Background
Current standard approaches for the treatment of human cancers typically employ broad acting radiotherapeutic and chemotherapeutic approaches.
There has been growing interest in approaches using immunotherapy with adoptive cell transfer (ACT): using the patient’s immune cells to treat their cancer. A specific type of ACT uses chimeric antigen receptors (CARs).
These are genetically engineered molecules, which are custom built to specifically target protein antigens expressed on malignant cells. There are multiple FDA-approved CAR T cell-based therapies. CAR19 treatment, of children with relapsed or refractory acute lymphoblastic leukaemia (ALL), and of adults with advanced lymphomas, has demonstrated remarkable success and complete remission in some patients.
Although approved therapies are limited to blood cancers, a growing number of CAR T cell therapies are being developed and tested in clinical studies in multiple solid tumours.
There are promising clinical data targeting tumour-associated antigens in melanoma, lung, liver, breast, and brain cancers. There are major differences between CAR therapies, mostly at the tumour-antigen recognition site, but CARs share similar components known as signalling domains that can affect the cells’ overall function, such as their ability to produce more cells after infusion into the patient (expansion), and to survive longer in circulation (persistence).
The ability to manipulate these domains to custom build CAR T cells to specifically target certain tumours, and avoid toxicity, is critical for the success of CAR T cell therapy.
Aim
The CAR T cell program at the Tumour Immunology Laboratory aims to design and test novel CAR T cell therapies for virus-associated cancers. We have designed a CAR T cells which targets a glioblastoma (GBM)-specific antigen, EphA3, that is has been tested for the treatment of GBM, an aggressive form of brain cancer (Martins et al., 2024).
In our clinical trial of ACT to treat GBM (Smith et al., 2020) we identified a distinct T cells expression signature associated with favourable long-term survival of GBM patients, The project will use this knowledge and expand the potential of the EphA3-specific CAR T cells. We will customise these products and ultimately build a CAR better suited for the treatment of GBM.