Safety and feasibility of anti-CD19 CAR T cells with fully-human binding domains in patients with B-cell lymphoma

Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are effective treatment for B-cell lymphoma but often cause neurologic toxicity. We treated 20 patients with B-cell lymphoma on a phase I, first-in-humans clinical trial of T cells expressing the novel anti-CD19 CAR Hu19-CD828Z (NCT02659943). The primary objective was to assess safety and feasibility of Hu19-CD828Z T-cell therapy. Secondary objectives included assessments of CAR T-cell blood levels, anti-lymphoma activity, second infusions, and immunogenicity. All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z T cells obtained complete remissions. Hu19-CD828Z T cells had similar clinical anti-lymphoma activity as T cells expressing FMC63–28Z, an anti-CD19 CAR tested previously by our group that contains murine binding domains and is used in axicabtagene ciloleucel. However, severe neurologic toxicity occurred in only 5% of patients who received Hu19-CD828Z T cells versus 50% of patients who received FMC63–28Z T cells (P=0.0017). T cells expressing Hu19-CD828Z released lower levels of cytokines than T cells expressing FMC63–28Z. Lower levels of cytokines were detected in blood of patients receiving Hu19-CD828Z T cells versus FMC63–28Z T cells, which could explain the lower level of neurologic toxicity with Hu19-CD828Z. Levels of cytokines released by CAR-expressing T cells particularly depended on the hinge and transmembrane domains included in the CAR design.