In a phase I trial (ALLCAR19) reported in the Journal of Clinical Oncology, Roddie et al found that the fast off-rate autologous CD19 chimeric antigen receptor (CAR) T-cell therapy CAT19-41BB-Z—also known as AUTO1—was well tolerated and produced high remission rates in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
As stated by the investigators, “The CD19-targeting single-chain variable fragment (scFv) in CAT19-41BB-Z has a lower affinity for CD19 than FMC63, the scFv used in all currently licensed CD19 CAR-T products…. The affinity of an scFv binding its target is determined by its binding on and off rates. The reduced affinity of CAT19-41BB-Z to CD19 is due to a fast off rate, which imparts rapid dissociation from CD19. We hypothesized that the subsequent shorter cell-cell contact may be advantageous by reducing cytokine release and thereby reducing toxicity, as well as reducing T-cell exhaustion, which may enhance CAR T-cell persistence.”
In the multicenter trial, 25 patients underwent leukapheresis, 24 CAR T products were manufactured, and 20 patients underwent AUTO1 treatment. Among the four not receiving treatment, one developed CD19-negative relapse following blinatumomab bridging, one developed graft-vs-host disease, and two died from infection in the setting of progressive refractory B-cell ALL. Among the 20 treated patients, treatment consisted of an initial infusion of 10 x 106 CAR T cells among those with bone marrow blasts > 20% and 100 x 106 CAR T cells in those with blasts ≤ 20%; in the absence of grade 3 or 4 cytokine-release syndrome or immune effector cell–associated neurotoxicity syndrome (ICANS)/grade 1 or 2 ICANS not fully resolved, a second dose was given 9 days later at 400 x 106 and 310 x 106 CAR T cells, respectively (total dose of 410 x 106 CAR T cells).
Among the 20 treated patients, the median age was 41.5 years, 25% had received prior treatment with blinatumomab, 50% had received prior treatment with inotuzumab ozogamicin, 65% had underwent prior allogeneic stem cell transplantation, and 45% had ≥ 50% blasts at time of preconditioning.
Cytokine-release syndrome occurred in 11 patients (45%, all grade 1–2). Any-grade ICANS occurred in four patients (20%); three had grade 3 ICANS that resolved to ≤ grade 1 within 72 hours with steroid treatment. At day 28, grade ≥ 3 cytopenias consisted of neutropenia in 9 (50%) of 18 patients and thrombocytopenia in 10 (56%). Grade 1 to 3 infection occurred in 8 (40%) of 20 patients, grade 4 in 9 (45%), and grade 5 in 3 (15%). No graft-vs-host disease was observed.
Of the 20 patients, 17 (85%, 95% confidence interval [CI] = 62.1%–96.7%) achieved measurable residual disease (MRD)-negative (< 1 x 10-4) complete response at 1 month, with 14 (70%, 95% CI = 45.7%–88.1%) having ongoing MRD-negative complete response at 3 months. Three patients underwent allogeneic stem cell transplantation while in remission. Event-free survival at 6, 12, and 24 months was 68.3%, 48.3%, and 48.3%; overall survival at 6, 12, and 24 months was 69.1%, 63.8%, and 58%.
The mean peak CAR T concentration was 127,152 copies/µg genomic DNA (range = 15,201–672,711 copies/µg genomic DNA) at a median of 13 days (range = 7–21 days) after treatment. Persistence of CAR T cells in peripheral blood was observed at a median of 166.5 days (range = 16–735 days) and B-cell aplasia was ongoing in 15 of 20 patients at last follow-up.
The investigators concluded, “AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in relapsed or refractory adult [B-cell ALL]. Preliminary data support further development of AUTO1 as a stand-alone treatment for relapsed or refractory adult [B-cell ALL].”
Martin A. Pule, MD, PhD, of the Cancer Institute, University College London, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the UK National Institute for Health Research, Cancer Research UK, and others. For full disclosures of the study authors, visit ascopubs.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.