Safety and efficacy of a novel anti-CD20/CD19 bi-specific CAR T-cell therapy (C-CAR039) in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL).
Authors: Liang Aibin , Zhou Lili , Li Ping , Yu Wenjuan , Yang Min , Xu Yangyang , Ye Shiguang , Zhu Judy , Huang Jiaqi , Zhang Yan , Li Lanfang , Zhao Jing , Li Jing , Zheng Chengxiao , Zhu Kevin , Lan Liping , Zhang Huilai , Zhou Daobin , Yao Yihong , Jin Jie 
Published: June 2021

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Background: C-CAR039 has been developed as a novel 2nd generation 4-1BB bi-specific CAR-T targeting both CD19 and CD20 antigens with an optimized bi-specific antigen binding domain. C-CAR039 can eradicate CD19/CD20 single or double positive tumor cells in vitro and in vivo. The tissue cross reactivity and whole genome membrane proteome array studies further confirmed the specificity of C-CAR039. Methods: GMP manufacturing of C-CAR039 was carried out in a serum free and fully closed semi-automatic system. Dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen. Results: As of 1/31/2021, 28 patients were infused and 25 (DLBCL, n = 22; PMBCL, n = 1; tFL, n = 1; FL, n = 1) were evaluable for safety and efficacy at dose ranges of 1.0 x 106 to 5.0x106 CAR-T cells/kg. The median age was 54 (range, 28-71) years, median number of prior lines of therapy was 3 (range, 1–5), 76% (19/25) of patients were in Ann Arbor Stage III/IV, and 80% (20/25) were refractory to their last treatment. 5 patients (20%) received bridging therapy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. Of the 25 patients, 24 (96%) experienced CRS, 23 (92%) were grade 1 or 2, 1 patient was grade 3. Median time to onset of CRS was 3 days (range, 0-10), with median duration of 4 days (range, 1-25). 2 patients had a grade 1 ICANS. Grade≥3 neutropenia, anemia, thrombocytopenia and infection were reported in 88%, 40%, 16% and 0% of patients, respectively. The best overall response rate was 92%, complete response (CR) rate was 84% and median time to response was 1.0 month (range, 0.9-1.2). With a median follow-up of 5.3 months, 76% remained in CR. Kaplan Meyer estimation of PFS at 6 months was 87.3% (95% CI, 71.2 to 100.0). Median duration of response has not been reached. Furthermore, C-CAR039 showed an encouraging cellular kinetic profile. In 25 evaluable patients, the median Tmax was 11 day, the median Cmax was 139,497 copies/mg gDNA, and the median AUC0̃28DAY of 1,673,844 day*copies/μg gDNA. Conclusions: C-CAR039 demonstrated a favorable safety profile and promising efficacy in this early clinical trial in patients with r/r B-NHL that might allow it to differentiate from existing therapies. The early clinical efficacy signal is encouraging and compares favorably to anti-CD19 CAR-T and peer therapies. These findings will be evaluated in more patients with longer follow-up to confirm safety, efficacy and duration of response. Clinical trial information: NCT04317885 , NCT04655677 , NCT04696432 , NCT04693676 .