Cancer is a battle within our own bodies: tumor cells grow uncontrollably and cause destruction, whereas the immune system attempts to locate and eliminate these malignant cells. For decades, scientists have been bolstering the immune system with medications, including chemotherapy, which also attacks the tumor. However, in recent years, innovative strategies have emerged that focus on retraining immune cells to develop into more effective against cancer. This approach, known as immunotherapy, has already saved thousands of lives and changed the prognosis for a number of tumors.
While promising in theory, immunotherapy doesn’t perform for all patients or all cancers. Sometimes, the tumor learns to evade the reinforced immune defenses, or the immune cells become exhausted after prolonged fighting. Many mechanisms still cause immunotherapy to fail, and the scientific community continues to seek ways to overcome these challenges. A recent study, published Thursday in Science, explores designing more robust, durable, and precise T lymphocytes – a type of immune cell – to target cancer. Researchers at the University of California and Stanford University were able to genetically engineer these immune cells in the lab, incorporating a molecular “hook” that allows them to better hunt down malignant cells. The research, still in its experimental stages, could pave the way for more potent cancer immunotherapies.
There are various types of immunotherapy available, each designed to strengthen the body’s defenses against tumors. This particular research focuses on T-cell TCR therapy, a technique that involves extracting T lymphocytes from a patient and genetically modifying them in the lab to express a receptor (TCR) that identifies molecules (antigens) found on the surface or within tumor cells, effectively flagging them as malignant. Once modified, these equipped lymphocytes are infused back into the patient to seek out and destroy cancer cells with greater accuracy.
T-cell TCR therapy has lagged behind other immunotherapies, the study’s authors admit. Currently, only one treatment – for synovial sarcoma – is approved by the U.S. Food and Drug Administration. However, researchers believe this strategy offers an “attractive alternative” to CAR-T therapy, which has a similar approach and is highly effective in blood cancers, but has struggled to gain traction in solid tumors.
The potential of T-cell TCR therapy lies in its ability to access a wider range of targets on tumor cells, allowing for more precise identification and destruction. However, challenges remain. Some antigens found on tumor cells are also present in healthy tissue, and the body has natural mechanisms to eliminate the most potent T cells to prevent damage to normal cells. This can result in weaker TCR receptors that, while avoiding harm to healthy tissue, may struggle to effectively recognize and destroy tumor cells.
Improving Immune Response
To address these challenges and optimize the potential of T-cell TCR therapy without causing harm to healthy cells, researchers developed a plan to strengthen the ability of T lymphocytes to recognize PAP, a protein commonly found in prostate cancer cells, and enhance the immune response against the tumor.
The team identified a weak TCR capable of detecting the PAP protein but ineffective at eliminating cancer cells, and manipulated it in the lab to improve its adhesion to the tumor and strengthen its hold. Specifically, they introduced a molecular “hook” that allows the TCR to bind more durably to cancer cells. “They don’t substantially increase the initial binding strength, but they prolong the interaction once it occurs, like a fish caught on a hook,” the researchers explained.
Subsequent lab experiments showed that the genetically modified T lymphocytes were strengthened in several ways: they remained attached to tumor cells for longer, secreted more molecules that assist kill cancer, and were more resistant to exhaustion. In mouse models, the strengthened immune cells delayed or completely halted tumor growth.
A First Step
The authors believe these findings could lead to improved immunotherapies for cancer and see the approach as broadly applicable to other tumor types beyond prostate cancer. This research is a promising step forward in the ongoing effort to harness the power of the immune system to fight cancer.
External experts have praised the research, but caution that further work is needed before it can be applied clinically. “This represents an initial experimental approach that demonstrates potential. It opens up a range of possibilities that didn’t exist before,” said Alena Gros, head of the Immunotherapy and Tumor Immunology Group at the Vall d’Hebron Institute of Oncology.
Luis Álvarez Vallina, director of Research at the Blood and Tissue Bank of Catalonia and head of the Cancer Immunotherapy Unit at CNIO-HMRIB, agreed that “the main novelty is that, through punctual changes in the TCR, T cells notably increase their ability to destroy tumors without losing specificity, which could reduce some of the safety problems observed in conventional TCR-based therapies.”
However, he also urged caution in interpreting the results: “This is a proof of concept based on simplified preclinical models and in a favorable experimental context. Its efficacy and safety in more complex systems remain to be demonstrated. Its real clinical impact is still uncertain.”
Manel Juan, head of Immunology at Hospital Clínic de Barcelona, believes this research “is a beginning that could lead not only to clinical trials in prostate cancer, but potentially to many others.” He noted that “the leap to humans will require new approaches and the development of a clinical trial” in patients.
Alejo Rodríguez Fraticelli, ICREA Professor and group leader at the Institute for Biomedical Research of Barcelona (IRB), said this innovative approach “is not going to replace CAR-T therapy,” but does “open up the range” of immunotherapy in other tumors: “The promise of this is that if the modified TCR works so well, One can start attacking antigens inside the tumor cell and open up immunotherapy to tumors that, until now, we weren’t sure how to attack.”
