Safety and efficacy of IL-6 knockdown anti-CD19 CAR-T cells (ssCART-19) in the treatment of primary/secondary central nervous system lymphoma

Abstract Background Although several CD19-targeting CAR-T cell therapies have been approved for the treatment of relapsed/refractory B-cell lymphomas, the risk of immune effector cell-associated neurotoxicity syndrome (ICANS) during treatment has led to the exclusion of patients with central nervous system involvement (CNSL) from the vast majority of clinical trials. This has created a therapeutic dilemma for patients with primary or secondary CNS lymphoma, who currently lack safe and effective CAR-T treatment options. In this study, we evaluated ssCART-19, an IL-6 knockdown “safety-enhanced” CAR-T cell product designed to mitigate neurotoxicity risks. As the first clinical assessment of ssCART-19 therapy specifically for CNSL patients, this study focuses on investigating the safety profile and preliminary efficacy of ssCART-19. Methods This open-label, multicenter investigator-initiated trial (NCT07093073) is the first study to assess ssCART-19 therapy for CNS lymphoma. After lymphodepleting chemotherapy, ssCART-19 was infused intravenously at doses ranging from 7.7×106 to 1.0×107 CAR-T cells/Kg.The primary endpoint was to assess the safety and preliminary efficacy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. Efficacy was assessed according to Lugano 2014 criteria and International PCNSL Collaborative Group (IPCG) criteria. Secondary endpoints included pharmacodynamics and pharmacokinetic evaluation. Results From August 19, 2024, to July 30, 2025, 14 patients with primary/secondary CNS lymphoma received ssCART-19 treatment. The median age was 61 years (range: 20-70), and 86% (12/14) were female. One patient (7%) had high-grade B-cell lymphoma (HGBL), one (7%) had Burkitt lymphoma (BL), and the remaining 12 (86%) had diffuse large B-cell lymphoma (DLBCL). 57% (8/14) had primary CNS lymphoma (PCNSL), while 43% (6/14) had secondary CNS lymphoma (SCNSL). Germinal center B-cell (GCB) and non-GCB subtypes each accounted for 50%. 64% (9/14) had Ki-67 75%, 29% (4/14) were double-expressor, 7% (1/14) had MYC rearrangement, and 21% (3/14) had TP53 mutations. 71% (10/14) of patients had an ECOG performance status of 1, while 14% (2/14) had a score of 2 and another 14% (2/14) had a score of 3. The median prior lines of therapy were 2 (range: 1-5), with 29% (4/14) receiving ≥3 lines. One patient (7%) had undergone autologous stem cell transplantation. All patients had CNS involvement with extranodal disease, and 14% (2/14) had ≥ 2 extranodal lesions. During ssCART-19 manufacturing, 93% (13/14) received bridging therapy, including radiotherapy (57%, 8/14) and chemotherapy (36%, 5/14). At enrollment, 71% (10/14) were relapsed, and 29% (4/14) were refractory. After ssCART-19 infusion, 57% (8/14) developed CRS, with 7% (1/14) of grade 3. 14% (2/14) experienced ICANS, both grade 1, with no grade ≥3 ICANS observed. 2 patients received tocilizumab, and 3 received steroids treatment. No CAR-T-related deaths occurred. The best overall response rate (BOR) was 93% (13/14), with 57% (8/14) achieving complete remission (CR) and 36% (5/14) partial remission (PR). Among the 8 PCNSL patients, the BOR was 100% (8/8), with 62% (5/8) CR and 38% (3/8) PR. Notably, a representative case involved a 27-year-old female with high-risk refractory right breast Burkitt lymphoma characterized by dual-expression, MYC-rearrangement, and TP53 deletion. Following multiple lines of chemotherapy and radiotherapy with subsequent CNS relapse, cerebrospinal fluid examination still revealed tumor cell infiltration three weeks post-autologous stem cell transplantation. Of particular significance, this patient had previously developed life-threatening grade 4 ICANS with blinatumomab treatment, manifesting as sudden unconsciousness and coma. Strikingly, after receiving ssCART-19 therapy, the case only experienced grade 2 CRS without any ICANS occurrence, demonstrating the favorable safety profile of ssCART-19 even in CNS lymphoma patients with prior severe ICANS history. The median Tmaxwas 10 days (range: 7-14), median Cmax was 71,300 copies/μg DNA (range: 1,870-532,000), and median AUC0-28was 346,391 (range: 18,091-1,750,222). Conclusion ssCART-19 demonstrated excellent safety and high response rates in CNSL patients, offering a promising new treatment option for primary/secondary CNS lymphoma. Additionally, radiotherapy may serve as an effective bridging strategy for CNS lymphoma.