Current Opinion in Molecular Therapeutics最新文献

In development by Antisoma plc, AS-1411 is the first oligodeoxynucleotide aptamer to reach phase I and II clinical trials for the potential treatment of cancers, including acute myelogenous leukemia (AML). As an aptamer, AS-1411 does not appear to engage in hybridization-requiring pathways such as antisense effect, siRNA or triple helix formation. Instead, AS-1411 appears to bind to nucleolin specifically, and is subsequently internalized into the tumor cell. Nucleolin is an abundant protein, with expression that is correlated with the proliferative status of the cell: nucleolin levels are higher in tumors and actively dividing cells. Because of the multifunctional nature of nucleolin, it is probable that many secondary targets are affected following treatment with AS-1411. AS-1411 has demonstrated preclinical growth inhibition activity against a wide variety of tumor cell lines at concentrations in the micromolar range, and resulted in good efficacy in mice xenografted with tumor cells of human origin. In a phase I clinical trial in patients with advanced, refractory cancers with metastases at multiple sites, AS-1411 was safe and well tolerated; in addition, one complete response and one ongoing partial response were reported in two patients with renal cell carcinoma. A phase II trial of AS-1411 in combination with cytarabine in patients with AML demonstrated the combination to be superior to cytarabine alone. Thus, AS-1411 appears to be a promising candidate for cancer treatment in these pathologies. A greater understanding of the mechanism of action of this agent is essential to aid in future research.

Gene-based vaccines are under development for a broad variety of applications, ranging from vaccines to immunotherapies for infectious diseases, cancer, autoimmune diseases and allergy. In addition, following the licensing of DNA vaccines for use in fish and horses, and DNA immunotherapy for the treatment of cancer in dogs, several veterinary uses of vaccines have been demonstrated for species ranging from fish and shrimp to cattle and horses. A variety of publications describing preclinical and clinical studies of the technologies used to increase the potency of gene-based vaccines, and research further elucidating the immune mechanisms involved have recently become available. This review discusses the progress and observations described in the recent literature, including a survey of the diseases and approaches that are being targeted with gene-based vaccines.

Persistent pain represents a major health problem, and most current therapeutic approaches are associated with unwanted effects and unsatisfactory pain relief. Therefore, an urgent need exists to develop more effective drugs that are directed toward new molecular targets. Nerve growth factor (NGF) is involved in pain transduction mechanisms, playing a key role as a master switch in many chronic and inflammatory pain states; the NGF ligand and its receptor TrkA constitute well-validated targets for pain therapy. Tanezumab (RN-624), a first-in-class recombinant humanized mAb targeting NGF, is being developed by Pfizer Inc for the potential treatment of pain associated with several conditions. In preclinical studies, tanezumab, and its murine precursor muMab-911, effectively targeted the NGF pathway in various chronic and inflammatory pain models. Phase I and II clinical trials in osteoarthritic pain and chronic lower back pain demonstrated good efficacy for the compound, as well as a good safety and tolerability profile. Given that tanezumab is an antibody, the drug demonstrates the general advantages of this class of products (including good specificity and favorable pharmacokinetics), and also appears to be particularly well suited for targeting the chronic and inflammatory-mediating pain actions of NGF and its receptor system.

Whole-cell vaccination has demonstrated efficacy in small phase I and II clinical trials. However, in the past 3 years several high-profile phase III trials have failed to meet the predicted endpoints, including trials of the GVAX technologies (BioSante Pharmaceuticals Inc [formerly Cell Genesys Inc]) conducted by Cell Genesys. This review discusses the potential reasons for the failure of selected phase III trials and summarizes the current status of whole-cell vaccination, with specific reference to trials conducted in the past 2 years. Recently, new paradigms have emerged in the field of cancer vaccine research. In particular, the potential use of combination therapies that incorporate immune modulators and standard radio- and chemotherapy to synergize with whole-cell vaccines is discussed. In addition, key measures for improvements within the field that may be required for the generation of effective antitumor immunity are identified.

More than 60 million individuals have been infected with HIV and approximately half of these individuals have died since the epidemic started. The quest for an effective vaccine to prevent HIV transmission, which is likely to be the most effective approach to halt the epidemic, has been and continues to be an insurmountable challenge. Traditional vaccine strategies that have been effective for other vaccines have proven unsuccessful or impractical for HIV because of safety concerns. Nonetheless, substantial efforts have been directed at the development and clinical testing of HIV vaccines during the past two decades. Four major HIV vaccine efficacy trials conducted by VaxGen Inc (AIDSVAX 003 and AIDSVAX 004) and the NIH-supported HIV Vaccine Trials Network (HVTN 502 and HVTN 503) failed to demonstrate efficacy; however, a recent trial conducted in Thailand (RV144 trial) demonstrated a low level of efficacy, resulting in some renewed optimism. Dissecting the causes for vaccine failure and, more importantly, for the partial level of efficacy observed in the RV144 trial should provide important guidance to the field. This review discusses the ongoing HIV vaccine trials and also highlights recent scientific advances that have provided the field with new leads to invigorate the search for effective vaccines.

Results from recent clinical trials of the therapeutic vaccines sipuleucel-T (Dendreon Corp), PROSTVAC-VF-TRICOM (National Cancer Institute/BN ImmunoTherapeutics Inc) and BiovaxID (Biovest International Inc) are highlighted. These data support the further development of such vaccines, and provide guidance for the development of improved agents and protocols for the use of therapeutic vaccination to treat cancer.

The growing prospect of avian influenza viruses achieving sustained interhuman transmission, combined with the recent emergence of a novel swine-origin A/H1N1 influenza strain, has brought the issue of influenza vaccine production capacity into sharp focus. It is becoming increasingly clear that traditional egg-based manufacturing processes may be insufficient to meet global vaccine demands in a pandemic situation that is caused by a highly pathogenic influenza virus. This review introduces the concepts of modern, cell culture-derived influenza vaccines and their manufacture, and explains the advantages of these vaccines in terms of both speed and efficiency of production as well as immunogenic efficacy. Vaccine production technologies using the mammalian cell lines Vero, MDCK and PER.C6, as well as the baculovirus/insect cell platform, are described in detail. Clinical data are provided from cell culture-derived vaccines that are at an advanced stage of development, and insights are provided into recent developments in the preclinical evaluation of more experimental technologies.

The treatment of patients with cancer using passive vaccination with antibodies has been demonstrated to be a promising option, particularly for 'soft tumors', most likely because of their greater accessibility compared with bulky solid tumors. While effector T-cells are efficient in the rejection of large organs and foreign tissues, the wide application of tumor-specific T-cells for cancer therapy has been limited by the inherent restriction of T-cell recognition to self antigens, and the difficulty in obtaining sufficient numbers of such cells with defined specificity. Advances in gene transfer and cell therapy have enabled the genetic modification of T-cells by the ectopic expression of predefined, specific receptor genes that redirect such 'designer cells' to any target of interest. This review discusses two approaches to applying redirected T-cells for adoptive cancer immunotherapy: the 'T-body' approach, which employs chimeric receptors with tumor-specific antibody-derived specificity, and the use of transgenes encoding tumor-specific T-cell receptors. Particular emphasis is placed on recent attempts using these approaches in the treatment of patients with cancer.

MVA-85A, in development by Oxford-Emergent Tuberculosis Consortium Ltd and the EU-funded research program TB-VAC, is a live attenuated viral vaccine expressing the immunodominant tuberculosis (TB) antigen 85A, and is intended for use in a heterologous prime-boost strategy to prevent TB. MVA-85A is highly immunogenic in both animals and humans, eliciting strong polyfunctional CD4+ T-cell responses when administered as a boost following BCG vaccination or when administered to individuals previously exposed to TB. Animal studies have demonstrated trends toward reduced pathology and bacillary burden for animals vaccinated with BCG prime followed by MVA-85A boost compared with BCG alone; however, these positive effects appear to be modest, and interpretation is limited by the small number of animals tested. The vaccine has an excellent safety profile in BCG-naïve, previously BCG-vaccinated and TB-exposed adults, as well as in BCG-vaccinated adolescents and children. At the time of publication, MVA-85A was in a more advanced stage of clinical development than other novel TB vaccine candidates, with a large-scale, proof-of-concept phase IIb clinical trial underway for the determination of safety, immunogenicity and prevention of TB in infants.

Recent data suggest that dengue immunity could be elicited via either humoral or cell-mediated routes. Directing the immune response to serotype-specific epitopes from domain (D)III of the dengue virus envelope protein (Env) may induce effective levels of neutralizing antibodies. Removing serotype-crossreactive epitopes from DIII, as well as DII, may reduce the potential for the vaccine to induce non-neutralizing antibodies associated with antibody-dependent enhancement (ADE) of infection. The use of consensus Env DIII sequences for each serotype, and perhaps even a single consensus sequence for all four serotypes of dengue virus, may direct the immune response to invariant neutralizing sequences, which might improve vaccine safety and long-term efficacy. Vaccines incorporating capsid and/or non-structural (NS) proteins may be capable of inducing tetravalent cell-mediated immunity without ADE. However, the potential of cell-mediated immunity to contribute to pathology is not well understood, and modifications of NS proteins, such as truncated NS1, may be necessary for optimal vaccine safety. This review discusses recent progress in the development of dengue vaccines.