CD19 CAR T cells for adults with relapsed or refractory acute lymphoblastic leukaemia
Mené sur 71 patients atteints d'une leucémie lymphoblastique aiguë à cellules B réfractaire ou récidivante, cet essai de phase II évalue l'efficacité, du point de vue du taux de rémission complète, et la toxicité de KTE-X19, une immunothérapie à base de lymphocytes CAR-T anti CD19
CD19-directed chimeric antigen receptor (CAR) T cells first showed potency in adults with chronic lymphocytic leukaemia and with acute lymphoblastic leukaemia a decade ago, but clinical development of CAR T cells in these two disease populations stalled. Chronic lymphocytic leukaemia did not respond to CAR T cells as frequently as hoped, in part because of challenges with making the product from patients whose T cells were not as fit, either due to the underlying disease or exposure to years of chemotherapy. In adults with acute lymphoblastic leukaemia, severe toxic effects led to delays in order to test modified dosing strategies, or even complete halting of trials. The toxic effects were a result of the high potency of CAR T cells, which led to remarkable cytokine elevations and permeability of the blood–brain barrier that resulted in cerebral oedema in a series of high-profile cases. Toxicity seemed to be particularly lethal with more chemotherapy lymphodepletion, with CAR T cells bearing the CD28 costimulatory signalling domain (so-called sprinter CAR T cells) or in the setting of a coincident infection, which is a fairly frequent occurrence in this patient population. Children and young adults with relapsed or refractory acute lymphoblastic leukaemia seemed to tolerate these cytokine elevations much better than adults, and the first pivotal study and approval from the US Food and Drug Administration (FDA) were secured in this population with a CAR T-cell product (tisagenlecleucel) bearing the 4-1BB costimulatory domain (so-called marathoner CAR T cells). The FDA has since approved both CD28-bearing and 4-1BB-bearing CAR T cells targeting the CD19 antigen for adults with large-cell lymphoma (CD28-bearing: axicabtagene cilolecuel; 4-1BB-bearing: tisagenlecleucel and lisocabtagene maraleucel), mantle cell lymphoma (CD28-bearing: brexucabtagene autoleucel), and follicular lymphoma (CD28-bearing: axicabtagene cilolecuel).
The Lancet 2021