A durable 4-1BB-based CD19 CAR-T cell for treatment of relapsed or refractory non-Hodgkin lymphoma

Zhitao Ying; Ting He; Shanzhao Jin; Xiaopei Wang; Wen Zheng; Ningjing Lin; Meifeng Tu; Yan Xie; Lingyan Ping; Weiping Liu; Lijuan Deng; Yanping Ding; Xuelian Hu; Bing Bu; Xin'an Lu; Yuqin Song; Jun Zhu

doi:10.21147/j.issn.1000-9604.2022.01.05

A durable 4-1BB-based CD19 CAR-T cell for treatment of relapsed or refractory non-Hodgkin lymphoma

Chin J Cancer Res. 2022 Feb 28;34(1):53-62. doi: 10.21147/j.issn.1000-9604.2022.01.05.

Authors

Zhitao Ying¹, Ting He², Shanzhao Jin², Xiaopei Wang¹, Wen Zheng¹, Ningjing Lin¹, Meifeng Tu¹, Yan Xie¹, Lingyan Ping¹, Weiping Liu¹, Lijuan Deng¹, Yanping Ding², Xuelian Hu², Bing Bu³, Xin'an Lu², Yuqin Song¹, Jun Zhu¹

Affiliations

¹ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing 100042, China.
² Beijing Immunochina Pharmaceuticals Co., Ltd., Beijing 100195, China.
³ Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China.

PMID: 35355931
PMCID: PMC8913256
DOI: 10.21147/j.issn.1000-9604.2022.01.05

Abstract

Objective: Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor (CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells, especially the lower incidence rate of severe adverse events. However, the median progression-free survival (mPFS) of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta (2.9 monthsvs. 5.9 months), suggesting that Kymriah was limited in the long-term efficacy. Thus, a safe and durable 4-1BB-based CD19 CAR-T needs to be developed.

Methods: We designed a CD19-targeted CAR-T (named as IM19) which consisted of an FMC63 scFv, 4-1BB and CD3ζ intracellular domain and was manufactured into a memory T-enriched formulation. A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory (r/r) B cell non-Hodgkin lymphoma (B-NHL). Dose-escalation investigation (at a dose of 5×10⁵/kg, 1×10⁶/kg and 3×10⁶/kg) was performed in 22 r/r B-NHL patients. All patients received a single infusion of IM19 after 3-day conditional regimen.

Results: At month 3, the overall response rate (ORR) was 59.1%, the complete response rate (CRR) was 50.0%. The mPFS was 6 months and the 1-year overall survival rate was 77.8%. Cytokine release syndrome (CRS) occurred in 13 patients (59.1%), with 54.5% of grade 1-2 CRS. Only one patient (4.5%) experienced grade 3 CRS and grade 3 neurotoxicity.

Conclusions: These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T, IM19, which is promising for further development and clinical investigation.

Keywords: 4-1BB; CD19 CAR-T; durable efficacy; safety.