In a pilot study reported by Myers et al in the Journal of Clinical Oncology, a humanized CD19-targeted chimeric antigen receptor (CAR) T-cell product developed by the investigators (huCART19) was found to produce durable remissions and prolonged CAR T-cell persistence in CAR-naive and CAR-exposed children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
As stated by the investigators—from Children’s Hospital of Philadelphia and Perelman School of Medicine—many CARs in development contain single-chain variable fragment (scFv) domains derived from mouse monoclonal antibodies, with potential antimurine immune responses leading to rejection and poor persistence of CAR T-cells. huCART19 was developed with a humanized anti-CD19 scFv domain together with a 4-1BB costimulatory domain, with the intention of avoiding antimurine immune response and prolonging persistence of CAR T cells.
HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-cell ALL, including after failure of prior CAR T-cell therapy.— Myers et al
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The study included 74 patients enrolled between March 2014 and November 2018 at Children’s Hospital of Philadelphia aged 1 to 29 years with relapsed or refractory B-cell ALL (n = 72) or B-cell lymphoblastic lymphoma (n = 2); 33 patients had prior CAR exposure (retreatment cohort) and 41 had no prior CAR exposure (CAR-naive cohort). Patients received a single infusion of huCART19; the target dose for the first 48 patients was 3 × 107 cells/kg, which was changed to 6 × 106 cells/kg in the remaining 26 patients after protocol amendment.
Cytokine-release syndrome of any grade occurred in 62 patients (84%) and was grade 3 or 4 in 11. Any-grade cytokine-release syndrome occurred in 76% of patients in the retreatment cohort and 90% of those in the CAR-naive cohort. Grade 3 and 4 cytokine-release syndrome occurred in 12% and 3% of patients in the retreatment cohort, respectively, and in 5% and 10% of the CAR-naive cohort. All episodes of cytokine-release syndrome were fully resolved.
Neurologic toxicity occurred in 29 patients (39%) and was grade 3 or 4 in 3 (4%). The most common adverse event was encephalopathy (24 patients [32%]; 1 grade 3 case and 1 grade 4 case). Any-grade neurologic toxicity occurred in 36% of patients in the retreatment cohort and 41% of the CAR-naive cohort. Toxicities resolved in all cases.
At day 28 after infusion, complete remission or complete remission with incomplete count recovery was achieved in 79% of the retreatment cohort; however, five patients were considered to have no biologic response because B-cell aplasia was not established, yielding a complete remission/complete remission with incomplete count recovery rate of 64%. Complete remission/complete remission with incomplete count recovery was achieved in 98% of the CAR-naive cohort, including in all 39 patients (100%) with B-cell ALL.
At 6 months, huCART19 T cell persistence was lost in 48% of patients in the retreatment cohort and 27% of the CAR-naive cohort. B-cell recovery was observed in 58% and 15%, respectively.
Relapse-free survival at 12 and 24 months was 74% and 58% in the retreatment cohort and 84% and 74% in the CAR-naive cohort.
The investigators concluded, “HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-cell ALL, including after failure of prior CAR T-cell therapy.”
Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by a clinical trial award funded by a research alliance between the University of Pennsylvania and Novartis Pharmaceuticals and the Children’s Hospital of Philadelphia Frontier Program. 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®.