Engineering cells of the immune system to target the complex mixtures of cells in adult and paediatric gliomas

Fast facts

• Official title: Enhancing CAR T-cell therapies for gliomas
• Lead researcher: Dr. Christopher Mount
• Where: Harvard Medical School, USA 
• When: October 2022 – September 2025
• Cost: £225,000 over three years
• Research type: Glioblastoma (GBM), High grade Glioma, Immunotherapy
• Award type: Future Leaders

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Brain tumours have a unique biology. Gliomas – a particularly aggressive and difficult to treat group of brain tumours – are a complex mixture of cells. One possible way to fight gliomas is to target distinct types of cells in the tumour. We know that the complexity is not random, and we can identify the different cells found in brain tumours. 

What is it?

CAR T-cell therapies are therapies where T-cells (cells of the immune system) are modified (engineered) to identify and destroy a specific target. Specifically, scientists modify T-cells to make them produce a protein on their surface called a chimeric antigen receptor (CAR), which can recognise and bind to specific proteins on the surface of cancer cells. In modern cancer treatments these therapies have a lot of potential. Dr Mount will engineer T-cells to target multiple types of different cells present in paediatric and adult gliomas and destroy them.  

Using an advanced technique called scRNA Seq (a technique to have a snapshot of what is present in a cell at a specific time), Dr Mount has already collected data to characterize the different cells of different gliomas. Dr Mount will also work to have CAR T-cells that are not just specific but also efficient. He will add proteins to the CAR T-cells to increase the activity of T-cells and he will eliminate inhibitory molecules that could interfere with the activity of CAR T-cells. Once Dr Mount has engineered the T-cells, he will evaluate the ability of these modified cells to find their target and destroy it. The evaluation will first be done using large clusters of brain tumour cells grown in vitro (in a dish). These clusters (also called organoids) will recapitulate the diversity of gliomas’ cells found in patients.  

In a second stage, Dr Mount will use mouse models (one fundamental step in brain tumour research to find new therapies) carrying gliomas (brain tumours of human origin). CAR T-cells can be delivered to the animal’s circulation and directly arrive at the brain tumour. The evaluation will make sure that the different subpopulations of cells within the gliomas are eliminated by the engineered CAR T-cells. 

Why is it important?

Brain cells in the vicinity of the tumour as well as the tumour cells can be a problem when it comes to fighting gliomas. When few dangerous cells are left behind and/or not targeted by the treatment, patients with gliomas can experience a regrowth of the tumour and an increased resistance to the therapies. Dr Mount’s research will try to overcome the problems associated with the current therapies in patients with gliomas by targeting different cells in the brain tumour. If his work is successful, this could lead to the launch of new clinical trials for brain tumour patients. Dr Mount has already shown how promising this type of research could be. In 2018 he completed a preclinical study using CAR T-cells to target paediatric gliomas. In 2022, 4 patients have already been treated clinically with the treatment that has emerged from the preclinical study completed in 2018. The development of new CAR T-cell therapies could have broader implications for the treatment of other cancers as well. 

Who will it help?

This project has the potential to help people with gliomas, their families and healthcare professionals. Improved therapies for gliomas could lead to better patient outcomes and quality of life. The identification of distinct cell subpopulations within gliomas using scRNA Seq could also aid in diagnosis and predicting treatment responses.  

How can we bring the immunotherapy revolution to brain tumour patients? We are unravelling the factors that limit the effectiveness of cell therapies in brain tumours and are inventing new strategies to overcome those limitations. 

Dr. Mount