Engineering immunotherapies to combat ovarian cancer 

This project builds on a growing understanding of how the immune system can be harnessed to fight cancer. While immunotherapy has transformed outcomes in some cancers, its success in ovarian cancer has been more limited, highlighting the need for new approaches.

Associate Professor Guimaraes’ research focuses on natural killer (NK) cells, a type of immune cell that can recognise and destroy cancer cells. The team is engineering these NK cells into what are known as chimeric antigen receptor (CAR)-NK cells, by attaching specific targets to them so they can be directed precisely to ovarian cancer cells.

The engineered NK cells will be designed to target a protein called Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1), which is linked to chemotherapy resistance and poor patient outcomes. CAR-NK cells also offer advantages including reduced toxicity, lower cost, and broader accessibility.

A key challenge, however, is that a molecule often present in ovarian cancers called TGF-β can weaken NK cells and help cancer avoid attacks by the immune system. This is one of the reasons current immunotherapies have had a limited impact in ovarian cancer. To address this, A/Prof Guimaraes and his team are also engineering the CAR-NK cells to lack the TGF-β receptor (called a TGFβRII knockout), meaning the cells are modified to be resistant to TGF-β so they stay active even in the tumour's suppressive environment.

By developing highly specific engineered NK cells, the research aims to improve how effectively the immune system can detect and eliminate cancer cells. 

Natural killer cells, including those engineered by A/Prof Guimaraes, have the potential to significantly enhance the body’s resistance to cancer. However, a molecule often present in ovarian cancers called TGF-β can weaken NK cells and helps cancer avoid attacks by the immune system.

The team will therefore engineer NK cells to target ROR1 on ovarian cancer cells, then modify them with a TGFβRII knockout so they are resistant to the suppressive effects of TGF-β in the tumour environment. These engineered cells will be tested in ovarian cancer cell lines to assess how well they recognise and kill cancer cells.

The most effective candidates will then be tested in pre-clinical models, both alone and in combination with standard-of-care chemotherapy, to identify the most effective strategies for improving NK cell-based immunotherapy in ovarian cancer.