Researchers find simple way to boost engineered T-cell therapies

Researchers at the UCLA Health Jonsson Comprehensive Cancer Center have identified a promising new strategy to make cancer-fighting immune cells stronger and potentially longer-lasting, a discovery that could help improve the effectiveness of immunotherapies that use a patient's own immune cells to attack cancer.

The study, published in Frontiers in Immunology, found that temporarily activating a protein called p53, best known for its role in preventing cancer, helped immune cells develop characteristics associated with longer-lasting immune responses. The treated cells showed fewer signs of exhaustion, had greater energy reserves and were more effective at killing melanoma cells in the laboratory.

The findings suggest that adding a drug during the preparation of engineered immune cells could offer a relatively simple way to improve existing T-cell therapies without requiring additional genetic modifications. 

Why it matters

Engineered T-cell therapies, including chimeric antigen receptor (CAR) T-cell therapy and T-cell receptor (TCR) therapy, have transformed treatment for certain blood cancers and are increasingly being investigated for solid tumors. 

These treatments involve collecting a patient's immune cells, genetically modifying them in a laboratory to recognize cancer and then infusing them back into the patient to attack tumors. 

Despite their success, one of the biggest challenges is T-cell exhaustion, which occurs when immune cells gradually lose their ability to multiply and attack tumors after repeated exposure to cancer. The process used to prepare these cells for treatment can also cause them to mature too quickly, making them less likely to survive and remain effective over time.

Scientists have been searching for ways to help these cells function longer and maintain their cancer-fighting abilities. UCLA researchers turned their attention to p53, a protein best known for its role in preventing cancer, to see whether it could help address this challenge.

What the study did

The researchers investigated whether temporarily activating p53, often called the "guardian of the genome" because of its role in preventing cancer, could improve how T cells develop and function.

Although p53 has been extensively studied for its ability to prevent damaged cells from becoming cancerous, its role in regulating human T cells is less understood.

To test the approach, the team collected human T cells and treated them with navtemadlin, an investigational drug that blocks another protein called MDM2, which normally keeps p53 levels under control. By blocking MDM2, the drug increases p53 activity.

Researchers compared treated and untreated cells to determine how the drug affected their development, energy production and ability to fight cancer.

The team also genetically engineered T cells to recognize a protein found on certain melanoma cells and tested how effectively they killed cancer cells in laboratory experiments. Using specialized imaging equipment, the researchers monitored the cells for nearly seven days.

What they found

Researchers found that temporarily activating p53 during the preparation of human T cells helped produce immune cells that were better equipped to fight cancer. The treated cells were more likely to develop into central memory T cells, which have a greater ability to survive and multiply when they encounter their target again. They also showed fewer molecular signs of exhaustion, suggesting they may be better equipped to maintain their effectiveness over time.

The cells also had greater energy reserves and were more likely to produce two important cancer-fighting proteins, interferon-gamma and granzyme B, which help immune cells coordinate an attack and destroy cancer cells.

Most importantly, when researchers tested the engineered T cells against melanoma cells, those prepared with navtemadlin were significantly more effective at killing cancer cells than untreated cells.

The treated cells began clearing cancer cells more effectively after approximately 40 hours and maintained their advantage throughout the experiment. They also showed improved cancer-fighting activity without additional interleukin-2, a protein commonly used to support T-cell growth and survival.

The researchers also found that the amount of drug used was important. At lower concentrations, navtemadlin promoted the development of healthy memory T cells without substantially reducing the overall number of viable cells. Higher concentrations, however, caused more cells to die, highlighting the need to carefully control p53 activation.

Impact of findings

The findings suggest that temporarily activating p53 during the preparation of engineered T cells could offer a new way to improve cancer immunotherapy. Rather than developing an entirely new treatment or introducing additional genetic modifications, researchers could potentially incorporate a drug such as navtemadlin into existing manufacturing processes to produce immune cells that are better equipped to fight cancer. 

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. 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."

Joseph Crompton, MD, PhD, assistant professor of surgery, David Geffen School of Medicine at UCLA and senior author of the study