p53 Gene Therapy

What Is p53 Gene Therapy?

An experimental treatment currently only available in clinical trials, p53 gene therapy is a healthy copy of the p53 gene, packaged inside a modified virus and delivered directly into tumor cells. This gene produces the tumor-suppressor protein p53, often called the “guardian of the genome.” It repairs DNA and prevents uncontrolled cell growth and cancer.

The p53 gene acts like a built-in alarm system. When a cell’s DNA is damaged, p53 stops it from dividing and, if the damage is too severe, forces it to die before it can become cancerous. In more than 50% of all cancers, including mesothelioma, that alarm system is broken. p53 gene therapy is an attempt to restore it.

The therapy delivers a working copy of that gene directly into tumor cells, giving them the instructions they lost. Once inside, the cell begins producing functional p53 protein again, restoring its ability to recognize damage and self-destruct.

How Does p53 Gene Therapy Work?

Each approach to p53 gene therapy restores the tumor cell’s ability to recognize damage and self-destruct. Which approach is used depends on the specific mutation present in a patient’s tumor, so genetic testing comes first. Some mutations simply shut the gene down. Others cause defective p53 protein to build up inside cancer cells, like some types of mesothelioma cells, where instead of stopping tumor growth it actively accelerates it. That distinction determines which approach is right.

Approaches to Treating p53 Mutations

• Degradation: Drugs remove defective p53 protein that has accumulated and is driving cancer growth.
• Induced cell death: Certain agents trigger cancer cells carrying p53 mutations to self-destruct.
• Reactivation: Small molecules help a mutated p53 protein refold into its correct shape so it can function without the gene being replaced.
• Replacement: A working p53 gene is delivered into tumor cells so they can produce normal p53 protein again.

Gene therapy for p53 is almost always combined with chemotherapy, radiation or immunotherapy. Restoring p53 function can make tumor cells vulnerable to treatments they’d previously stopped responding to, which is why combination treatment tends to produce better results than either approach alone.

Can p53 Gene Therapy Be Used to Treat Mesothelioma?

Research shows p53 gene therapy may treat certain mesothelioma cases, but only when the tumor carries a p53 mutation. A 2022 research study found p53 mutations in 18% of pleural mesothelioma and 15% of peritoneal mesothelioma cases. This means more than 80% of mesothelioma patients have a functioning wild-type p53 gene and may not benefit from this treatment.

Cell culture research shows p53 gene therapy can boost the effectiveness of chemotherapy for pleural mesothelioma, helping pave the way for clinical trials testing p53-based treatments. As research advances, mesothelioma treatments focusing on p53 and its role in tumor growth may change how this cancer is treated.

Challenges of Delivering the p53 Gene

The biggest hurdle in p53 gene therapy isn’t developing the treatment, it’s getting it where it needs to go. A working p53 gene has to reach the right cells, enter them successfully and be incorporated into their DNA before it can do anything. The immune system can intercept the delivery vehicle before it reaches the tumor, and even when it does arrive, it may not reach every cancer cell. Researchers have developed several methods to tackle this problem, each with its own advantages and limitations.

Nonreplicating Vectors

Adenoviruses are the most commonly used carrier in p53 gene therapy. Scientists remove the gene that controls replication, leaving the virus able to enter cells and deposit the p53 gene but unable to replicate or cause infection. Unlike some other vectors, adenoviruses don’t integrate into the patient’s DNA, which reduces the risk of unintended genetic changes. Doctors inject them directly into the tumor, where they enter cancer cells and deliver the gene.

The method is well studied and has a strong safety record, but it has limitations. The effects are relatively short-lived and may require multiple administrations. The body can also develop neutralizing antibodies over time that weaken the therapy’s effectiveness, and even direct injection may not penetrate every cancer cell in the tumor.

Oncolytic Viruses

Oncolytic viruses are modified viruses that attack cancer cells and spare healthy ones. They can also serve as vectors to carry DNA to cancer cells. Research shows oncolytic viruses can transfer p53 genes to cancer cells. This boosts their ability to kill cancer cells.

Researchers have used a modified variation of the measles virus to fight mesothelioma. Laboratory studies show oncolytic viral therapy may treat mesothelioma effectively on its own, even without the addition of a p53 gene.

Nanoparticles

Nanoparticles can transfer DNA or other molecules into cells. They’re no larger than 100 nanometers. That’s 1,000 times smaller than a human hair’s thickness.

These nanoparticles are more efficient than viruses for delivering gene therapy to cancer cells. Scientists can design nanoparticles to target only cancer cells. Research suggests nanoparticles may safely restore p53 function in cancer cells.

Reactivating p53 with Drugs

Some new and existing drugs affect the p53 gene or protein. There are many possible mutations in the p53 gene. Some prevent cells from making p53 protein. Others cause abnormal p53. Unlike gene therapy, which adds a working copy of the gene, these drugs help the existing mutant protein refold into its correct shape so it can function again.

Drugs that let cells make a working p53 protein can treat some mutations. These mutations block cells from making this protein. Other drugs can stabilize the p53 protein’s 3-D shape. This shape is vital for the protein to work properly. Several drugs are in trials to test their ability to treat cancer. These treatments only work when specific p53 mutations are present and are not effective for tumors with normal, functioning p53.

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Benefits of p53 Gene Therapy

A major benefit of p53 gene therapy is that it targets cancer cells specifically rather than healthy ones. Traditional cancer drugs can harm healthy cells, causing significant side effects. Targeting only cells with TP53 mutations may reduce that risk.

What p53 Gene Therapy Can Offer

• Combination synergy: Works best with chemo, radiation or immunotherapy, potentially improving outcomes for patients whose cancer has stopped responding to standard treatment.
• Reduced side effects: More precise targeting may lower the severity of treatment-related side effects compared to traditional chemo.
• Reversing resistance: Studies show p53 gene therapy can reverse cancer cells’ resistance to radiation and lessen its side effects.
• Targeted action: Focuses treatment on TP53-mutant tumor cells, reducing harm to healthy tissue.

Research shows this therapy is safe and effective for certain cancers with p53 mutations. Gendicine, a viral vector containing the p53 gene, has been tested in trials across several cancer types. Studies in cells and animals have also shown promising results, and human trials are ongoing.

Adding p53 to some tumor cells or activating WT p53 in tumor cells can result in cell death, tumor remission or even cures.

Arnold J. Levine , Institute for Advanced Study, Princeton

Side Effects of p53 Gene Therapy

The side effects of p53 gene therapy seen in clinical trials are typically mild compared to those of chemo or radiation. The most common are flu-like symptoms, fever, pain at the injection site and gastrointestinal symptoms.

Some side effects depend on the cancer’s location. For example, treatment can harm the lungs of lung cancer patients and cause urinary problems in cervical cancer patients.

Possible Adverse Reactions to p53 Gene Therapy

• Decreased blood cell production (bone marrow suppression)
• Fever
• Flu-like symptoms
• Gastrointestinal symptoms
• Liver dysfunction
• Muscle or joint pain
• Pain at the injection site
• Red blood cells breaking down (hemolysis)

Serious side effects are uncommon but can include kidney and liver dysfunction. In rare cases, platelet crisis, a condition that can cause spontaneous bleeding, can occur.

Because p53 gene therapy is only available through clinical trials, participants receive contact information for the trial’s medical team before treatment begins. Any unusual or severe symptoms should be reported to that team promptly. Serious adverse events are monitored and documented throughout the trial, and the medical team can pause or adjust treatment if needed.

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p53 Gene Therapy Clinical Trials

There is no FDA-approved gene therapy for mesothelioma. The only way to access this treatment is through a clinical trial. Trials for p53 gene therapy and p53-based treatments are ongoing around the country.

Clinical trials are also testing drugs that interact with p53 and MDM2, the protein that regulates p53. Because eligibility depends on your specific mutation and treatment history, finding the right trial takes some navigation. Our Patient Advocates work with mesothelioma patients every day and can help you identify trials you may qualify for, answer your questions about participation and connect you with the right research team.

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