Immunotherapy and clear cell ovarian cancer

Ovarian cancer is an umbrella term that describes several cancers that affect the ovary. This project will involve clear cell ovarian cancer (CCOC). Unfortunately, when CCOC has spread beyond the ovary, patients have a poor response to conventional chemotherapy treatment and a limited life expectancy. The objective of this project is to understand whether one type of immunotherapy will be of benefit to patients with advanced CCOC.

Immunotherapy drugs work in a variety of ways but ultimately have the same goal of trying to assist, train or enhance our bodies' own immune system to allow it to recognise and attack cancer cells.

The research centres around a molecule called programmed cell death protein 1 (PD-1) which is on the surface of certain cells of the immune system. PD-1 limits the ability of the immune system to eliminate cancer cells. By inhibiting PD-1 we hope to "take off the breaks" of the immune system to help target CCOC cancer cells, an approach that has already been successful in other cancers.

Encouraging responses have been observed in patients with advanced CCOC who have received drugs inhibiting PD-1 as part of clinical trials; however we do not know what factors influence how this treatment works in CCOC. Understanding this is important in improving patient outcomes and perhaps designing new treatment strategies.

Our research will involve samples taken from patients with CCOC, some of whom will be receiving treatment with pembrolizumab, a drug which inhibits PD-1, as part of a clinical trial. The patients will have given their consent for the use their tissue in this research. We will also be taking tumour samples from mice who are known to develop a CCOC which is thought to be similar to the CCOC that affects humans.

We will investigate the type, frequency and location of different cells involved in the immune system and how they exist in relation to the cancer cells. We will also explore, if and how these observations change following treatment with anti-PD-1 treatment.

If we are able to improve our understanding of how this type of drug impacts on the interaction between the immune system and CCOC cells, we may be able to identify new targets or treatment strategies that may result in more patient's responding to treatment.

If we demonstrate that the mouse model of CCOC is similar to human CCOC, it will help provide a better understanding of the complex biological processes at work within the tumour and how this changes with immunotherapy, or indeed other treatments. This will help the translation of knowledge from the laboratory to clinical trials for patients.

Clear cell ovarian cancer (CCOC) displays a chemo-resistant phenotype and patients with advanced disease have a poor overall survival. Four of five patients with advanced, heavily pre-treated CCOC had a complete or partial response following treatment with drugs inhibiting the PD-1 checkpoint however the mechanism behind the anti-tumour response is unknown.

In several other cancer types the frequency and location of immune cells in the tumour microenvironment, as well as the levels of overexpression of PD-1/PD-L1 either on the cancer cell or tumour, influence response to checkpoint blockade. Immune related gene expression signatures (irGES) can also predict response to treatment in certain tumour types.

This proposal has three aims. First we will undertake a comprehensive analysis of the immune landscape of advanced CCOC biopsies using immunohistochemistry with Definiens digital analysis as well as mass cytometry to profile the quantity of the major populations of immune cells alongside their spatial arrangement. We will also detail their irGES at baseline via nanoString. Second, we will use this information to validate the immune landscape of a mouse model of CCOC using the same techniques above and performing a cross species analysis of the results. Third, we will assess how anti-PD1 therapy changes the immune ecosystem using the techniques described above in samples taken from the mouse model following treatment with anti-PD-1 therapy and in samples from a clinical trial that will provide baseline and on-treat biopsies from patients.

These aims will enable us to achieve our overall objective of understanding the mechanism behind response and resistance to anti-PD1 in CCOC in order to devise treatment plans that will improve response rates and duration of response in patients.

As described in "Pathways to Impact", academic groups such as those involved in the treatment of ovarian cancer or immunity, will benefit from an increased understanding of how the immune environment predicts response to, and is influenced by, checkpoint inhibition.

By validating a mouse model alongside this information, we will allow translational scientists and clinicians to explore novel agents or potential combination strategies identified in a pre-clinical setting, generating data that may accelerate future clinical trials and new treatment strategies for patients with clear cell ovarian cancer.

Novel targets identified during this research may also be of benefit to drug developers in the private sector. The identification of a biomarker will help select those patients who will gain benefit from this treatment approach and also make an application for a licence in this population more likely to be successful. If a biomarker is identified that is pathology specific (clear cell) rather than organ specific, this may offer hope to patients with clear cell cancer of the cervix, vagina and endometrium amongst other sites.

Finally, I hope that this project will inspire clinicians and scientists working with other rare tumours by demonstrating that comprehensive research can be successfully undertaken and lead not only to an improved academic understanding of the disease but result also in real life treatment options and strategies for their patients.