A chimeric antigen is an engineered protein that combines different functional parts into a single molecule. These synthetic receptors are expressed on the surface of immune cells, such as T cells, to enhance their ability to recognize and eliminate target cells. This allows for precise targeting, a key aspect of advanced medical therapies.
Building a Chimeric Antigen
The design of a chimeric antigen involves combining several distinct modular components. It features an extracellular antigen-binding domain, which recognizes specific targets, typically on diseased cells. This domain often consists of a single-chain variable fragment (scFv), derived from a monoclonal antibody and connected by a flexible peptide linker.
The scFv links to a hinge region or spacer, providing flexibility and connecting the extracellular part to the cell membrane. The transmembrane domain anchors the chimeric antigen to the cell surface and is important for stability. Extending into the cell’s interior are one or more intracellular signaling domains, which initiate an immune response once the antigen-binding domain recognizes its target.
How Chimeric Antigens Empower Immune Cells
When expressed on immune cells, particularly T-cells, chimeric antigens form Chimeric Antigen Receptors (CARs). These engineered receptors equip T-cells to directly recognize and bind to specific antigens on target cells, such as cancer cells, without needing the body’s natural major histocompatibility complex (MHC) presentation system. This MHC-independent recognition allows CAR T-cells to identify a broader range of antigens on cancer cells, even those that have reduced MHC expression.
Upon binding to the targeted antigen, the CAR triggers a cascade of intracellular signaling events within the T-cell. This activation leads to T-cell proliferation, meaning it rapidly multiplies, and acquires cytotoxic capabilities.
These CAR T-cells eliminate target cells through various mechanisms. They secrete inflammatory cytokines, such as interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), which contribute to the immune response. They also release perforin and granzymes, which induce programmed cell death (apoptosis) in the target cells. This targeted killing and proliferation allow CAR T-cells to effectively attack cancer cells.
Current Clinical Uses
Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of certain blood cancers. Several CAR T-cell therapies are approved for specific types of blood cancers, including:
Acute lymphoblastic leukemia (ALL)
Diffuse large B-cell lymphoma (DLBCL)
Mantle cell lymphoma (MCL)
Follicular lymphoma (FL)
Multiple myeloma (MM)
The success of these therapies relies on targeting specific antigens highly expressed on cancer cells. For B-cell malignancies, a common target is Cluster of Differentiation 19 (CD19), found on most B-cell lineage cancers. For multiple myeloma, B-cell maturation antigen (BCMA) is frequently targeted due to its high expression on myeloma cells.
Research is exploring CAR T-cell therapy beyond these indications, including other blood cancers and solid tumors. Efforts also focus on overcoming challenges like antigen loss and improving CAR T-cell activity, which may broaden future applications.
Navigating Chimeric Antigen Receptor (CAR) T-Cell Therapy
Undergoing CAR T-cell therapy involves a multi-step process, typically requiring specialized medical centers. The journey begins with apheresis, where a patient’s T-cells are collected from their blood. These collected T-cells are then sent to a manufacturing facility for genetic modification.
In the laboratory, T-cells are engineered to express the chimeric antigen receptor (CAR) on their surface. After this modification, the CAR T-cells are expanded in number, a process that can take several weeks. Before reinfusion, patients may undergo a conditioning chemotherapy regimen.
Once ready, the CAR T-cells are reinfused back into the patient. While effective, patients are closely monitored for potential side effects. Two recognized side effects are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
CRS is a systemic inflammatory response with symptoms like fever, fatigue, low blood pressure, or breathing difficulties. ICANS can manifest as neurological effects including altered mental status, speech changes, or seizures. These side effects are generally manageable with supportive care and specific medications like tocilizumab or corticosteroids.