Improving therapeutic success by directing CAR-T cell metabolism through co-stimulation

CAR-T therapy is a "living drug" used to treat cancer. The main component of CAR-T therapy are T cells, a type of immune cell which can directly kill diseased or infected cells. T cells are collected from the patient and redirected towards their cancerous cells by engineering them to carry a CAR (Chimeric Antigen Receptor) on their surface.

This CAR allows the T cells to recognise cancer-associated proteins and direct the T cells to kill the cancer. These therapies have currently been approved for patients with blood cancers, where they can lead to long term survival in up to half of patients. CAR-T therapy has been significantly less successful in treating solid tumours.

Key challenges include the failure of the CAR-T cells to survive long enough in the patient, the loss of CAR-T cell killing function and a lack of biomarkers which would allow patient-specific tailoring of the product.

We will address these challenges by building on our previous research in the field of immune-metabolism. The metabolism of a cell is the way in which it turns nutrients into energy. To produce an effective immune response, it is vital for T cells to adjust their metabolism to fuel their function.

T cells use a range of nutrients, such as sugars, proteins and fats; their preference varies depending on the functions that need to be supported. The CAR-T products on the market are built slightly differently, they contain different co-stimulatory domains - either CD28 or 4-1BB. These two domains differentially impact T cell metabolism and can therefore affect their function.

We and others have shown that if the metabolism of a T cell becomes impaired, the T cell will lose its function. However, it is not known which types of metabolism, and the nutrients that fuel them, are required to support effective CAR-T cell function over time and how these could be manipulated to increase treatment success.

To address this gap in knowledge my proposal has three aims:

1) We will investigate the metabolism of patient-derived T cells both before and after they are engineered to become CAR-T. We will assess current CAR-T (CD28 and 41BB) and a novel CAR-T which we have contributed to developing and which will be used in patients for the first time in an upcoming clinical trial. We will determine how CAR-T cell metabolism changes over treatment course and how this correlates to clinical outcome, with the aim of biomarker discovery.

2) We will determine the unknown nutrient requirements of human CAR-T cells, which is of great scientific interest, but could also allow improved CAR-T cell production by providing the correct fuel.

3) Finally, we will explore how to optimise CAR-T cell function by a) choosing the product that leads to the best CAR-T cells from any given patient and, b) use specific drug treatment during production of CAR-T cells to achieve optimal function.

By defining the fundamental requirements of optimally fuelling CAR-T cell anti-cancer responses, our project will address the key challenges of improving CAR-T cell function and defining much needed biomarkers to predict treatment outcome in human patients.