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Nat Med. 2019 Jun;25(6):947-953. doi: 10.1038/s41591-019-0421-7. Epub 2019 Apr 22.

A safe and potent anti-CD19 CAR T cell therapy.

Author information

1
Key Laboratory of Carcinogenesis and Translational Research, Departments of Lymphoma, Radiology and Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China.
2
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
3
Marino Biotechnology Corp., Beijing, China.
4
Key Laboratory of Carcinogenesis and Translational Research, Departments of Lymphoma, Radiology and Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China. zhujun@csco.org.cn.
5
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. siyichen@usc.edu.

Abstract

Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. Here we generated a new anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. We found that CD19-BBz(86) CAR T cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T cells, although they retained potent cytolytic activity. We performed a phase 1 trial of CD19-BBz(86) CAR T cell therapy in patients with B cell lymphoma (ClinicalTrials.gov identifier NCT02842138 ). Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 2 × 108-4 × 108 CD19-BBz(86) CAR T cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. No significant elevation in serum cytokine levels after CAR T cell infusion was detected in the patients treated, including in those who achieved complete remission. CD19-BBz(86) CAR T cells persistently proliferated and differentiated into memory cells in vivo. Thus, therapy with the new CD19-BBz(86) CAR T cells produces a potent and durable antilymphoma response without causing neurotoxicity or severe CRS, representing a safe and potent anti-CD19 CAR T cell therapy.

PMID:
31011207
DOI:
10.1038/s41591-019-0421-7
[Indexed for MEDLINE]

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