Dr. Mark Ward

Immunotherapy, including immune checkpoint inhibitors (ICIs) and antibody"drug conjugates (ADCs), has recently demonstrated clinical benefit in triple-negative breast cancer (TNBC). However, only a subset of patients respond, and reliable predictive biomarkers remain lacking. This project proposes the use of liquid biopsy components"circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA)"as minimally invasive biomarkers to stratify patients and predict response to immunotherapy. CTCs are viable tumour cells shed from primary and metastatic sites that provide real-time insight into tumour biology and metastatic potential. We will investigate PD-1/PD-L1 expression on CTCs and assess longitudinal changes in CTC enumeration during neoadjuvant and adjuvant immunotherapy. In parallel, we will evaluate ctDNA fragmentation patterns as surrogate markers of treatment response. Using established TNBC cell lines and ex vivo CTC cultures, we will further assess the efficacy of novel immunotherapies and ADCs in preclinical models.

High-grade serous ovarian cancer (HGSC) comprising cancers of the ovary, fallopian tube, and peritoneum, is the most common and aggressive form of epithelial ovarian cancer with a dismal 5-year survival rate of 28%. Unfortunately, even with surgery, cytotoxic, and maintenance therapies, most patients relapse, and some develop platinum-resistant disease resulting in a median survival of 12-15 months. Natural killer (NK) cells are crucial anti-cancer immune cells and their lower prevalence in ovarian tumours is associated with poorer prognosis. NK cell therapies are emerging as an adept alternative to T cell therapies and their lack of requirement for antigen specificity places them as excellent candidates for an off-the-shelf approach to cellular therapy. It is well established that HGSC exhibits a `cold" or `immune-excluded" phenotype and this can be influenced by their chemokine profiles. Engineering an NK cell therapy to home towards the chemokine profiles of HGSC tumours presents an opportunity to improve their infiltration of such tumours and offers a novel treatment option for HGSC patients with platinum-resistant disease. Using primary patient material together with cutting-edge molecular cell engineering and xenograft models we aim to develop novel tumour-informed, near-patient immunotherapeutic approaches through the following: 1. Retrospectively characterise the NK cell receptor ligand (activation and inhibitory) and chemokine profiles of HGSC to inform NK cell therapy design. 2. Prospectively characterise NK cell phenotypes and function in blood, and tumour and correlate to the soluble profiles detected in the retrospective screen. 3. Generate highly cytotoxic NK cell therapy and engineer to home towards HGSC tumours, based on chemokine profile of platinum-resistant tumours. 4. Evaluate engineered tumour homing engineered-NK therapy using an established platinum resistant orthotopic xenograft mouse model of HGSC. Ultimately, this study aims to improve treatment options for women with platinum resistant HGSC.

Venous thromboembolism(VTE) is the leading cause of non cancer death in cancer patients. Patients are particularly at risk during chemotherapy where rates of up to 20% have been reported. Guidelines recommend primary prophylaxis with direct oral anticoagulants(DOACs) in intermediate/high risk patients undergoing chemotherapy following risk assessment with a validated risk score(Khorana score). However, the Khorana score performs poorly in lung, ovarian and gastric cancers and relies on a single assessment at the start of therapy. The development of VTE is a dynamic process which cannot be accurately represented by a single risk assessment. Our data suggests that markers of procoagulant activity are implicated in chemotherapy associated VTE and could be measured serially as predictive biomarkers. This may provide a more effective method of identifying patients at risk of VTE and facilitate targeted prophylaxis. Prophylaxis with DOACs carries a risk of bleeding hence decisions regarding prophylaxis should be shared between doctor and patient. However, studies have shown that cancer patients receive limited information about VTE risk and tools to aid decision making in this area are lacking. Cost is also a consideration for both the health service and the patient. In this study we will: measure procoagulant biomarker levels serially during chemotherapy as dynamic predictors of VTE. investigate the prothrombotic mechanisms involved in chemotherapy associated VTE. identify patient needs and priorities for shared decision making with regard to prophylaxis during chemotherapy perform a cost benefit analysis of biomarker screening and targeted VTE prophylaxis during chemotherapy This study aims is to develop dynamic predictive biomarkers for VTE during chemotherapy and to understand patient priorities with regard to VTE prevention during chemotherapy. Identification of high risk patients and increased understanding or patient priorities and costs will lead to effective shared decision between doctor and patient ultimately reducing the burden of VTE in cancer.