Cancer t-cells

What we do

Our study of the immune cells both in the peripheral blood and within the tumour/ascites of patients with ovarian cancer has led us to discover immunological biomarkers to predict both diagnosis and prognosis in patients with ovarian cancer (PD-L1 and PD1) and identify new targets for therapy. We have also shown that ovarian tumour cells and some immune cells (particularly monocytes associated with ovarian cancer) are very effective in downregulating the immune response and that PD-L1 immune checkpoint inhibitor plays an important role in this interaction. We are currently studying interactions between chemotherapy, epigenetic therapy and immune cell or immune checkpoint antibody therapy in ovarian cancer in combination.

We have a large programme of research that encompasses diagnostic, surgical/therapeutic as well as prognostic areas as relevant to this cancer. One of the challenges of treating ovarian disease is making an accurate diagnosis of an ovarian mass that looks indeterminate or complex before an operation is proposed. An accurate diagnosis will determine whether a radical operation is necessary for a cancer or whether a more limited and laparoscopic operation can be done for a benign or a borderline tumour. We have shown that upregulation of some immune markers such as PD-L1 and PD1 on the immune cells in the peripheral blood can predict the nature of an ovarian mass. This novel finding seems helpful in the diagnosis of early stage ovarian cancers and appropriate planning for surgery.

In collaboration with Professor Tom Bourne, and as part of the International Ovarian Tumour Analysis Collaboration, we are working on three projects which focus on the investigation and management of adnexal masses, both benign and malignant, in pre- and post-menopausal women. Trans-IOTA is a multi-centre study detecting new biomarkers for the diagnosis of adnexal masses selected for surgical management. Professor Bourne, the IOTA group and Dr Sadaf Ghaem-Maghami have used plasma samples for immune biomarker discovery and validation of previously discovered immune biomarkers (such as soluble plasma PD-L1) from Trans-IOTA. IOTA-5 is a multi-centre study on the pre-operative characterisation of ovarian tumours and conservative management of benign-looking adnexal masses. Finally, IOTA-7 is a prospective validation and comparison of subjective assessment, ADNEX model, logistic regression model LR2, Simple Rules and the Risk of Malignancy Index (RMI) for discrimination between benign and malignant adnexal masses in the hands of ultrasound examiners with different levels of experience.

The iKnife, which was invented at Imperial College (Professor Zoltan Takats) is new technology that uses mass spectrometry to inform about tissue types. We have used this technology successfully to make an accurate tissue diagnosis in over 300 ovarian tissue samples. This technology can be used in the patient during an operation as a part of a commonly used surgical instrument for tissue identification. We have shown that the iKnife is able to distinguish between benign or malignant tumour of the ovary with almost 100% accuracy in samples analysed outside the patients and also for tumour recognition within the patients with great success.

A major issue in the surgery for ovarian cancer is the extent of disease in some patients. This can be prohibitive of carrying out primary surgery without unacceptable morbidity. Neoadjuvant chemotherapy helps reduce the burden of disease but can make tumour recognition more challenging during the operation. We have shown that the iKnife can help with accurate diagnosis of ovarian tumour nodules within the peritoneal tissue and hence result in removal of all the disease, leaving no tumour cells behind in the margins. This has the potential to revolutionise ovarian surgery both in the upfront and neoadjuvant setting, helping to remove the tumour affected areas more accurately leaving behind unaffected disease. A clinical study to assess the effect of this approach on patient survival is planned for the near future. In collaboration with Professor Dan Elson, imaging the peritoneum at cellular level is used to identify tumour nodules rapidly intraoperatively, whilst the iKnife is used for complete resection of the nodules with clear margins.

Radical resection of tumours in ovarian cancer may not be appropriate for all ovarian cancers. We have shown that differential methylation of MYLK3 may predict prognosis after radical upfront surgery and hence may be used to stratify patients to more or less radical surgery and identify cases at high risk of recurrence that may require targeted therapies. Interestingly these markers also appear to predict prognosis in patients with ovarian cancer.

Why is it important?

Gynaecological cancers include ovarian, endometrial, cervical, vulval and vaginal cancers; with ovarian having the worst prognosis as patients with ovarian cancer present at a late stage with widespread disease. Symptoms of ovarian cancer can be non-specific, making the diagnosis at an early stage more challenging and currently there is no effective screening available. Women who present with stage 3 or 4 ovarian cancer, at best have a five-year survival rate of 30-35%, with little improvement in this figure over the last few years. Ovarian cancer is treated with a combination of surgery and chemotherapy. There is currently still much debate as to which patients should have surgery first and which should be treated with chemotherapy followed by surgery. New targeted and immunological therapies are also being tested in ovarian cancer.

Impact

We have published a series of studies that have clearly established the relationship between immune cells, ovarian cancer cells, the role of PD1 and PD-L1 in ovarian cancer and their potential place as targets for treatment in ovarian cancer. The use of modified T cells that we generate in our laboratory that effectively kill ovarian cancer cells has placed us in an ideal position to test different combinations of standard and immune therapies in ovarian cancer, in collaboration with Industry.

We have identified an epigenetic biomarker that predicts survival of patients after surgery for ovarian cancer, hence predicting which patients are most likely to benefit from radical upfront surgery. This is the first biomarker of its kind.

We have shown that preoperative diagnosis of ovarian cancer can be significantly improved using novel imaging algorithms and immune biomarkers.

We have for the first time used the iKnife to operate on women with ovarian cancer and have shown that it can be used to effectively distinguish between benign and malignant ovarian masses in real time intraoperatively with near complete accuracy. This is likely to have a major impact on the surgical management of patients with indeterminate masses, saving many women with potentially no malignant masses the cost and morbidity of major surgery.