LY007, a Novel Anti-CD20 CAR-T Cell Therapy for Relapsed or Refractory B Cell Non-Hodgkin Lymphoma (R/R B-NHL): Results from a Phase 1 Study
Year: 2024
Type: conference-abstract
Abstract: Introduction Despite the improvements in relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) therapies, more than 60% of patients (pts) with diffuse large B cell lymphoma (DLBCL) eventually progress or relapse following CD19-CAR-T therapy, especially those with a heavy tumor burden. Novel approaches are critically needed for R/R B-NHL pts. LY007 is a novel CD20-targeting CAR-T cell therapy, in which inclusion of OX40 co-stimulation for enhancing CAR proliferation, persistence and anti-tumor response, showed promising safety and efficacy in dose-escalation part of on-going phase 1 study in 9 pts with R/R B-NHL. Here, we present updated data from the finished dose-escalation and dose-expansion parts of 12 pts in the study. Methods In this phase 1 study, eligible pts with CD20-positive R/R B-NHL received lymphodepletion with fludarabine (30 mg/m2 Day -5 to -3) and cyclophosphamide (300 mg/m2 Day -5 to -3) before a single CAR-T cell infusion. Pts were allowed bridging radiotherapy, if needed, prior to lymphodepletion. LY007 was infused at doses of 0.5, 1.5, and 5.0 × 106 cells/ kg in the dose-escalation part in “3+3” module and additional pts received 5.0 × 106 cells/ kg in the dose-expansion part. The primary objectives were to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D), safety and tolerability, pharmacokinetics (PK), and preliminary clinical efficacy of LY007. Results As of June 25, 2024, 12 pts received a single infusion of LY007 at doses of 0.5 (n = 3), 1.5 (n = 4), 5.0 (n = 5) × 106 cells/ kg with a median age of 65 years (range, 37 to 69), of which 5 (42%) were ≥65 years. 10 pts (83%) had extranodal involvement, 8 pts (67%) had an International Prognostic Index (IPI) score of ≥2, 5 pts (42%) had a maximum tumor length of ≥ 5 cm, including 2 pts (17%) had a maximum tumor length of >8 cm. Among all, 5 pts (42%) had received three prior lines of therapy and 3 pts (25%) were refractory to prior lines of therapy, including 1 pt (8%) who received prior CD19-directed CAR T-cell therapy and autologous stem-cell transplantation (ASCT). Ten pts (87%) had ≥50% Ki67 expression, and 1 pts (8%) had MYC, BCL2 and/or BCL6 rearrangements. The best overall response rate (ORR) was 92% (11/12) among all enrolled study participants, with 100% (5/5) in 5.0 × 106 cells/ kg and pts aged ≥ 65 years, respectively. Best complete response (CR) rate was 67% (8/12). The ORR was 75% (9/12) at day 28 and 73% (8/11) at month 3, with 100% (5/5) and 75% (3/4) in 5.0 × 106 cells/ kg at day 28 and month 3, respectively. The CR rate was 42% (5/12) at day 28 and 55% (6/11) at month 3. Encouragingly, 1 pt treated with prior CD19-directed CAR T-cell therapy and ASCT, and 1 pt with MYC, BCL2 and/or BCL6 rearrangements achieved CR at month 3. Median duration of response (DoR), median progression-free survival (PFS) and median overall survival (OS) had not been reached with a median follow-up of 7.2 months (range, 2.8-11.6). By the data cutoff, 58% of responses (7/12) were ongoing, with 58% of responses (7/12) lasting > 3 months and 1 pt still CR at 24 months. Pts at all 3 dose levels had good CAR-T expansion and long-term persistence, especially in the DL3 cohort, with a median peak of CAR-T cells in the peripheral blood of 43,200 copies/μg (range, 25,000-173,000) DNA and a median peak time of day 11 (range 11-18 day). The highest mean cell copy number was achieved on day 11 and was still detectable at day 264 in the DL2 cohort. No dose-limiting toxicities (DLTs) were observed, no immune effector cell-associated neurotoxicity syndrome (ICANS) or Grade (G) 3+ cytokine release syndrome (CRS) was reported even with increasing dose levels. G3+ treatment-emergent adverse events (TEAEs) occurred in 12 (100%) pts without severe infectious events and G1/2 CRS occurred in 9 (75%) pts. No Grade 3+ hypogammaglobulinemia was observed and 3 pts (25%) experienced Grade 1/2 hypogammaglobulinemia related to LY007. Conclusions In this phase 1 study, LY007 was well tolerated at the dose levels up to 5.0 × 106 cells/kg with no DLTs or ICANS observed and the RP2D was recommended as 5.0 × 106 cells/kg. LY007 showed a favorable safety profile, promising efficacy and good PK characteristics at all tested dose levels with 92% best ORR including pts with a high tumor burden, such as extranodal involvement, maximum tumor length of ≥5 cm, aged ≥ 65 years and prior CD19-directed CAR T therapy and ASCT. Follow-up of enrolled pts is on-going and the planned phase 2 study will start for enrollment shortly.
Source: Blood
Authors: Lingshuang Sheng, Zixun Yan, Li Wang, Wen Wu, Yilun Zhang, Rong Shen, Weiguo Cao, Lei Li, Sheng Chen, Xufeng Jiang, Hongmei Yi, Qi Song, Li Wang, Shu Cheng, Pengpeng Xu, Xuanming Yang, Yuxiang Zhu, Xikang Xu, Fuzhe Wang, Jianyong Li, Wei Li Zhao
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4405039363