Safety and efficacy of low-dose, cord blood-derived CD19 CAR-NK cells with 4-1BB co-stimulation in refractory systemic lupus erythematosus.

Zhiru Zeng W. Lei Wenhai Deng Mo Chen Weihong Xu Liang Zhu Jing Xue Min Yuan James Q. Wang Qianzhi Ye Songzhao Zhang Qiaohong Wang Wenbin Qian Huaxiang Wu

Jul 2026 · i Medicina · pp. 101226 · 1 citation · 46 references

Medicine

TL;DR

Low-dose UCB-derived CD19-BBz CAR-NK cell therapy demonstrated an excellent safety profile and induced robust, durable clinical responses in refractory SLE.

Abstract

Background

B cell-targeting chimeric antigen receptor (CAR) T cell therapy has shown efficacy in autoimmune diseases but is limited by toxicity, complex manufacturing, and high cost. Umbilical cord blood (UCB)-derived CAR-natural killer (CAR-NK) cells offer an alternative "off-the-shelf" platform with a potentially superior safety profile. We developed a UCB-derived CD19-targeting CAR-NK product incorporating the 4-1BB costimulatory domain (CD19-BBz) and evaluated its safety and efficacy in refractory systemic lupus erythematosus (SLE). This study was registered at ClinicalTrials.gov (ClinicalTrials.gov: NCT06421701).

Methods

In this phase 1, open-label, dose-escalation study, five patients with refractory SLE received lymphodepletion chemotherapy followed by infusion of allogeneic CD19-BBz CAR-NK cells. Dosing followed a step-up regimen, with the highest total dose being 1.35 × 109 cells-2.2- to 3.3-fold lower than the highest doses previously reported for CAR-NK therapy in SLE.

Findings

Treatment was exceptionally well tolerated. No grade ≥2 cytokine release syndrome and no neurotoxicity or graft-versus-host disease occurred. All patients achieved profound B cell depletion, with nadir circulating B cell levels ranging from 0.16 to 1.44 cells/μL. All patients achieved an SLE Responder Index-4 response by month 1. The lupus low disease activity state was attained in all patients by month 9, and 80% (4/5) met the definition of remission in SLE by the last follow-up (median, 12 months). Reconstituted B cells displayed a sustained naive-dominant repertoire.

Conclusions

Low-dose UCB-derived CD19-BBz CAR-NK cell therapy demonstrated an excellent safety profile and induced robust, durable clinical responses in refractory SLE.

Funding

This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0501300).

DOI PubMed Semantic Scholar

View source

Similar papers

#gene editing Clinical trial Aug 2026

A phase 1 feasibility trial of BE-CAR33, an "off-the-shelf" base-edited CAR33 T cell therapy for acute myeloid leukemia.

This first-in-human study demonstrated the feasibility of an "off-the-shelf" base-edited CAR T cell approach and informs future multiantigen strategies against AML.

C. Georgiadis, Robert Chiesa, Hebatalla Rashed et al. · Science Translational Medici... · 0 citations

Jul 2026

Safety and clinical outcomes of a first-in-human trial of point-of-care manufactured trispecific CAR T cells targeting CD19, CD20, and CD22.

A trispecific CAR targeting CD19, CD20, and CD22 with OX40 co-stimulatory domain with overall response rate was 50%, including complete responses in 83% of lymphoma patients, and one-year overall survival rate was 61%, with durable remissions observed in lymphoma.

S. Vasu, N. Denlinger, No-Joon Song et al. · Blood Cancer Discovery · 0 citations

Jul 2026

CircRNA-based CD19-targeted CAR-NK therapy for B-cell acute lymphoblastic Leukemia using a Coccidioides immitis-derived group II intron platform.

The potential of circRNA-based CD19-targeted CAR-NK therapy as an effective approach for enhancing the safety and efficacy of cancer immunotherapy is supported.

Qisheng Dong, Ying Liu, Na Chen et al. · International Immunopharmaco... · 0 citations

Open access Jul 2026

Allogeneic CD70-Targeted Chimeric Antigen Receptor T-Cell Therapy for Advanced Renal Cell Carcinoma: Results From the Phase I TRAVERSE Trial

The TRAVERSE trial demonstrates proof of concept for the role of allogeneic CAR T-cell therapy in solid tumors and had manageable safety and encouraging antitumor activity in CD70-positive ccRCC.

S. Srour, J. Chahoud, A. Drakaki et al. · Journal of Clinical Oncology · 0 citations

Open access Jul 2026

Safety and feasibility of 5T4 antibody-coupled allogeneic NK cell therapy for solid tumors: a first-in-human phase 1 trial.

BACKGROUND Patients with unresectable locally advanced or metastatic solid tumors have limited therapeutic options. Antibody-guided allogeneic natural killer (NK) cell therapy represents a novel immunotherapeutic strategy to enhance tumor targeting and cytotoxicity by coupling NK cells with tumor-specific antibodies targeting antigens such as 5T4. OBJECTIVE To evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary efficacy of IBR854, a non-viral, non-genetically modified, 5T4 antibody-coupled allogeneic NK cell therapy, in patients with advanced solid tumors. PATIENTS AND METHODS This open-label, first-in-human phase 1 dose-escalation study enrolled 19 patients with unresectable locally advanced or metastatic solid tumors across five dose cohorts (3.0 × 109-12.0 × 109 cells per dose). Patients received intravenous IBR854 in a 3 + 3 escalation design. Safety, dose-limiting toxicities, adverse events, pharmacokinetics, anti-drug antibodies, and antitumor activity (RECIST v1.1) were assessed. RESULTS No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were elevated interleukin levels (42.1%), infusion-related reactions (31.6%), and fever (21.1%). No anti-drug antibodies were detected. The disease control rate was 43.8%. Median progression-free survival was 43 days. Pharmacokinetic analysis based on transgene copy number showed a dose-dependent prolongation of Tmax (0.867-3.433 h), with a relatively consistent half-life (1.390-2.648 h). CONCLUSIONS IBR854 demonstrated an acceptable safety and tolerability profile and achieved disease stabilization in a subset of heavily pretreated patients with advanced solid tumors. These findings support further clinical development of 5T4-targeted antibody-coupled allogeneic NK cell therapy. Trial registration This study was registered at ClinicalTrials.gov (registration number: NCT06001684).

Liangjie Sun, Peiwen Ma, Zhenwei Miao et al. · Cancer Immunology and Immuno... · 0 citations

Clinical trial Sep 2026

CD19 CAR T-cell therapy (GLPG5101) for relapsed or refractory B-cell non-Hodgkin lymphoma (ATALANTA-1): phase 1 results from a single-arm, multicentre, phase 1/2 study.

This phase 1 dose-escalation part of the ATALANTA-1 phase 1/2, single-arm study was executed in five hospitals in the Netherlands and Belgium to evaluate the safety and determine the recommended phase 2 dose of GLPG5101.

M. Kersten, M. Kuipers, P. Mutsaers et al. · The Lancet Haematology · 0 citations