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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Study Details
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.
Key Findings
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.
