CD19 a starting point for CAR-T therapies
At the time of writing there are 62 clinical trials examining the treatment of haematological (blood cancers) malignancies with Chimeric Antigen Rector T-Cell therapies (CAR-T). It may not be surprising that almost 80% of these studies are targeting CD19+ cell (B cells) malignancies, lymphoma and leukaemia with compelling results reported by:
· Juno Therapeutics https://www.junotherapeutics.com/pipeline/clinical/
to list but a few.
CD19 is an attractive target for CAR-T therapies because it is only found on B Cells, thus reprogramming T-Cell to identify CD19 should provide a method for treating B-Cell related malignancies whilst excluding other healthy cell lines from the cytotoxic effect of these genetically modified T-Cells.
It has been breath-taking to see the clinical development of these genuinely curative therapies, which have provided hope to the previously incurable. However, these CD19+ targeting therapies do have both acute and chronic side-effects.
One of the acute effects is known as cytokine storm (prosaically known as cytokine release syndrome) which is a result of cytokine release follow T-cell activation when it binds to its CD19 target. The systemic inflammatory response gives the patient fever-like symptoms and can lead to pulmonary edema. Cytokine release syndrome can be life-threatening but can be manged at the point of care using a combination of therapeutic agents including IL-6 antagonists (tocilizumab) and steroids. The next generation CAR-T therapies may include a method of modulating the activity of these cells so that the cytotoxic activity of the CAR-T cells and the subsequent release of cytokines could be attenuated when the first symptoms of cytokine release syndrome present.
A chronic side effect is associated with the specificity and longevity of the therapy; modified T-cells cannot differentiate between malignant and healthy B Cells and so all B Cells are targeted and destroyed, furthermore these modified T-Cells remain within the patient and so long-term immunoglobulin therapy is required to counteract the loss of the patient’s healthy B-Cell population which would normally produce antibodies.
Until the chronic effects of CAR-T therapy for B Cell Malignancies are addressed, it is unlikely that these therapies will be used as frontline standard of care for newly diagnosed patients but will be reserved for patients whose illness has progressed to a refectory state and untreatable with traditional chemotherapeutic agents.