CD19 CAR T cells for adults with relapsed or refractory acute lymphoblastic leukaemia

CD19-directed chimeric antigen receptor (CAR) T cells first showed potency in adults with chronic lymphocytic leukaemia 1 Porter DL Levine BL Kalos M Bagg A June CH Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011; 365: 725-733 Crossref PubMed Scopus (2417) Google Scholar and with acute lymphoblastic leukaemia 2 Brentjens RJ Davila ML Riviere I et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013; 5177ra38 Crossref PubMed Scopus (1390) Google Scholar 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. 3 Porter DL Hwang WT Frey NV et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015; 7303ra139 Crossref PubMed Scopus (1024) Google Scholar , 4 Frey NV Gill S Hexner EO et al. Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified T cells in relapsed chronic lymphocytic leukemia. J Clin Oncol. 2020; 38: 2862-2871 Crossref PubMed Scopus (36) Google Scholar In adults with acute lymphoblastic leukaemia, severe toxic effects led to delays in order to test modified dosing strategies, 5 Frey NV Shaw PA Hexner EO et al. Optimizing chimeric antigen receptor T-cell therapy for adults with acute lymphoblastic leukemia. J Clin Oncol. 2020; 38: 415-422 Crossref PubMed Scopus (65) Google Scholar or even complete halting of trials. 6 Cancer DiscoveryJCAR015 in ALL: a root-cause investigation. Cancer Discov. 2018; 8: 4-5 Google Scholar 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. 6 Cancer DiscoveryJCAR015 in ALL: a root-cause investigation. Cancer Discov. 2018; 8: 4-5 Google Scholar 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, 7 Grupp SA Kalos M Barrett D et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013; 368: 1509-1518 Crossref PubMed Scopus (2268) Google Scholar 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). 8 Maude SL Laetsch TW Buechner J et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018; 378: 439-448 Crossref PubMed Scopus (1950) Google Scholar 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). KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 studyKTE-X19 showed a high rate of complete remission or complete remission with incomplete haematological recovery in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia, with the median overall survival not reached in responding patients, and a manageable safety profile. These findings indicate that KTE-X19 has the potential to confer long-term clinical benefit to these patients. Full-Text PDF