期刊
CLINICAL CANCER RESEARCH
卷 25, 期 23, 页码 6995-7003出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-19-0101
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资金
- National Natural Science Foundation of China [81520108003, 81830007, 81600155, 81670716]
- National Key Research and Development Program of China [2016YFC0902800]
- Chang Jiang Scholars Program
- Shanghai Commission of Science and Technology [16JC1405800]
- Shanghai Rising-Star Program [19QA145600]
- Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai [2017YQ075]
- Shanghai Municipal Education Commission Gaofeng Clinical Medicine [20152206, 20152208]
- Clinical Research Plan of SHDC [16CR2017A]
- Shanghai Jiao Tong University School of Medicine [DLY201601]
- Collaborative Innovation Center of Systems Biomedicine
- Samuel Waxman Cancer Research Foundation
Purpose: Anti-CD19 chimeric antigen receptor (CAR) T cells represent a novel immunotherapy and are highly effective in treating relapsed/refractory B-cell non-Hodgkin's lymphoma (B-NHL). How tumor microenvironment influences clinical response to CAR T therapy remains of great interest. Patients and Methods: A phase I, first-in-human, dose-escalation study of anti-CD19 JWCAR029 was conducted in refractory B-NHL (NCT03355859) and 10 patients received CAR T cells at an escalating dose of 2.5 x 10(7) (n = 3), 5 x 10(7) (n = 4), and 1 x 10(8) (n = 3) cells. Core needle biopsy was performed on tumor samples collected from diffuse large B-cell lymphoma patients on Day -6 (1 day before lymphodepletion) and on Day 11 after CAR T-cell infusion when adequate CAR T-cell expansion was detected. Results: The overall response rate was 100%, with 6 of 9 (66.7%) evaluable patients achieving complete remission. The most common adverse events of grade 3 or higher were neutropenia (10/10, 100%), anemia (3/10, 30%), thrombocytopenia (3/10, 30%), and hypofibrinogenemia (2/10, 20%). Grade 1 cytokine release syndrome occurred in all patients and grade 3 neurotoxicity in 1 patient. The average peak levels of peripheral blood CAR T cells and cytokines were similar in 3 different dose levels, but CAR T cells were significantly higher in patients achieved complete remission on Day 29. Meanwhile, RNA sequencing identified gene expression signatures differentially enriched in complete and partial remission patients. Increased tumor-associated macrophage infiltration was negatively associated with remission status. Conclusions: JWCAR029 was effective and safe in treating refractory B-NHL. The composition of the tumor microenvironment has a potential impact in CAR T therapy response.
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