T-cell engagers (TCEs) are engineered molecules that represent a significant advance in cancer immunotherapy. They function by physically bridging immune cells and cancer cells, serving as a double-sided molecular connector. This approach redirects the potent cell-killing capabilities of the immune system’s T-cells directly toward the tumor, overcoming the cancer’s ability to hide. The goal is to generate a powerful, localized immune reaction specifically at the tumor site.
How T Cell Engagers Activate the Immune System
T-cell engagers function as bispecific antibodies, meaning they have two distinct binding sites engineered onto a single molecule. One arm attaches to the CD3 protein complex found on the surface of a T-cell. The other arm recognizes and binds a tumor-associated antigen (TAA) expressed on the cancer cell. By binding both cells simultaneously, the engager physically brings the two cells into close proximity.
This forced connection creates an immunological synapse, regardless of whether the T-cell was previously capable of recognizing the cancer. The binding to the CD3 complex delivers the necessary activation signal, turning the T-cell on. Once activated, the T-cell begins to proliferate, rapidly multiplying its numbers. It also initiates its cytotoxic function, which is the process of cell killing.
The activated T-cell proceeds to destroy the linked cancer cell by releasing potent cytotoxic molecules. These molecules include perforin, which creates pores in the cancer cell membrane, and granzymes, which enter the cell through these pores to trigger programmed cell death. This mechanism is highly efficient because it bypasses the complex natural process of T-cell activation, which is often suppressed or avoided by tumors. The activation also leads to the secretion of cytokines, signaling proteins that further amplify the localized immune response against the tumor.
Clinical Applications and Target Selection
T-cell engagers have demonstrated success, particularly in the treatment of hematological malignancies, which are cancers of the blood and bone marrow. The first approved agent, blinatumomab, targets the CD19 protein found on B-cells, and is used for acute lymphoblastic leukemia (ALL). Other successful targets in liquid tumors include B-cell maturation antigen (BCMA) for multiple myeloma and CD20 for non-Hodgkin lymphoma. The uniformity and high expression of these targets contribute to the strong anti-tumor responses observed.
Targeting specific proteins is a fundamental aspect of this therapy, with agents selected for antigens that are highly, and ideally uniquely, expressed on the tumor surface. The availability of multiple targets, such as CD19, CD20, and BCMA, allows for therapeutic options even when a patient’s cancer relapses after initial treatment.
While the application in blood cancers has been transformative, the translation of TCEs to solid tumors presents greater challenges. Solid tumors often exhibit heterogeneous antigen expression, meaning the target protein may not be uniformly present across all cancer cells. Furthermore, the dense tumor microenvironment can physically impede the T-cells from effectively reaching the cancer cells. Despite these hurdles, research is progressing, with tebentafusp, a TCE targeting the gp100 protein, showing efficacy in treating uveal melanoma.
Managing Safety Risks
The powerful immune activation induced by T-cell engagers is associated with unique adverse effects requiring careful management. The most frequently observed side effect is Cytokine Release Syndrome (CRS), resulting from the rapid and widespread release of inflammatory signaling proteins by the activated T-cells. Symptoms of CRS can range from mild (fever, fatigue, headache) to severe, involving hypotension and organ dysfunction. CRS typically occurs early in the treatment course when the immune system first encounters the large tumor burden.
Another potential side effect is Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which involves a range of neurological symptoms. These symptoms can include confusion, delirium, difficulty speaking, and seizures. While the exact cause is still being studied, ICANS is thought to be related to the inflammatory response and subsequent damage to the blood-brain barrier.
Clinical teams use several strategies to mitigate these risks and manage symptoms. One approach is step-up dosing, where the initial dose of the T-cell engager is low and gradually increased over several days or weeks. This allows the body to adjust to the immune activation and helps reduce the overall severity of CRS. For patients who develop CRS, supportive care measures like intravenous fluids and anti-inflammatory medications are used. The drug tocilizumab, which blocks the receptor for the inflammatory cytokine Interleukin-6, is a standard treatment for managing serious cases of CRS.