Immunotherapy of Epithelial Ovarian Cancer using Autologous Gamma Delta T-cells

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Ovarian cancer remains one of the most deadly tumours, largely because patients do not develop symptoms until the disease is advanced. Our goal here is to develop a new form of treatment for this disease.Our treatment is a combination of two elements. The first component involves a drug called a bisphosphonate. These drugs are widely used to treat patients with bone diseases and a variety of cancer types. Bisphosphonates can exert some direct toxic effects on cancer cells. However, they also cause cancer cells to become more "visible" to immune white blood cells called gamma delta T-cells, and which comprise the second element in this treatment strategy.Gamma delta T-cells patrol throughout the body, helping to identify cancer at its early stages and eliminating it. These cells can be isolated from a blood sample taken from the patient. To generate sufficient numbers for treatment purposes, gamma delta T-cells cells can then be expanded using medical-grade bags over a 2 week period. We have recently developed a greatly improved system to "grow" these cells, such that the number of cells and their ability to kill cancer cells are both substantially increased. Throughout the world, a number of groups have already infused expanded gamma delta T-cells into patients with various cancers, in the hope of exploiting their ability to kill cancer cells. Although the results have not been very impressive, these studies are important since they have demonstrated the safety of this approach. In our study, we plan to test these "improved" gamma delta T-cells to treat patients with ovarian cancer. We will test the gamma delta T-cells alone and in combination with a bisphosphonate drug.In this project we want to:- deliver bisphosphonates to ovarian cancer cells by injection of the drug into the abdominal space (called the peritoneal cavity), because that is where ovarian cancer spreads. - Next, we will inject gamma delta T-cells (expanded from the patient) into the same location.The project must be carried out in mice that have no immune system, meaning that we can test human cancer cells and human gamma delta T-cells in this model. The purpose of these animal experiments is to show two things: evidence that the treatment has anti-cancer activity and evidence that side effects are acceptable. This is an appropriate requirement of regulatory bodies in the UK before "first in man" testing can be carried out.Once this approach is optimised in mice, the next step would entail its clinical development to treat women with ovarian cancer. Gamma delta cells would be grown from the patients own blood over a period of 2 weeks in an "ultraclean" laboratory which we have within our clinical research facility. The patient would receive the bisphosphonate injected into the peritoneal cavity using a tube. Twenty-four hours later, the gamma delta T-cells would be infused through the same tube. Depending on results obtained, we may wish to repeat this cycle of treatment on more than one occasion.