Effective treatment of intractable cutaneous metastases of breast cancer with electrochemotherapy: Ten-year audit of single centre experience.

Purpose: Electrochemotherapy (ECT) is the application of electric pulses to tumour tissue to render the cell membranes permeable to usually impermeant hydrophilic anti-cancer drugs, thereby enhancing cytotoxic effects. We sought to ascertain whether ECT can be an effective palliative treatment for cutaneous metastases of breast cancer.

Methods: This work reports data from the European Standard Operating Procedures for Electrochemotherapy trial (EudraCT Number: 2004-002183-18).

Electrochemotherapy for the treatment of ocular basal cell carcinoma; a novel adjunct in the disease management.

Basal Cell Carcinoma (BCC) affecting the ocular region is potentially problematic due to its ability to infiltrate aesthetic and functional structures. Due to the paucity of local tissue, resection frequently requires reconstruction with skin grafts or local flaps. Surgical treatment may not be suitable for patients with multiple co-morbidities.

In vivo optical imaging in gene & cell therapy.

Integral to the development of all gene therapy technologies is the ability to monitor gene delivery, in terms of distribution, levels and kinetics of vector transgene expression. This can be achieved to some extent at the preclinical level through use of traditional ex vivo analytical methods, but these hold several drawbacks, not least the requirement for death of experimental subjects for such end-point assays. Real-time in vivo analysis of reporter gene expression empowers the investigator with the ability to non-invasively assess gene delivery over time, as well as host responses to vector administration and therapeutic interventions.

Targeting regulatory T cells in cancer.

Infiltration of tumors by regulatory T cells confers growth and metastatic advantages by inhibiting antitumor immunity and by production of receptor activator of NF-κB (RANK) ligand, which may directly stimulate metastatic propagation of RANK-expressing cancer cells. Modulation of regulatory T cells can enhance the efficacy of cancer immunotherapy. Strategies include depletion, interference with function, inhibition of tumoral migration, and exploitation of T-cell plasticity.

Preclinical evaluation of gene delivery methods for the treatment of loco-regional disease in breast cancer.

Preclinical results with various gene therapy strategies indicate significant potential for new cancer treatments. However, many therapeutics fail at clinical trial, often due to differences in tissue physiology between animal models and humans, and tumor phenotype variation. Clinical data relevant to treatment strategies may be generated prior to clinical trial through experimentation using intact patient tissue ex vivo.

The use of Listeria monocytogenes as a DNA delivery vector for cancer gene therapy.

Listeria monocytogenes is an intracellular pathogen that lyses the phagosomal vacuole of infected cells, proliferates in the host cell cytoplasm and can actively enter adjacent cells. The pathogen is therefore well suited to exploitation as a vector for the delivery of DNA to target cells as the lifecycle favors cellular targeting with vector amplification and the potential for cell-to-cell spread. We have recently demonstrated DNA transfer by L.

Progress in genomics, metabolism and biotechnology of bifidobacteria.

Members of the genus Bifidobacterium were first described over a century ago and were quickly associated with a healthy intestinal tract due to their numerical dominance in breast-fed babies as compared to bottle-fed infants. Health benefits elicited by bifidobacteria to its host, as supported by clinical trials, have led to their wide application as probiotic components of health-promoting foods, especially in fermented dairy products. However, the relative paucity of genetic tools available for bifidobacteria has impeded development of a comprehensive molecular understanding of this genus.

Murine bioluminescent hepatic tumour model.

This video describes the establishment of liver metastases in a mouse model that can be subsequently analysed by bioluminescent imaging. Tumour cells are administered specifically to the liver to induce a localised liver tumour, via mobilisation of the spleen and splitting into two, leaving intact the vascular pedicle for each half of the spleen. Lewis lung carcinoma cells that constitutively express the firefly luciferase gene (luc1) are inoculated into one hemi-spleen which is then resected 10 minutes later.

Orally administered bifidobacteria as vehicles for delivery of agents to systemic tumors.

Certain bacteria have emerged as biological gene vectors with natural tumor specificity, capable of specifically delivering genes or gene products to the tumor environment when intravenously (i.v.) administered to rodent models.

Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation.

Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies.

A novel Listeria monocytogenes-based DNA delivery system for cancer gene therapy.

Bacteria-mediated transfer of plasmid DNA to mammalian cells (bactofection) has been shown to have significant potential as an approach to express heterologous proteins in various cell types. This is achieved through entry of the entire bacterium into cells, followed by release of plasmid DNA. In a murine model, we show that Listeria monocytogenes can invade and spread in tumors, and establish the use of Listeria to deliver genes to tumors in vivo.

Prostate stem cell antigen DNA vaccination breaks tolerance to self-antigen and inhibits prostate cancer growth.

Prostate stem cell antigen (PSCA) is a cell surface antigen expressed in normal human prostate and over expressed in prostate cancer. Elevated levels of PSCA protein in prostate cancer correlate with increased tumor stage/grade, with androgen independence and have higher expression in bone metastases. In this study, the PSCA gene was isolated from the transgenic adenocarcinoma mouse prostate cell line (TRAMPC1), and a vaccine plasmid construct was generated.

Viral vectors in cancer immunotherapy: which vector for which strategy?

Gene therapy involves the transfer of genetic information to a target cell to facilitate the production of therapeutic proteins and is now a realistic prospect as a cancer treatment. Gene transfer may be achieved through the use of both viral and non-viral delivery methods and the role of this method in the gene therapy of cancer has been demonstrated. Viruses represent an attractive vehicle for cancer gene therapy due to their high efficiency of gene delivery.

Immune gene therapy as a neoadjuvant to surgical excision to control metastatic cancers.

We investigated if the range of efficacy of a gene-based immunotherapy of solid tumours against systemic disease could be extended when used as a neoadjuvant to surgery. Hundred percent mice whose subcutaneous tumours were surgically removed 4 days post-electroporation with GM-CSF and B7-1 plasmid were systemically resistance to tumour rechallenge. In mice bearing both subcutaneous and hepatic tumours, neoadjuvant treatment of the primary tumour resulted in significant reduction in, or elimination of, hepatic tumour growth, with a significant increase in survival, indicating that control of the primary tumour by immunotherapy was not a prerequisite for containment of systemic disease.

Local gene therapy of solid tumors with GM-CSF and B7-1 eradicates both treated and distal tumors.

Gene therapy-induced expression of immunostimulatory molecules at tumor cell level may evoke antitumor immune mechanisms by recruiting and enhancing viability of antigen-processing cells and specific tumoricidal lymphocytes. The antitumor efficacy of a plasmid, coding for granulocyte-macrophage colony-stimulating factor (GM-CSF) and the B7-1 costimulatory immune molecule, delivered into growing solid tumors by electroporation was investigated. Murine fibrosarcomas (JBS) growing in Balb/C mice ( View Article and Find Full Text PDF

Non-viral in vivo immune gene therapy of cancer: combined strategies for treatment of systemic disease.

Many patients with various types of cancers have already by the time of presentation, micrometastases in their tissues and are left after treatment in a minimal residual disease state [Am J Gastroenterol 95(12), 2000]. To prevent tumour recurrence these patients require a systemic based therapy, but current modalities are limited by toxicity or lack of efficacy. We have previously reported that immune reactivity to the primary tumour is an important regulator of micrometastases and determinant of prognosis.

Successful application of targeted electrochemotherapy using novel flexible electrodes and low dose bleomycin to solid tumours.

Electroporation is the application of very brief electric pulses to cells or tissues to render the cell membranes transiently and reversibly permeable, facilitating cellular uptake of otherwise impermeant molecules. Flexible electrode arrays were developed which may be used with endoscopic and laparoscopic devices for delivery of therapeutic electroporation. Their efficacy in enhancing the delivery of bleomycin, an impermeant drug, was assessed in vitro and in vivo in both human and murine cancer cell lines, and growing tumours (xenografts).