New T cell therapy targets CTNNB1 cancer mutation with promising results in animal studies

Researchers at the University of Oslo and Oslo University Hospital have developed a promising new immunotherapy targeting the CTNNB1 gene mutation associated with various aggressive cancers like lung and prostate cancer. This approach has effectively eliminated tumors in animal studies and could benefit thousands of patients with this mutation. Published in Nature Immunology, it represents a significant breakthrough in T-cell receptor (TCR) therapy.

Cancer is often caused by changes in our DNA, known as mutations. While many mutations are unique to each patient, some mutations affect multiple individuals and are referred to as "public driver mutations". These can open the door for developing immunotherapies that treat groups of patients, rather than just individuals. In this study, the researchers focused on a specific mutation called CTNNB1S37F. It occurs in more than 7,000 new cancer cases annually in the U.S. and is found in several solid tumors, including endometrial, lung, and prostate cancers.

This CTNNB1S37F mutation is particularly difficult to target with traditional drugs. Our research shows that we can use engineered immune cells to successfully eliminate tumor cells that carry this mutation."

Professor Johanna Olweus, senior author and group leader, University of Oslo and Oslo University Hospital

Targeting a common cancer mutation

In cancer cells, mutations can result in the production of altered proteins. Small fragments of these altered proteins, known as peptides, can be displayed on the surface of cancer cells, where they may be recognised as foreign to the immune system. If recognised, these mutation-derived peptides can become targets for immune attack. T cells, which are crucial components of our immune system, use their T cell receptors to recognise these peptides presented on the cell surface by molecules known as human leukocyte antigens (HLA).

In this study, the researchers examined blood from healthy donors to find rare T cells that recognise the peptides from the CTNNB1S37F mutation, when displayed by two common HLA molecules. These HLA molecules are found in many people, increasing the chances that this treatment could be effective for a larger group of patients. "We engineered human T cells to express these specific receptors, effectively reprogramming them to seek out and destroy cancer cells that carry the mutation," explains Maria Stadheim Eggebø, PhD student and first author of the study.

Importantly, the researchers found that these engineered T-cell receptors were safe, selectively targeting only the cells with the cancer-specific mutation and leaving normal cells unharmed.

Promising results in eliminating tumors derived directly from patients

In a major step forward, the modified T cells were tested against cancer organoids, mini tumors grown from patient tissue, as well as in mouse models implanted with human tumors. In both cases, the engineered T cells effectively killed the cancer cells. "We were especially excited to see full tumor clearance in models derived from human patients," says researcher and co-corresponding author Morten Milek Nielsen. "To our knowledge, this is the first time TCR therapy targeting a mutation has shown such convincing elimination of tumors derived from patients with solid cancers."

These findings demonstrate that T-cell receptor therapy can be designed to effectively target shared mutations that are present across various patients and cancer types. "Because this mutation is present in many patients, this therapy has the potential to benefit large groups of patients," Nielsen says.

A new angle on a difficult cancer target

Former strategies to target the pathway which the CTNNB1 mutation influences, have largely failed due to side effects and low specificity. "What makes our approach different is that we're targeting the actual mutation itself, the root cause, and doing so with precision. This ensures a targeted attack on cancer cells that leaves healthy cells unharmed," says Olweus. The findings represent a breakthrough in the field of cancer immunotherapy, particularly for solid tumors, where effective treatments are still limited.

"Our findings confirm that TCR T-cell therapy can effectively target shared mutations in solid tumors across various cancer types," adds Eggebø. "It's a significant step forward, and we hope it will pave the way for future therapies that can be offered to many patients. Since no single mutation appears in all cancer cells, combining these TCR T cells with others, or with different treatments, could offer a powerful way to fight cancer." Looking ahead, the team plans to develop TCR T-cell therapies that target additional common cancer mutations, which could expand treatment possibilities for a larger group of patients and limit tumor escape.