Immunotherapy uses the body’s immune system to fight cancer. Bispecific T-cell engagers, or BiTEs, are a targeted form of immunotherapy. These engineered molecules guide immune cells to cancer cells, initiating an attack that destroys tumors.
The Mechanism of Bispecific T-Cell Engagers
Bispecific T-cell engagers are antibody-derived molecules engineered to bind to two different targets simultaneously. They act as a bridge, physically connecting a T-cell, a type of immune cell, with a cancer cell. One arm of the BiTE molecule attaches to the CD3 receptor on T-cells, which is involved in T-cell activation.
The other arm binds to a specific antigen on the surface of cancer cells. For example, in certain blood cancers, this arm might target CD19, an antigen commonly found on lymphoma or leukemia cells. This dual binding brings the T-cell into very close proximity with the cancer cell.
Once the BiTE molecule has successfully linked a T-cell and a cancer cell, it forces a direct engagement between them. This close contact activates the T-cell, prompting it to recognize the cancer cell as a threat. The activated T-cell then releases substances, including cytolytic proteins and inflammatory cytokines, that directly destroy the cancer cell. This targeted activation leads to the lysis of the tumor cell.
Approved Uses and Patient Candidacy
Bispecific T-cell engager therapies are approved for specific blood cancers. Blinatumomab, for example, is approved for certain forms of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), meaning the cancer has returned or not responded to previous treatments.
BiTEs are also approved for other blood cancers, including types of non-Hodgkin lymphoma and multiple myeloma. Examples include epcoritamab and mosunetuzumab for specific relapsed or refractory lymphomas, and teclistamab and talquetamab for relapsed or refractory multiple myeloma after multiple prior therapies.
Patients are candidates for BiTE therapy if they have a confirmed diagnosis of one of these approved cancer types that has resisted conventional treatments or recurred. While most approvals are for blood cancers, research is exploring BiTEs for solid tumors. Tarlatamab recently received accelerated approval for extensive-stage small cell lung cancer, marking the first BiTE approval for a solid tumor.
The Treatment and Monitoring Process
Bispecific T-cell engager therapy involves a specific administration schedule. Many BiTEs are given as a continuous intravenous (IV) infusion, meaning the medication flows into a vein constantly over an extended period, lasting several weeks.
The initial “step-up dosing” phase, where the dose is gradually increased, typically occurs in a hospital setting. This inpatient stay allows healthcare teams to closely monitor patients for potential side effects. Patients may remain hospitalized for several days during this dose escalation phase.
Close monitoring continues throughout the treatment course, even for outpatient cycles. Medical teams perform frequent assessments, including vital signs and neurological checks, to detect any changes early. This continuous oversight ensures that any emerging complications can be identified and addressed promptly.
Managing Potential Complications
Bispecific T-cell engager therapy can lead to significant side effects. The most common and serious complications are Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). CRS results from a widespread inflammatory response caused by the release of inflammatory proteins called cytokines into the bloodstream. Symptoms of CRS can range from mild, flu-like symptoms such as fever, chills, and fatigue, to more severe manifestations like low blood pressure, rapid heart rate, and difficulty breathing.
ICANS involves neurological changes due to inflammation in the central nervous system. These symptoms can vary from subtle issues like headache and confusion to more pronounced problems, including difficulty speaking, tremors, or even seizures. While ICANS often occurs alongside CRS, it can also manifest independently or after CRS symptoms have resolved.
Medical teams manage these complications with established protocols. For CRS, treatment often involves supportive care and medications such as tocilizumab, an interleukin-6 receptor antagonist, to block the action of inflammatory cytokines. Corticosteroids like dexamethasone are also commonly used to reduce inflammation, particularly for higher grades of CRS or for ICANS. These management strategies are implemented to control symptoms and ensure patient safety throughout the therapy.
Comparison with CAR-T Therapy
Bispecific T-cell engagers and CAR-T cell therapies both represent advanced immunotherapies that redirect T-cells to target cancer, yet they differ fundamentally in their approach. BiTEs are “off-the-shelf” drugs, meaning they are manufactured in a laboratory as a ready-to-use pharmaceutical product. In contrast, CAR-T therapy is a highly personalized treatment that involves collecting a patient’s own T-cells, genetically modifying them in a lab to recognize cancer, and then reinfusing them back into the patient. This modification process for CAR-T cells can take several weeks.
The administration methods also vary significantly. BiTEs typically require continuous intravenous infusion over several weeks due to their relatively short half-life in the body. CAR-T therapy, on the other hand, is generally administered as a single infusion. Both therapies are engineered to target specific cancer antigens, such as CD19 or BCMA, but their structural design and delivery mechanisms are distinct.
Another key difference lies in their persistence within the body. Once the continuous infusion of a BiTE drug stops, the molecules are cleared from the body relatively quickly. CAR-T cells, however, are designed to persist and multiply within the patient’s body for a longer duration, potentially offering extended immune surveillance against cancer. While both therapies can cause similar severe side effects like cytokine release syndrome and neurotoxicity, their manufacturing, administration, and persistence profiles represent distinct therapeutic strategies.