T-cell engagers represent an innovative class of cancer immunotherapy. These engineered molecules are designed to help a patient’s own immune system recognize and fight cancer cells. By creating a connection between the immune system and the tumor, these therapies provide a targeted approach to treatment. This field has expanded treatment options for various types of cancer.
How T-Cell Engagers Work
T-cell engagers function as molecular bridges, physically linking a patient’s T-cells to cancer cells. These therapies are a type of bispecific antibody, meaning they have two different arms. One arm attaches to a protein on T-cells, a primary type of immune cell, while the other arm binds to a specific protein, known as an antigen, on a tumor cell.
This dual-binding action forces the T-cell and cancer cell together, activating the T-cell to recognize the cancer cell as a threat. Once activated, the T-cell releases cytotoxic granules that puncture the cancer cell’s membrane and initiate apoptosis, or programmed cell death. This mechanism redirects the patient’s immune cells to target and eliminate malignant cells.
The design of these molecules allows them to be highly specific. Many T-cell engagers are built to recognize the CD3 protein on T-cells. For the cancer-targeting arm, the choice of antigen depends on the type of cancer being treated. This specificity helps to focus the immune attack directly on the tumor.
Approved T-Cell Engager Therapies and Their Targets
Regulatory bodies have approved several T-cell engager therapies, each designed for specific cancers by targeting distinct surface proteins.
- Blinatumomab: Targets the CD19 protein on B-cells and is used to treat certain types of B-cell precursor acute lymphoblastic leukemia (ALL).
- Teclistamab: Targets BCMA on myeloma cells to treat relapsed or refractory multiple myeloma.
- Elranatamab: Also targets BCMA and is another option for patients with multiple myeloma.
- Mosunetuzumab: Targets the CD20 protein found on cancerous B-cells and is used for follicular lymphoma.
- Glofitamab: Also targets the CD20 protein and is approved for diffuse large B-cell lymphoma.
- Tarlatamab: Targets a protein called DLL3 and was approved for extensive-stage small cell lung cancer.
- Tebentafusp: Targets a gp100 peptide complex and was approved for uveal melanoma, a rare eye cancer.
Key Considerations and Side Effect Management
Treatment with T-cell engagers requires careful monitoring due to potential side effects related to widespread immune activation. A primary concern is Cytokine Release Syndrome (CRS), which occurs when activated T-cells release a flood of inflammatory molecules called cytokines. This systemic response can cause symptoms like high fever, fatigue, and changes in blood pressure. Medical teams manage CRS with supportive care and medications that dampen the inflammation.
Another significant consideration is Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). This condition involves neurological side effects that can range from confusion and difficulty with language to more severe symptoms like seizures. The precise mechanisms of ICANS are still being studied, but it is believed to be related to the inflammatory environment affecting the central nervous system. Due to the risk of CRS and ICANS, patients often begin treatment in a hospital setting where they can be closely observed.
Healthcare providers have established specific protocols to monitor for these side effects. This includes regular neurological assessments and monitoring of inflammatory markers in the blood. The grading of these side effects allows for a standardized approach to management, ensuring that interventions are timely and appropriate for the severity of the symptoms. Early detection and intervention are fundamental to safely administering these therapies.
The Role of T-Cell Engagers in Cancer Treatment
T-cell engagers occupy a specific niche within the broader landscape of cancer treatment. They are most commonly used in patients with relapsed or refractory cancers, meaning their disease has returned or stopped responding to standard therapies. For these individuals, who may have exhausted other options, T-cell engagers can offer a new possibility for achieving remission.
These therapies are a distinct form of immunotherapy and differ from other approaches like CAR-T cell therapy. While both treatments leverage T-cells, T-cell engagers are “off-the-shelf” products. They are manufactured as a consistent drug product and can be administered to any eligible patient without personalization. This makes them more readily accessible than CAR-T therapy, which requires extracting, genetically engineering, and then infusing a patient’s own T-cells back into them.
The approval for a solid tumor was a significant step forward, as early efforts focused on hematologic malignancies. As research continues, the number of available T-cell engagers and the types of cancers they can treat are expected to grow. This will further integrate the approach into cancer care protocols.