Chimeric antigen receptor (CAR) engineered immune cells have shown great promise by enhancing the tumour cell recognition and anti-tumour activity of cell-based immunotherapies. The success of this technology is best exemplified by CAR T cells, where remarkable results have been observed in the treatment of haematological cancers. CAR natural killer (NK) cells are considered a promising alternative to T cells, due to reduced side effects, ease of manufacturing, and innate ability to kill cancer cells. However, their relatively short life span increases the risk of residual disease and relapse.
To address the long-term persistence issues hampering cell-based immunotherapies, this project seeks to use the potent regenerative capacity of haematopoietic stem cells (HSC). By transducing HSCs with our CAR construct, we aim to achieve self-sustaining, in-situ generation of anti-tumour CAR-NK cells for life-long monitoring and eradication of cancer.
To evaluate CAR-HSC / CAR-NK based cell immunotherapy, we are constructing a 3rd generation anti-CD19 CAR driven by an NK cell-specific promotor. This restricts the expression of CAR to the NK cell progeny, thereby avoiding inappropriate expression of CAR on other immune cell types.
Using our established humanised NSG mouse model, where engraftment of human cord blood CD34 cells results in the reconstitution of a human-like immune system, we aim to assess the ability of CAR-HSC transplants to generate CAR NK cells in situ. Here, further assessments can be made on the long-term therapeutic efficacy in the context of CD19-expressing tumour models, such as NALM6 tumours and patient-derived xenografts.
This novel approach has the potential to improve current CAR-based immunotherapies by providing a persistent in situ source of CAR NK cells to eliminate residual cancer and guard against relapse.