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Nat Med ; 25(6): 947-953, 2019 06.
Article in English | MEDLINE | ID: mdl-31011207

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.


Subject(s)
Antigens, CD19/immunology , Immunotherapy, Adoptive/methods , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/therapy , Receptors, Chimeric Antigen/immunology , Adult , Aged , Antigens, CD19/genetics , Cytokines/blood , Female , Humans , Immunotherapy, Adoptive/adverse effects , Lymphoma, B-Cell/diagnostic imaging , Male , Middle Aged , Positron Emission Tomography Computed Tomography , Remission Induction , T-Lymphocytes/immunology , Treatment Outcome , Young Adult
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