1. Chimeric antigen receptor-modified T cells directed against CD19 in patients with relapsed or refractory CD19-positive B-cell lymphomas: interim analysis of a phase 1 study.
- Author
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Ying, Zhitao, Xiang, Xiaoyu, Song, Yuqin, Ding, Ning, Lin, Yufu, Zheng, Wen, Wang, Xiaopei, Lin, Ningjing, Tu, Meifeng, Xie, Yan, Zhang, Chen, Liu, Weiping, Deng, Lijuan, Liu, Yanling, Yue, Yunqiang, Yu, Xueyun, Liu, Hanzhi, Duan, Panpan, Mamuti, Mierzhati, and Guo, Xiaokai
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LYMPHOMA treatment , *CHIMERIC antigen receptors , *T cells , *B cell lymphoma , *CD19 antigen , *CANCER relapse - Abstract
Background Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have poor outcomes with the available strategies. Based on the promising results seen in patients treated with anti-CD19 CAR T-cell therapy in relapsed or refractory B-cell non-Hodgkin lymphoma, we initiated a phase 1 study to evaluate the safety and efficacy in patients. Autologous T cells were genetically modified to express a chimeric antigen receptor consisting of an anti-CD19-scFv domain with CD3ζ and 4–1BB signalling domains. Methods We did this phase 1 study in patients with relapsed or refractory B-cell non-Hodgkin lymphoma in Peking University Cancer Hospital, Beijing, China. Patients received a CAR T-cell infusion after a conditioning regimen of cyclophosphamide (250 mg/m 2 ) and fludarabine (25 mg/m 2 ) daily for 3 days. Three CAR T cell doses were tested: 5 × 10 4 CAR T cells/kg, 1 × 10 5 CAR T cells/kg, and 1 × 10 6 CAR T cells/kg. Primary endpoints included safety and pharmacokinetics of CAR T cells. Secondary endpoints include complete response, overall response, and duration of response per International Working Group Criteria. This trial is registered at ClinicalTrials, number NCT02842138 . Findings As of March 2017, 14 patients were enrolled and ten patients, with a median age of 37 years (range 24–68) underwent response evaluation. Of the ten evaluable patients, four were women, six were men, three had follicular lymphoma, and seven had diffuse large B-cell lymphoma. The median number of previous therapies was 2·5 (range 2–7). The first group of three patients (two with follicular lymphoma and one with diffuse large B-cell lymphoma) received 5 × 10 4 CAR T cells/kg. Two patients with follicular lymphoma achieved partial remission on day 28, and one of these patients achieved complete remission 3 months later. The second group of three patients (one with follicular lymphoma and two with diffuse large B-cell lymphoma) received 1 × 10 5 CAR T cells/kg. The patient with follicular lymphoma achieved partial remission on day 28. The last group of four patients (all were diagnosed with diffuse large B-cell lymphoma) received 1 × 10 6 CAR T cells/kg. Three patients (75%) achieved partial remission on day 28. One patient attained progressive disease on day 28, and died 10 days later due to disease progression. A significant CAR T-cell expansion was detected in this case. On day 26, 26·8% of the patient's peripheral blood mononuclear cells were CAR T cells. PD1 expression was significant in her expanded CAR T cells. 78·3% of CD8-positive CAR T cells and 71·4% of CD4-positive CAR T cells expressed PD1 on day 26, as compared with 22% and 42% on day 13, respectively in the same patient. Increased PD1-expressing CAR T cells were also found in other patients' peripheral blood. No serious adverse event was observed in any patient. Two patients had mild fever (grade 1–2). In-vivo expansion of CAR T cells was detected in all patients between day 14–28. All responding patients were still in remission at the last follow-up (range 2·5–9·0 months). Interpretation This study demonstrated early promising activity of anti-CD19 CAR T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. The toxicities of cytokine release syndrome were mild and manageable. Our study also provided the first clinical evidence that expanded CAR T cells could express PD1. Blocking PD1 pathway might enhance the effector function of CAR T cells and improve the clinical outcomes of CAR T-cell therapy. Funding Marino Biotechnology Co, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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