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.”
Study Details
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.
KEY POINTS
- No grade ≥ 3 cytokine-release syndrome was observed.
- MRD-negative complete response was observed in 85% of patients.
Toxicity
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.
Responses
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.
