p53 activation boosts T-cell potency against solid tumours

Researchers have identified a potential new way to strengthen cancer-fighting immune cells, which could help improve treatments that use a patient’s own immune system to target cancer.

The UCLA Health Jonsson Comprehensive Cancer Center study found that temporarily activating a protein called p53 helped human immune cells develop characteristics associated with longer-lasting immune responses.

The results of the research showed that treated immune cells displayed fewer signs of exhaustion, had greater energy reserves and were more effective at killing melanoma cells in laboratory experiments.

The approach could offer a relatively straightforward way to improve existing immunotherapies without requiring additional genetic modifications.

Addressing T cell exhaustion

Engineered T cell therapies, including chimeric antigen receptor (CAR) T cell therapy and T cell receptor (TCR) therapy, involve collecting a patient’s immune cells, genetically modifying them to recognise cancer and infusing them back into the body to attack tumours.

Although these methods have hugely improved the treatment of certain blood cancers, they aren’t as effective against solid tumours.

One significant obstacle is T cell exhaustion, where immune cells gradually lose their ability to multiply and destroy cancer cells following repeated exposure to tumours. The preparation process can also cause T cells to mature too quickly, reducing their ability to survive and remain effective over time.

To address this, the researchers investigated whether p53, a protein best known for preventing damaged cells from becoming cancerous, could help maintain T cell function.

The team collected human T-cells and treated them with navtemadlin, an investigational drug that blocks a protein called MDM2. MDM2 normally keeps p53 levels under control, meaning that blocking it increases p53 activity.

Researchers compared treated and untreated cells, examining their development, energy production and ability to attack cancer.

They also genetically engineered the T-cells to recognise a protein found on certain melanoma cells before testing their cancer-killing ability in laboratory experiments, using specialised imaging equipment to monitor activity for almost seven days.

Improved cancer-killing ability

The results showed that temporarily activating p53 encouraged the development of central memory T-cells, which can survive longer and multiply when they encounter their target again.

The treated cells also displayed fewer molecular signs of exhaustion and had greater energy reserves. They were more likely to produce interferon-gamma and granzyme B, two proteins involved in coordinating immune responses and destroying cancer cells.

When tested against melanoma cells, T-cells prepared with navtemadlin were significantly more effective at killing cancer cells than untreated cells.

They began clearing cancer cells more effectively after approximately 40 hours and maintained their advantage throughout the experiment. This improvement was also observed without additional interleukin-2, a protein commonly used to support T-cell growth and survival.

However, the researchers found that drug concentration was key. Lower doses encouraged the development of memory T-cells without substantially reducing cell viability, while higher doses caused more cells to die.

Potential for future immunotherapies

The findings suggest that incorporating drugs such as navtemadlin into existing T cell manufacturing processes could help produce immune cells better equipped to fight cancer.

Rather than introducing additional genetic modifications, temporarily activating p53 could provide a relatively simple way to improve the durability and effectiveness of engineered immune cells.

“This is one of the first studies to link p53, one of the most extensively studied proteins in biology, to T-cell exhaustion in humans,” said Dr Joseph Crompton, Assistant Professor of Surgery at the David Geffen School of Medicine at UCLA and senior author of the study. “While p53 has long been known for its role in preventing cancer, our findings suggest it may also play an important role in helping immune cells maintain their ability to fight it. This opens up a new avenue for developing more effective cancer immunotherapies.”