A novel dose-dense strategy for CD19-directed CAR T-cell therapy is associated with durable responses without increased toxicity in patients with B-cell non-Hodgkin lymphoma

CD19-directed chimeric antigen receptor (CAR) T-cell therapy induces durable remissions in only 30-40% of patients with relapsed or refractory (R/R) B-cell non- Hodgkin lymphoma (B-NHL), highlighting a major need to improve outcomes. In dose-escalation studies, higher CAR T-cell doses improved tumor control but caused prohibitive toxicities. Having established the maximum tolerated JCAR014 dose in patients with B-NHL at 2 x 106 CAR+ cells/kg, we hypothesized that a second infusion at day 14 ("dose-dense") at the same dose and without repeat lymphodepletion, would be safe and enhance antitumor efficacy. We report outcomes from the pilot dose-dense cohort of a phase 1/2 trial (ClinicalTrials.gov identifier: NCT01865617) with 8-year follow-up. Two CAR T-cell products, each containing 2 x 106 CAR+ cells/kg, were manufactured for all 20 treated patients; 17 received both infusions. Any-grade cytokine release syndrome (CRS) and neurotoxicity (NT) occurred in 10 (59%) and 3 (18%) of dose-dense patients, respectively, and-except for one grade 2 CRS-events followed the first infusion only. Despite no additional lymphodepletion, CAR T-cell re-expansion after the second infusion occurred in 16 (94%) patients. By Lugano criteria, overall and complete response rates were 47% (8/17) and 41% (7/17), respectively. Among responders, the 8-year durationof- response rate was 63% (95% CI: 37-100), comparing favorably with the 26% (95% CI: 14-48) observed in patients treated with a single infusion. In conclusion, early redosing on day 14 was feasible, safe and led to durable responses in patients with R/R B-NHL.