7027 Background: Approved chimeric antigen receptor (CAR) T cell therapies targeting CD19 with a single co-stimulatory domain in the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL) may face challenges including drug resistance and disease recurrence. This Phase 1 study was conducted to evaluate the safety and tolerability of LY007, a novel CD20-targeting CAR-T cell containing both OX40 and 4-1BB co-stimulatory domains to enhance CAR-T cell proliferation and anti-cancer cytotoxicity, for the treatment of r/r B-NHL pts. Methods: In this open-label, single-arm phase 1 trial, r/r B-NHL pts were infused with LY007 in 3 dose levels (DLs) (DL1, 0.5 x 10 6 cells/ kg; DL2, 1.5 x 10 6 cells/ kg; DL3, 5.0 x 10 6 cells/ kg) based on a standard 3+3 dose escalation design after cyclophosphamide/fludarabine lymphodepletion. The main objectives were to determine the safety and tolerability, pharmacokinetics, and preliminary efficacy of LY007. The key eligibility criteria included pts with cytologically or histologically confirmed CD20 positive r/r B-NHL according to WHO 2016 including diffuse large B cell lymphoma (DLBCL) and transformed follicular lymphoma (TFL). Results: As of December 25th, 2023, 9 pts were treated with single LY007 infusions at 3 dose levels with a median follow-up of 5.09 (range 0.92-18.10) months. The median age of treated pts was 65 years (range, 44 to 69), and 44% (4/9) of pts had received three prior lines of therapy. Their B-NHL subtypes were all DLBCL. Among the treated pts, 78% (7/9) relapsed after prior lines of treatment, 89% (8/9) had extranodal involvement, 78% (7/9) had an International Prognostic Index (IPI) score of ≥ 2, and 44% (4/9) had a maximum tumor length of ≥ 5 cm. The overall response rate (ORR) and complete response (CR) were 67% (6/9) and 33% (3/9) at day28, 83% (5/6), and 67% (4/6) at month 3 of the pts evaluable for efficacy. Among all study participants, the best reported ORR was 89% (8/9). The longest duration of remission was 12.3 months to date. The overall survival (OS) and progression-free survival (PFS) were 100% and 88.9% at 6 months, respectively. The LY007 was generally well tolerated. No dose-limiting toxicities (DLTs) were observed. And no immune effector cell-associated neurotoxicity syndrome (ICANS) or G3+ cytokine release syndrome (CRS) was reported. The most common G3+ AEs were lymphopenia (9/9), leukopenia (9/9), and neutropenia (7/9). No pts discontinued, withdrew, or died due to AE. 6 pts experienced G1/2 CRS. Pts at all 3 dose levels had good CAR-T expansion and long-term persistence, particularly in the LD3 cohort, where the highest mean cell copy number of 93,750 copies/μg DNA was achieved at day 11 and was still detectable to date. Conclusions: This phase 1 trial demonstrated that LY007 was well tolerated at the dose levels up to 5.0 x 10 6 cells/ kg and showed a favorable dose-response relationship for the treatment of r/r B-NHL. Clinical trial information: NCT06279611.