Some cancers can now be treated by boosting and modifying your attacking immune T-cells, causing them to attack cancer cells more effectively. Learn more about CAR T-cell therapy.
Chimeric antigen receptor T-cell (CAR-T) therapy for B-cell lymphoma involves a multi-step protocol.
Eligibility for CAR-T therapy is determined by factors including the specific subtype and stage of lymphoma, the patient's prior treatment history (e.g., relapsed or refractory after two or more lines of therapy), the expression of the target antigen protein (e.g., CD19), and the patient's overall health and performance status.
CAR-T is actually a type of gene therapy, as it involves the genetic modification of your own T-cells to make them attack a cancer more effectively. T-cells are also called cytotoxic T-lymphocytes. They are the primary attackcell in the Innate immune system, the one you were born with. Since different cancers have different antigens to each, a single CAR is made for a specific cancer's antigen. CAR T-cell therapies are described as monoclonal—each is designed to recognise just one target.
CAR-T therapy are approved by the FDA in the USA for certain lymphomas, leukaemias and Multiple Myeloma. For example, CAR-T is now considered standard-of-care for patients with refractory or relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) after prior treatments. The multistep protocol involves:
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Separating out the white mononuclear cells
It begins with leukapheresis to collect the patient's peripheral blood mononuclear cells. This procedure involves drawing blood through an intravenous line, separating the white blood cells, and returning the remaining blood components to the patient, often requiring two to three hours to complete.
Peripheral blood mononuclear cells (PBMCs) are a heterogeneous population of blood cells characterized by a single round nucleus, including lymphocytes (T cells, B cells, and natural killer, NK, cells), monocytes, and dendritic cells.
In humans, lymphocytes typically constitute 70–90% of the PBMC population, monocytes make up 10–20%, and dendritic cells are rare, accounting for only 1–2%.
PBMCs are critical components of the immune system, playing essential roles in both extracellular and cell-based immunity, and are widely used in research and clinical applications such as immunology, infectious disease, oncology, vaccine development, toxicology, and transplant immunology.
PBMCs are isolated from whole blood using density gradient centrifugation, a process that separates them from red blood cells and granulocytes based on their lower density.
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Genetic modification
The PBMCs are then genetically modified in a laboratory to express a chimeric antigen receptor (CAR) - this is a synthetic receptor protein, engineered to redirect T-lymphocytes to target specific proteins (antigens) on the surface of cancer cells.
The typical target protein is CD19, which is present on the surface of B-lymphoma cells.
After manufacturing, which typically takes about 17 days, the expanded CAR-T cells are cryopreserved and shipped back to the treatment center.
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Chemotherapy
Prior to infusion, patients undergo lymphodepleting conditioning chemotherapy, most commonly a regimen of fludarabine and cyclophosphamide (FluCy), administered over three days before the CAR-T cell infusion. Lymphodepletion is the destruction of lymphocytes and T regulatory cells (T-regs). It gets the poorer rivals and the regulatory mechanisms out of the way. It clears space for the newly modified T-cells to operate fully.
This lymphodepletion step is crucial also increases the availability of homeostatic cytokines (these are crucial for maintaining normal T-cell counts and restoring T-cell numbers after depletion or expansion) like IL-7 and IL-15, which promote CAR-T cell expansion, persistence, and anti-tumor efficacy.
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Infusion
The infusion of the patient’s own genetically modified T-cells is typically administered in an inpatient setting to allow for close monitoring of potential severe side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), although outpatient infusion is feasible with appropriate monitoring. As CAR-T cells multiply, they can release large amounts of chemicals called cytokines into the blood, which can ramp up the immune system. However, sometimes this reaction is ‘overcooked’ resulting in a cytokine storm, which is potentially very dangerous.
The infusion is rather like giving blood, and can take from 5-30 minutes.
The number of CAR-T cell infusions a patient receives typically depends on the specific therapy and individual patient circumstances. For most patients, a single infusion of engineered CAR-T cells is sufficient to initiate a response, as the cells can multiply and persist in the body for years, acting as a "living therapy".
Side-effects of CAR-T
While CAR T-cell therapy can be very effective against some hard-to-treat cancers, it may occasionally cause serious and even life-threatening side-effects. You should always be treated in a specialist medical center specially trained in its use, and you must be watched closely for several weeks after receiving the CAR-T cells.
Side-effects apart from the extreme Cytokine Storm include:
Fast heartbeat
Trouble breathing
Severe nausea, vomiting, diarrhoea
Feeling lightheaded and dizzy
High fever with chills
Headaches
Feeling very tired