Cancer immunotherapy using recombinant Listeria monocytogenes Transition from bench to clinic
ABSTRACT Cancer immunotherapy has developed into a field of intense study as aspects of the immune system involved in the eradication of cancer have become delineated. Listeria monocytogenes is a gram-positive, facultative intracellular bacterium which infects antigen presenting cells (APC), and is being used as a cancer vaccine to deliver tumor antigens directly to the APC. This results in the generation of a strong immune response towards the tumor associated antigen and direct targeting of the tumor by the immune system. Advances in this field have led to the development of a series of L. monocytogenes-based cancer vaccines, which are currently in clinical trials. A phase I study has shown these vaccines can be safely administered and well-tolerated in terminal stage cancer patients and an efficacy signal was observed in patients who did not respond to other therapies. Additional data on the efficacy of these vaccines is expected in the near-term.
- SourceAvailable from: Surasak Wanram[Show abstract] [Hide abstract]
ABSTRACT: Background: Listeria monocytogenes (LM) has been used as a vaccine vector based upon its ability to induce a strong cell-mediated immune response. LM inactivated with γ-irradiation retains immunogenic properties and is an attractive platform for clinical use since it would have improved safety concerns compared to live vectors. Activated charcoal has been shown to enhance expression of LM proteins such as PrfA. Aim: To investigate the effect of various growth conditions supplemented with activated charcoal on recombinant antigen expression. Methods: We prepared γ-irradiated ovalbumin-expressing LM (LM-OVA) after growth under various culture conditions. We cultured LM-OVA at various temperatures including 25°C, 37°C and 37°C with activated charcoal and compared OVA expression by western blot analysis, dendritic cells maturation and OVA-specific T cells. Results: The OVA expression was highest in γ-irradiated LM-OVA grown with activated charcoal at 37°C. Compared to other growth conditions, γ-irradiated LM-OVA grown with activated charcoal at 37°C induce better DC maturation as well as production of the highest number of antigen-specific IFN γ-secreting T cells. Conclusion: The further study should be demonstrated the potential to alter growth conditions to enhance OVA expression resulting for vaccine vectors, thereby improving their safety and efficacy.The Kobe journal of medical sciences 01/2012; 58(3):E63-71.
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ABSTRACT: HPV infection is a direct cause of neoplasia and malignancy. Cellular immunologic activity against cells expressing HPV E6 and E7 is sufficient to eliminate the presence of dysplastic or neoplastic tissue driven by HPV infection. Live attenuated Listeria monocytogenes- (Lm-) based immunotherapy (ADXS11-001) has been developed for the treatment of HPV-associated diseases. ADXS11-001 secretes an antigen-adjuvant fusion (Lm-LLO) protein consisting of a truncated fragment of the Lm protein listeriolysin O (LLO) fused to HPV-16 E7. In preclinical models, this construct has been found to stimulate immune responses and affect therapeutic outcome. ADXS11-001 is currently being evaluated in Phase 2 clinical trials for cervical intraepithelial neoplasia, cervical cancer, and HPV-positive head and neck cancer. The use of a live attenuated bacterium is a more complex and complete method of cancer immunotherapy, as over millennia Lm has evolved to infect humans and humans have evolved to prevent and reject this infection over millennia. This evolution has resulted in profound pathogen-associated immune mechanisms which are genetically conserved, highly efficacious, resistant to tolerance, and can be uniquely invoked using this novel platform technology.Journal of Oncology 02/2012; 2012:542851. DOI:10.1155/2012/542851
Article: Recombinant bacterial vaccines[Show abstract] [Hide abstract]
ABSTRACT: Vaccines are currently available for many infectious diseases caused by several microbes and the prevention of disease and death by vaccination has profoundly improved public health globally. However, vaccines are not yet licensed for use against many other infectious diseases and new or improved vaccines are needed to replace suboptimal vaccines, and against newly emerging pathogens. Most of the vaccines currently licensed for human use include live attenuated and inactivated or killed microorganisms. Only a small subset is based on purified components and even fewer are recombinantly produced. Novel approaches in recombinant DNA technology, genomics and structural biology have revolutionized the way vaccine candidates are developed and will make a significant impact in the generation of safer and more effective vaccines.Current opinion in immunology 04/2012; 24(3):337-42. DOI:10.1016/j.coi.2012.03.013 · 7.87 Impact Factor