T cells are specialized white blood cells that are part of the body’s immune system, playing a role in adaptive immunity. They identify and eliminate specific threats, including cells infected with viruses or those that have become cancerous. These cells circulate throughout the body, awaiting activation. Upon detecting a threat, T cells can multiply extensively to locate and destroy harmful cells.
T cell engineering involves modifying these immune cells to enhance or redirect their abilities for therapeutic applications. This aims to improve their targeting, helping them recognize and eradicate specific threats that might otherwise evade the immune system. Genetically altering T cells reprograms their functions, making them more potent against various diseases.
The Basis of T Cell Engineering
T cells naturally recognize targets through structures on their surface, called T-cell receptors (TCRs). These TCRs bind to antigens, which are presented on the surface of other cells by major histocompatibility complex (MHC) molecules. This interaction triggers T cell activation and a targeted immune response.
Scientists engineer T cells to overcome limitations in their targeting, especially in cancer. Cancer cells often evade detection by reducing MHC expression or presenting unrecognized antigens. Modifying T cells helps them bypass these strategies and precisely target diseased cells. The goal is to create T cells more effective at finding and destroying specific threats. This can involve making T cells more sensitive to certain antigens or allowing them to recognize targets independently of MHC presentation.
Methods of T Cell Modification
T cell engineering uses two main genetic modification approaches: Chimeric Antigen Receptor (CAR) T-cell therapy and T-cell Receptor (TCR) engineering. Both introduce new genetic material into T cells to alter their recognition capabilities. Viral vectors, like lentiviruses or gamma retroviruses, deliver and integrate this material into host cell genomes.
CAR T-cell therapy engineers T cells to express a synthetic receptor, a Chimeric Antigen Receptor (CAR). A CAR enables T cells to recognize specific antigens on target cells independently of MHC. It consists of an extracellular antigen-binding domain (often from an antibody) fused to intracellular signaling domains (like CD3ΞΆ) and co-stimulatory molecules (such as CD28 or 4-1BB). When the CAR binds to its antigen, it activates the T cell, leading to proliferation, toxicity, and cytokine release for an anti-tumor response.
T-cell Receptor (TCR) engineering modifies the natural TCRs of T cells to enhance or redirect antigen recognition. This involves replacing existing TCR genes with new ones that encode TCRs recognizing specific antigens presented by MHC molecules, often on cancer cells. Unlike CARs, engineered TCRs rely on MHC presentation, mimicking natural T cell activation. The aim is to introduce TCRs with higher affinity for tumor antigens or specificity against antigens the patient’s original T cells might not recognize.
T Cell Engineering in Disease Treatment
Engineered T cells have shown promise, especially in cancer treatment. CAR T-cell therapy is a successful treatment for certain blood cancers. Approved for relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in pediatric and young adults, and various non-Hodgkin lymphoma and multiple myeloma in adults. These therapies target specific antigens, like CD19 on B-cell malignancies, leading to anti-tumor responses and, in some cases, long-term remission.
Beyond blood cancer, research explores broader uses for engineered T cells. Efforts adapt CAR T-cell therapy for solid tumors, which present challenges due to complex microenvironments and heterogeneous antigen expression. Other applications include using engineered T cells to combat chronic infections, like HIV, by enhancing the immune response against infected cells. T cell engineering is also being investigated for autoimmune diseases, aiming to modulate or suppress immune responses that cause tissue damage.
Patient Considerations and Process
Receiving engineered T cell therapy is a multi-step process, typically in specialized medical centers. It begins with collecting the patient’s T cells via apheresis. During apheresis, blood is drawn, T cells are separated, and the rest is returned. This usually takes several hours.
After collection, T cells go to a manufacturing facility for genetic modification and expansion. They are engineered to express new receptors, like CARs, and multiplied until enough cells are ready for treatment. This phase can take several weeks. Once ready, engineered cells are shipped back and infused into the patient, usually via a central venous catheter, taking 30 minutes to an hour. Patients are monitored for weeks post-infusion to manage side effects and assess effectiveness.