Background: T cells expressing chimeric antigen receptors (CARs) targeting CD19 have powerful activity against B-cell lymphoma. A limitation to CAR T-cell therapy for lymphoma is occurrence of toxicities, especially neurologic toxicities. Methods: We designed an anti-CD19 CAR with fully human variable regions (Hu19CAR). This CAR has CD8α hinge and transmembrane domains and a CD28 costimulatory domain; T cells expressing this CAR release relatively low levels of cytokines. A phase I dose-escalation trial was conducted to investigate the safety of Hu19CAR T cells and to assess efficacy for patients with previously treated B-cell lymphoma. Patients received cyclophosphamide and fludarabine chemotherapy to enhance CAR T-cell activity. Two days after the completion of chemotherapy, Hu19CAR T cells were infused. Results: Twenty patients have received Hu19CAR T-cell infusions. Of these patients, 75% had lymphoma that was chemotherapy-refractory or relapsed after autologous stem cell transplant. Patients received a median of 4 prior lines of therapy. The overall response rate is 75%, with 55% complete remissions (CRs). CRs were observed in patients with chemotherapy-refractory lymphomas and in patients with double-hit diffuse large B-cell lymphoma. Durations of response currently range from 1 to 17 months. Forty percent of patients are in ongoing remissions. Only one patient experienced greater than Grade 2 neurotoxicity (5%), which is a neurotoxicity rate lower than that of many anti-CD19 CAR trials. This patient had Grade 4 neurotoxicity which reversed in less than 24 hours with corticosteroid therapy. Three patients had Grade 3 cytokine release syndrome (CRS), and 1 patient had Grade 4 CRS; all other patients had Grade 2 or lower CRS. CRS and neurotoxicities resolved completely in all patients. Loss of CD19 expression by lymphoma cells was observed in 4 of the 8 patients who underwent biopsies of recurrent or residual lymphoma after Hu19CAR T-cell infusions. CAR T cells were detected in the blood of all patients at levels ranging from 4-2216 cells/µL. Conclusions: Hu19CAR T cells have substantial activity against advanced lymphoma with a low rate of neurotoxicity. Clinical trial information: NCT02659943