Chronic Lymphocytic Leukemia (CLL) stands as one of the most common types of leukemia affecting adults, where the bone marrow produces an excess of abnormal white blood cells called lymphocytes. These cancerous cells accumulate slowly, often without immediate symptoms, but can eventually crowd out healthy blood cells and spread to lymph nodes, the liver, and the spleen. CAR T cell therapy represents a significant advancement, offering a personalized and innovative approach for specific cancers, including CLL. This therapy harnesses the body’s own immune system to target and destroy cancer cells.
Understanding CAR T Cell Therapy
CAR T cell therapy involves modifying a patient’s own T cells, a type of white blood cell, to enhance their ability to identify and eliminate cancer cells. In the laboratory, a new gene is introduced into the T cells, which instructs them to produce a Chimeric Antigen Receptor (CAR). This engineered receptor combines an antigen-binding part with components that activate the T cell. This fusion allows the modified T cell to directly recognize and bind to specific proteins, known as antigens, found on the surface of cancer cells.
Once engineered, these CAR T cells are multiplied in the laboratory to produce millions of cells for treatment. These CAR T cells can then multiply and persist within the patient’s body, continuously seeking out and destroying cancer cells.
CAR T Cell Therapy’s Role in CLL Treatment
Treating advanced or relapsed/refractory CLL presents considerable challenges, particularly when prior therapies like Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL-2) inhibitors have not been effective. In such situations, CAR T cell therapy offers an additional option. This therapy specifically targets antigens expressed on CLL cells, with CD19 being a primary target. CAR T cells are engineered to recognize and bind to CD19, a protein widely present on the surface of CLL cells.
While CD19 is the most common target, ongoing research explores other potential targets such as CD20 and ROR1, aiming to broaden the applicability and effectiveness of CAR T cell therapy in CLL. The U.S. Food and Drug Administration (FDA) has approved CD19-directed CAR T cell therapies for CLL. For instance, lisocabtagene maraleucel (Breyanzi) received FDA approval in March 2024 for adults with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. Tisagenlecleucel (Kymriah) is another CD19-directed CAR T cell therapy approved for certain leukemias and lymphomas.
The CAR T Cell Therapy Process
The journey through CAR T cell therapy begins with a thorough patient evaluation to determine eligibility. This assessment considers overall health, prior treatments received, and organ function, including kidney, liver, and heart health.
Once deemed eligible, the next step is apheresis, which is the collection of T cells from the patient’s blood. During this outpatient procedure, T cells are separated from the blood.
The collected T cells are then transported to a specialized manufacturing facility. Here, the cells undergo genetic modification to express the Chimeric Antigen Receptor (CAR) and are then expanded, or grown, to reach the millions of cells needed for treatment. This intricate manufacturing process usually takes several weeks, often ranging from 3 to 6 weeks.
Before the modified CAR T cells are infused back into the patient, a short course of lymphodepleting chemotherapy is administered. This chemotherapy, often involving cyclophosphamide and fludarabine, helps to reduce the number of existing immune cells in the patient’s body. This “makes space” for the newly infused CAR T cells, allowing them to expand and persist more effectively in the body.
Finally, the engineered CAR T cells are infused back into the patient, similar to a blood transfusion, usually through an intravenous line. Following the infusion, patients require close monitoring in a specialized center for several weeks to manage any potential side effects.
Managing Outcomes and Potential Complications
After CAR T cell infusion, the primary goal is to achieve remission, with the potential for durable responses. Clinical trials have shown that CAR T cell therapy can induce deep and lasting remissions in some patients with relapsed or refractory CLL, with responses extending for several years. For instance, some studies have reported ongoing durable remissions for up to 99 months in CLL patients.
CAR T cell therapy can lead to specific side effects that require careful management. Cytokine Release Syndrome (CRS) is a common and potentially serious complication, occurring when activated CAR T cells release a large number of inflammatory proteins called cytokines into the bloodstream. Symptoms can range from fever, muscle pain, and low blood pressure to more severe issues like breathing difficulties or organ dysfunction. CRS is typically managed with supportive care, and for more severe cases, medications like tocilizumab, an IL-6 receptor blocker, are used to counteract the inflammatory response.
Another significant side effect is Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). This neurological complication can manifest with symptoms such as confusion, headaches, language difficulties, or even seizures. ICANS often develops within 3 to 10 days after CAR T cell infusion, sometimes following the onset of CRS. Management of ICANS primarily involves supportive care and corticosteroids, such as dexamethasone, which help to reduce neuroinflammation.
Patients may also experience other complications, including prolonged cytopenias, which are reductions in blood cell counts. These can persist for weeks to months after treatment, increasing the risk of infections. Long-term follow-up is necessary to monitor for these and other potential delayed effects, such as prolonged B-cell aplasia and hypogammaglobulinemia, which can lead to increased susceptibility to infections.