules. Disease stabilization has been seen in up to 37% of patients treated with these vaccines. CONCLUSION: Tolerance to CEA in patients with cancer can be overcome with several different vaccination approaches, and such vaccinations are safe and immunologically active. Poxvirus-based vaccines can reproducibly generate T-cell responses to CEA and to tumors expressing CEA. Clinical activity has been seen with poxvirus or dendritic cell approaches. Other approaches are also being explored.     

RNA interference as a plausible anticancer therapeutic tool

RNA interference has created a breakthrough in gene silencing technology and there is now much debate on the successful usage of RNAi based methods in treating a number of debilitating diseases. Cancer is often regarded as a result of mutations in genomic DNA resulting in faulty gene expression. The occurrence of cancer can also be influenced by epigenetic irregularities in the chromatin structure which leads to alterations and mutations in DNA resulting in cancer cell formation. A number of therapeutic approaches have been put forth to treat cancer. Anti cancer therapy often involves chemotherapy targeting all the cells in common, whereby both cancer cells as well as normal cells get affected. Hence RNAi technology has potential to be a better therapeutic agent as it is possible to deactivate molecular targets like specific mutant genes. This review highlights the successful use of RNAi inducers against different types of cancer, thereby paving the way for specific therapeutic medicines.     

Anti-idiotypic monoclonal antibody cancer vaccines

Anti-idiotypic monoclonal antibodies (MAb) can mimic both protein and non-protein antigenic epitopes. In animal models, and now in patients, it is possible to induce immune responses against tumor antigens using anti-idiotypic MAb vaccines. While it is not clear how the efficacy of anti-idiotypic MAb vaccines compares with the efficacy of vaccines constructed from antigen, there are two situations where anti-idiotypic vaccines have potential advantages: (1) when the antigen is not readily available in sufficient quantities or purity, and (2) when the antigen is a non-protein. Clinical trials are underway using anti-idiotypic MAb vaccines in both of these situations.     

Cationic amphiphilic drugs as potential anticancer therapy for bladder cancer

More effective therapy for patients with either muscle‐invasive or high‐risk non‐muscle‐invasive urothelial carcinoma of the bladder (UCB) is an unmet clinical need. For this, drug repositioning of clinically approved drugs represents an interesting approach. By repurposing existing drugs, alternative anticancer therapies can be introduced in the clinic relatively fast, because the safety and dosing of these clinically approved pharmacological agents are generally well known. Cationic amphiphilic drugs (CADs) dose‐dependently decreased the viability of a panel of human UCB lines in vitro. CADs induced lysosomal puncta formation, a hallmark of lysosomal leakage. Intravesical instillation of the CAD penfluridol in an orthotopic mouse xenograft model of human UCB resulted in significantly reduced intravesical tumor growth and metastatic progression. Furthermore, treatment of patient‐derived ex vivo cultured human UCB tissue caused significant partial or complete antitumor responses in 97% of the explanted tumor tissues. In conclusion, penfluridol represents a promising treatment option for bladder cancer patients and warrants further clinical evaluation.

Abbreviations

CAD

cationic amphiphilic drug

MIBC

muscle‐invasive bladder carcinoma

NMIBC

non‐muscle‐invasive bladder carcinoma

TS

explanted tumor tissue slices

TURBT

transurethral resection of the bladder tumor

UCB

urothelial carcinoma of the bladder

     

预防性 HPV 疫苗的临床应用进展及思考

宫颈癌是女性生殖系统最常见的恶性肿瘤,并且高危型人乳头瘤病毒（human papillomavirus, HPV）持续感染与宫颈癌的密切关系已经得到流行病学及临床研究证实。因此,HPV 疫苗在预防 HPV 持续感染及宫颈相关病变等方面备受瞩目。本文对目前美国 FDA 批准上市的3种预防性疫苗的临床应用进展进行综述,同时列举出一些尚存在争议的问题,旨在引起人们的重视及共同思考。     

L523S,an RNA-binding protein as a potential therapeutic target for lung cancer

Approaches to vaccine-based immunotherapy of human cancer may ultimately require targets that are both tumour-specific and immunogenic. In order to generate specific antitumour immune responses to lung cancer, we have sought lung cancer-specific proteins that can be targeted for adjuvant vaccine therapy. By using a combination of cDNA subtraction and microarray analysis, we previously reported the identification of an RNA-binding protein within the KOC family, L523S, to be overexpressed in squamous cell cancers of the lung. We show here that L523S exhibits significant potential for vaccine immunotherapy of lung cancer. As an oncofetal protein, L523S is normally expressed in early embryonic tissues, yet it is re-expressed in a high percentage of nonsmall cell lung carcinoma. The specificity of L523S expression in lung cancer was demonstrated by both mRNA and protein measurements using real-time PCR, Western blot, and immunohistochemistry analyses. Furthermore, we show that immunological tolerance of L523S is naturally broken in lung cancer patients, as evidenced by detectable antibody responses to recombinant L523S protein in eight of 17 lung pleural effusions from lung cancer patients. Collectively, our studies suggest that L523S may be an important marker of malignant progression in human lung cancer, and further suggest that treatment approaches based on L523S as an immunogenic target are worthy of pursuit.     

Cytokine-modified Mycobacterium smegmatis as a novel anticancer immunotherapy

Intravesical administration of live M. bovis BCG organisms for carcinoma in situ of the urinary bladder is the most successful immunotherapy for solid malignancy. Nevertheless BCG-therapy is associated with significant toxicity and is ineffective in 30-40% of cases. Recently it has been proposed that cytokine-modified mycobacteria may give greater efficacy. As any immunotherapy involving administration of live BCG organisms (wild-type or recombinant) is likely to have associated toxicity (notably in the immunocompromised), we examined the anti-tumour potential of the closely related nonpathogenic organism, Mycobacterium smegmatis, and a TNFalpha gene-modified recombinant M. smegmatis. When wild-type M. smegmatis were delivered to immunocompetent C57Bl/6 mice bearing the transplantable MB49 bladder tumour, efficacy comparable to live BCG was observed with 10-20% long-term survival. However, this effect was lost in both Nude and Beige mice, lacking functional T and NK cells, respectively. Recombinant M. smegmatis secreting TNFalpha, however, gave a 70% durable tumour-free survival. Lymphocytes from draining lymph-nodes and spleens of these mice exhibited pronounced IFNgamma production to mycobacterial-antigen and tumour-lysate, indicating a bias towards cell-mediated immunity. This was further supported by histopathological examination of the tumour site, which revealed significantly increased numbers of CD3+ lymphocytes in animals receiving the recombinant vaccine, but not in those receiving wild-type bacteria. Importantly, tumour rejection following M. smegmatis/TNFalpha was independent of T lymphocytes, as athymic Nude mice efficiently eradicated MB49 tumours. In contrast, the therapeutic efficacy of M. smegmatis/TNFalpha was reduced in animals deficient in NK cytolytic function, suggesting a role for NK-cells in initial tumour destruction. Furthermore the absence of NK-function in Beige mice did not prevent the establishment of tumour-protective memory. No toxicity was observed with wild-type or recombinant M. smegmatis in immunocompetent, T-deficient or NK-deficient models. We demonstrate for the first time that recombinant mycobacteria expressing mammalian cytokines have markedly increased anti-tumour properties. The lack of toxicity suggests that M. smegmatis is a "safe" vehicle for use in immunocompromised patients.     

Interference with polyamine biosynthesis and/or function by analogs of polyamines or methionine as a potential anticancer chemotherapeutic strategy

The obvious goal in cancer chemotherapy is selectivity. Highly cytotoxic agents abound but their usefulness as anticancer agents extends only so far as their specificity for tumor cells and tissues. In this context, we have reviewed those aspects of polyamine and AdoMet metabolism and function which might contribute to their potential as target sites for chemotherapeutic intervention. Although largely untested to date and far from unequivocal, these various considerations seem to provide sufficient rationale for continued evaluation of the therapeutic potential of these sites. Polyamine analogs and methionine analogs designed to modulate polyamine biosynthesis directly or through AdoMet formation have been discussed as strategies to effect this goal and previous studies with similar analogs have been reviewed. Progress achieved thus far with analogs derived from our own laboratories provides novel insights into polyamine and AdoMet metabolism and/or function as well as new leads towards the design of more effective agents and drug combinations. More detailed reading of the biochemistry of polyamines in eukaryotes and prokaryotes is available in several very excellent current reviews (6-9, 77).     

Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy

The vacuolar ATPases are ATP-dependent proton pumps whose functions include the acidification of intracellular compartments and the extrusion of protons through the cell cytoplasmic membrane. These pumps play a pivotal role in the regulation of cell pH in normal cells and, to a much greater extent, in tumor cells. In fact, the glucose metabolism in hypoxic conditions by the neoplasms leads to an intercellular pH drift towards acidity. The acid microenvironment is modulated through the over-expression of H⁺ transporters that are also involved in tumor progression, invasiveness, distant spread and chemoresistance. Several strategies to block/downmodulate the efficiency of these transporters are currently being investigated. Among them, proton pump inhibitors have shown to successfully block the H⁺ transporters in vitro and in vivo, leading to apoptotic death. Furthermore, their action seems to synergize with conventional chemotherapy protocols, leading to chemosensitization and reversal of chemoresistance. Aim of this article is to critically revise the current knowledge of this cellular machinery and to summarize the therapeutic strategies developed to counter this mechanism.     

Transvaginal ultrasound diagnosis of a live twin tubal ectopic pregnancy

A case of live twin tubal ectopic pregnancy diagnosed by transvaginal ultrasound is presented. This is a rare occurrence and we have calculated the incidence to be ~ 1:125 000 pregnancies. There have been more than 100 case reports of twin tubal ectopic pregnancy but only four previous reports where two foetal heart motions have been visualized. The introduction of high-resolution transvaginal ultrasound has resulted in earlier diagnosis of ectopic pregnancy and contributed to the decrease in morbidity that has occurred over recent years.     

Dominant B cell epitope from NY-ESO-1 recognized by sera from a wide spectrum of cancer patients: implications as a potential biomarker

Monitoring the spontaneous antibody (Ab) response against a panel of relevant tumor-associated antigens (TAA) in cancer patients may provide useful information regarding the clinical status of cancer. However, current Ab detection approaches require the purification of recombinant proteins, which is often difficult to achieve. In order to bypass the purification of recombinant proteins, we identified a dominant B-cell epitope from a shared tumor antigen NY-ESO-1. A synthetic peptide of the epitope, ESO:1-40, was as sensitive as the recombinant protein for detecting Ab against NY-ESO-1 in most patients. NY-ESO-1 specific Ab present in the sera of patients with melanoma, prostate cancer, nonsmall cell lung cancer, esophageal cancer, gastric cancer and hepatocellular carcinoma reacted with the dominant peptide at a similar frequency as the recombinant protein. To our knowledge, ESO:1-40 is the first peptide epitope recognized by sera from a wide spectrum of cancer patients but not healthy donors. This simple and straightforward approach may allow the investigation of the clinical significance of spontaneous Ab responses against multiple TAA and their correlation with the clinical course of malignant diseases in the future.     

Impact of tumour volume on the potential efficacy of therapeutic vaccines

With the recent approval by the U.S. Food and Drug Administration of the first therapeutic vaccine for cancer, the long-awaited goal of harnessing a patient's immune system to attack cancer through this modality is finally realized. However, as researchers in the field of cancer immunotherapy continue to perform randomized definitive studies, much remains to be learned about potential surrogate endpoints and appropriate patient populations for therapeutic vaccines. The present review addresses available data from clinical trials of immunotherapeutic agents relevant to the selection of appropriate patient populations. We believe that the weight of evidence supports the use of immunotherapy earlier in the disease course and in patients with less aggressive disease, and that the relevant findings have important implications for the design of clinical trials with therapeutic vaccines.