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

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.

Epithelial ovarian cancer (EOC) represents the most lethal gynaecological malignancy, with particularly poor outcome seen in patients with high-grade serous tumours (HGSOC). Our goal is to develop a gd T-cell-based immunotherapy to address this need. gd T-cells contribute to cancer immunosurveillance, owing to their ability to recognise markers of cell stress. Vg9Vd2 cells are the primary circulating gd T-cell subset in man and undergo HLA-independent activation by phosphoantigen (PAg) intermediates of mevalonate metabolism. PAgs are increased in EOC cells, owing in part to p53 mutation. Amino-bisphosphonate drugs (NBP) further enhance PAg accumulation, sensitising EOC cells to gd T-cell-mediated killing. We have shown that Vg9Vd2 T-cells can be expanded from EOC patients and that they destroy autologous and immortalised EOC tumour cells and cause regression of derived xenografts. Building on this, we have recently developed a novel GMP-compliant system to expand these cells (method 2), which substantially improves both their yield and intrinsic tumouricidal activity. In this DPFS project, we will evaluate anti-tumour activity of method 2-expanded Vg9Vd2 T-cells from patients against EOC. First, we will use high-throughput in-vitro luciferase assays to determine their anti-tumour activity (alone and in combination with licensed NBPs) against a panel of HGSOC and other EOC cells. Next, we will assess their in-vivo therapeutic activity using a panel of HGSOC xenograft models. Owing to transcoelomic metastasis, all therapeutic agents will be administered to the peritoneal cavity (an established route of drug delivery in EOC). Iterative optimisation will then be undertaken to determine the optimum schedule of repeated cell/NBP administration and need for cytokine support. Finally, we will develop a maximally closed and clinically compliant manufacturing process for large-scale method 2 production of these cells, paving the way for first in man testing in EOC patients.

1. Who will benefit from this research?

Four groups of beneficiaries have been identified.
First, we hope that the main beneficiaries of the project will prove to be patients with ovarian cancer.
Second, successful translation of this approach may also benefit the owners of Intellectual Property pertaining to this technology, namely King's College London.
Third, we can envision that translational and clinical researchers who work in related fields may also benefit from the work.
Fourth, governments may benefit from availability of better treatments of ovarian cancer.

2. How will they benefit from this research?

First, patients may benefit through amelioration of the morbidity and mortality associated with ovarian cancer. Groups considered most likely to benefit are those individuals in whom disease has been maximally de-bulked by conventional surgical and chemotherapy and those individuals with relapsed disease following primary therapy.
Second, owners of intellectual property may benefit through Royalties derived from (i) the sale or supply of services/ products which infringe claim(s) made in patent(s) pertaining to relevant intellectual property or (ii) any licence, assignment or transfer under/of relevant patent(s).
Third, the means by which certain Academic groups may benefit is described in the Academic Beneficiaries section.
Fourth, development of a successful immunotherapeutic approach for ovarian cancer could impact upon the economic cost of cancer, measured as direct (eg healthcare-related) and indirect costs (pertaining to lost productivity).