Improving CAR T-cell therapy to target solid tumours

Dual CAR T-cells

Dr Rachel Perret leads the Malaghan Institute's Freemasons CAR T-cell Research Programme team in the Weinkove Laboratory and works alongside Clinical Director Dr Rob Weinkove to improve the CAR T-cells’ ability to find and target cancer.

“We’re trying to design a dual CAR system where we’ll make T-cells that can target two different cancer proteins instead of one,” says Dr Perret. “That way, we can guard against cancers losing a single protein and becoming ‘invisible’ to the immune response.”

Current CAR T-cells can only recognise a limited range of proteins – one CAR can only target one cancer protein. Using dual CARs, the resulting CAR T-cells are more likely to respond to more cancer cells within a tumour. The team are currently investigating whether dual CAR T-cells are effective in patients with different forms of blood cancer, with the hope to broaden their work to target solid cancers.

“Solid tumours typically express their proteins ‘heterogeneously’ – as in not every cell expresses the same target,” says Dr Perret. “By applying dual CARs to our CAR T-cells, we increase the chances that the therapy will recognise all the cells in a tumour and so more effectively remove it from the body.”

Combination therapies

Unfortunately, even with dual CAR T-cells recognising up to two different proteins on a cancer cell, when it comes to solid tumours, it’s unlikely that current CAR T-cells will correctly identify every cell in a tumour as cancerous. This is simply because of how cancer cells in a solid tumour vary in their expression.

However, rather than relying on CAR T-cells to correctly identify every single variation of a cancer cell in a solid tumour, Professor Ian Hermans’ lab is investigating ways to get around this limitation by creating CAR T-cells that work in combination with chemotherapy. 

The research involves arming the CAR T-cells with an enzyme that activates a chemotherapeutic drug once it binds to a cancer cell. Once this chemotherapy drug is activated, it destroys the surrounding cells, which hopefully includes the parts of the tumour the CAR T-cells could not target.

The added benefit of this method is that it allows very direct and targeted chemotherapy application without the negative side-effects that chemotherapy injected into the bloodstream can bring.

Both these research projects represent the wide range of approaches under investigation that may lead to the development of CAR T-cells that are more durable and effective at targeting different types of tumours for destruction.