T-cell receptor (TCR) therapy is a personalized cancer immunotherapy that enhances a patient’s own immune cells to combat their specific cancer. This treatment involves genetically modifying a T-cell, a type of white blood cell, to more effectively identify and destroy cancerous cells.
How T-Cells Naturally Target Threats
T-cells are a component of the immune system that identifies and eliminates threats like infections or malignant cells. These cells use specialized proteins on their surface called T-cell receptors (TCRs) for this task. A TCR recognizes small fragments of proteins, called antigens, that are displayed on the surface of other cells.
This presentation is handled by a group of proteins known as the Major Histocompatibility Complex (MHC), which exists on almost all cells in the body. The MHC acts like a display case, presenting a sampling of the proteins found inside a cell. T-cells continuously inspect these presented antigens; if a TCR recognizes an antigen as foreign or abnormal, such as one from a cancer cell, it triggers the T-cell to destroy that cell.
This mechanism allows the immune system to detect internal problems by examining a cell’s internal proteins from the outside. The specificity of the TCR-antigen interaction is a foundation of healthy immune function. TCR therapy leverages this recognition system to direct a patient’s immune response toward their cancer.
The Patient Journey Through TCR Therapy
T-Cell Collection
The first step in TCR therapy is collecting T-cells from the patient’s body. This is accomplished through a procedure called leukapheresis, which involves drawing blood and processing it through a machine that separates white blood cells, including T-cells, from the other blood components. The remaining blood is then returned to the patient’s body.
Genetic Engineering
Once the T-cells are harvested, they are sent to a laboratory for genetic modification. Scientists use a disabled virus, known as a viral vector, to act as a delivery vehicle. This vector carries a new gene into the T-cells, which instructs the cells to produce a specific TCR designed to recognize the patient’s particular cancer. The selection of the right TCR is dependent on the patient’s individual genetic makeup, specifically their Human Leukocyte Antigen (HLA) type, which is the human version of MHC.
Cell Expansion
After the T-cells have been engineered, they are multiplied into a large quantity to be effective against the cancer. This is achieved through cell expansion, where the modified T-cells are cultured in the lab. Over several weeks, the engineered cell population grows into millions of cancer-fighting cells.
Infusion
Before the engineered T-cells are returned to the patient, the individual may undergo a short course of chemotherapy. This is not intended to treat the cancer directly but to reduce the number of existing white blood cells in the body. This step, known as lymphodepletion, helps create space for the newly engineered T-cells to grow. Finally, the expanded, engineered T-cells are infused back into the patient’s bloodstream through an IV drip.
Comparing TCR Therapy to CAR-T Therapy
TCR therapy and Chimeric Antigen Receptor (CAR) T-cell therapy both modify a patient’s T-cells to fight cancer, but differ in how they recognize their targets. The engineered TCRs recognize cancer-specific protein fragments that are presented on the cancer cell’s surface by the MHC complex, allowing them to target proteins from within the cell.
CAR-T therapy, on the other hand, employs a synthetic receptor, the CAR, which is engineered to bind directly to proteins on the outer surface of a cancer cell. This process does not require the MHC for antigen presentation. This direct targeting has proven highly effective against certain blood cancers, like leukemia and lymphoma, where specific surface antigens are readily available.
The primary distinction gives each therapy unique advantages. Because TCRs can recognize internal proteins, they can target a much broader array of cancer markers, including those specific to solid tumors. An analogy is that TCR therapy can see a target displayed through a window (the MHC), while CAR-T therapy can only see targets located on the front door (the cell surface). This makes TCR therapy a promising strategy for cancers that do not have unique surface markers, a common characteristic of solid tumors.
Applications and Associated Risks
TCR therapy is showing promise in treating various cancers, particularly solid tumors that have been difficult to treat with other immunotherapies. Clinical trials have demonstrated its potential in cancers such as melanoma, synovial sarcoma, and cervical cancer. The ability of TCRs to target intracellular antigens also makes this approach suitable for malignancies including lung, bladder, and pancreatic cancers.
TCR therapy carries risks that require careful management. A common and serious side effect is Cytokine Release Syndrome (CRS), a systemic inflammatory response caused by the massive activation of engineered T-cells. This can lead to high fevers, flu-like symptoms, and in severe cases, organ dysfunction. Another potential risk is Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), which can cause neurological symptoms ranging from confusion and difficulty speaking to more severe complications. Medical teams are trained to monitor for and manage these toxicities.