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

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.