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

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.