Researchers at the UCLA Health Jonsson Comprehensive Cancer Center have identified a method to enhance T-cell therapy by temporarily activating the p53 protein. This discovery, published in Frontiers in Immunology, suggests that treating immune cells with the drug navtemadlin during laboratory preparation can reduce cell exhaustion and improve their ability to eliminate melanoma.
Activating p53 to improve T-cell longevity
Scientists have long recognized p53 as the “guardian of the genome” due to its role in preventing cancer, but its function in T-cell regulation was previously unclear. To test its potential, researchers blocked the protein MDM2, which typically suppresses p53. By utilizing the investigational drug navtemadlin, the team increased p53 activity within human T cells during the manufacturing process.
The study found that cells treated with the drug exhibited fewer molecular signs of exhaustion. These T cells were more likely to develop into central memory T cells, which are characterized by an increased capacity to survive and multiply upon repeated exposure to cancer cells. These treated cells also maintained higher energy reserves and produced greater quantities of granzyme B and interferon-gamma, two proteins vital for coordinating anti-tumor attacks.
Comparing T-cell performance against melanoma
In laboratory experiments, researchers genetically engineered T cells to recognize specific proteins on melanoma cells. Those prepared with navtemadlin demonstrated significantly higher success in clearing cancer cells than untreated T cells. This performance advantage began approximately 40 hours into the experiment and persisted for the duration of the seven-day observation period.
The study noted that drug concentration is a critical factor in the treatment process. While lower concentrations of navtemadlin promoted the development of healthy memory T cells without sacrificing cell viability, higher concentrations led to increased cell death. This indicates that precise control of p53 activation is necessary to balance immune cell potency and survival.
Addressing T-cell exhaustion in immunotherapy
Engineered T-cell therapies, such as chimeric antigen receptor (CAR) T-cell therapy, have become standard treatments for certain blood cancers and are currently being studied for use against solid tumors. A primary limitation of these treatments is T-cell exhaustion, where immune cells lose their efficacy after repeated exposure to cancer. The standard preparation process can also cause cells to mature too rapidly, limiting their long-term survival.
“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,” said Joseph Crompton, MD, PhD, assistant professor of surgery at the David Geffen School of Medicine at UCLA and senior author of the study. The research suggests that incorporating a drug like navtemadlin into existing manufacturing processes could improve immunotherapy outcomes without requiring new genetic modifications.
How does navtemadlin affect T cells?
How does navtemadlin affect T cells?
Navtemadlin blocks MDM2, a protein that normally keeps p53 levels low. By inhibiting MDM2, the drug increases p53 activity, which helps T cells maintain energy and resist exhaustion during the preparation phase for immunotherapy.
What is the role of memory T cells in cancer treatment?
Central memory T cells are better equipped to survive and multiply when they encounter cancer targets. This improved longevity helps the immune system sustain a longer-lasting response against tumors compared to cells that reach maturity too quickly.