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.