T-cell engagers represent an advancement in immunotherapy, a field of medicine that leverages the body’s own immune system to combat disease. These therapies are designed to redirect T-cells, a type of white blood cell that plays a central role in immune responses, to identify and eliminate diseased cells, primarily cancer cells. By acting as a bridge between the immune system and the disease, T-cell engagers offer a novel approach to treatment, offering new possibilities for patients facing challenging conditions.
How T-Cell Engagers Work
T-cell engagers operate through a mechanism that brings immune cells directly into contact with target cells. These molecules are engineered as “bispecific antibodies,” meaning they possess two distinct binding sites. One binding site attaches to a specific protein found on the surface of T-cells, most commonly the CD3 protein, which is a component of the T-cell receptor complex. The other binding site recognizes and binds to a particular target protein, also known as a tumor-associated antigen (TAA), located on the surface of diseased cells, such as cancer cells.
When a T-cell engager binds simultaneously to both a T-cell and a diseased cell, it forms a molecular bridge, bringing the T-cell close to its target. This direct connection activates the T-cell. Once activated, the T-cell releases specialized proteins, such as perforin and granzymes, which create pores in the target cell’s membrane and induce programmed cell death. This process allows the T-cell to destroy the diseased cell.
Conditions Treated by T-Cell Engagers
T-cell engagers show promise, particularly in the treatment of various blood-borne cancers. Blinatumomab, the first Food and Drug Administration (FDA)-approved T-cell engager, targets CD19 on cancer cells and CD3 on T-cells. It is effective in treating B-cell acute lymphoblastic leukemia (B-ALL), with studies showing complete response rates in many patients.
The success seen in B-ALL has led to the development of other T-cell engagers for different blood cancers. For instance, several CD20/CD3-bispecific T-cell engagers are in advanced stages of clinical development for patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma, often achieving complete response rates over 50%. Multiple myeloma, a cancer of plasma cells, has also seen advancements with T-cell engagers that target B-cell maturation antigen (BCMA) or GPRC5D on myeloma cells, alongside CD3 on T-cells. These therapies, including teclistamab and talquetamab, have shown overall response rates over 60% in heavily pretreated patients.
While T-cell engagers have had success in blood cancers, their application in solid tumors is an active area of research. Challenges in solid tumors include the presence of tumor-associated antigens on normal tissues, which can lead to “on-target” toxicities, and the immunosuppressive environment within solid tumors that can hinder T-cell activity. Despite these hurdles, new strategies are being explored, such as modifying T-cell engagers to overcome physical barriers around solid tumors or targeting intracellular antigens. Tebentafusp, which targets a peptide-MHC complex found in uveal melanoma cells, represents an approval in solid tumors.
Important Considerations for Patients
T-cell engager therapies are administered through intravenous infusion, often with a “step-up” dosing schedule where initial doses are lower and gradually increased. This approach helps the body adjust to the therapy and can reduce the severity of potential side effects. Patients require close monitoring in a hospital setting, particularly during the initial phases of treatment, to manage reactions.
One common side effect is cytokine release syndrome (CRS), an immune system overreaction that can cause flu-like symptoms such as fever, fatigue, muscle aches, and sometimes more severe issues like low blood pressure or breathing difficulties. Most CRS cases are manageable with supportive care, including medications like tocilizumab or steroids. Another side effect is immune effector cell-associated neurotoxicity syndrome (ICANS), which can involve neurological symptoms such as confusion, difficulty speaking, or tremors. These neurological effects are less frequent than CRS and occur within the first few weeks of treatment. Patients are monitored for these side effects through physical assessments.
Patient eligibility for T-cell engager therapy depends on the specific type and stage of cancer, as well as prior treatments received. Many of these therapies are approved for patients with certain cancers who have already undergone multiple lines of other treatments, such as proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. Patients should discuss with their healthcare providers if T-cell engager therapy is a suitable option for their circumstances, considering their health and treatment history.