Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are aneffective treatment for B-cell lymphoma, but often cause neurologic toxicity. Wetreated 20 patients with B-cell lymphoma on a phase I, first-in-human clinical trialof T cells expressing the new anti-CD19 CAR Hu19-CD828Z (NCT02659943). The primary objective was to assess safety and feasibility ofHu19-CD828Z T-cell therapy. Secondary objectives included assessments of bloodlevels of CAR T cells, anti-lymphoma activity, second infusions and immunogenicity.All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z Tcells obtained complete remission. Hu19-CD828Z T cells had clinical anti-lymphomaactivity similar to that of T cells expressing FMC63-28Z, an anti-CD19 CAR testedpreviously by our group, which contains murine binding domains and is used inaxicabtagene ciloleucel. However, severe neurologic toxicity occurred in only 5% ofpatients who received Hu19-CD828Z T cells, whereas 50% of patients who receivedFMC63-28Z T cells experienced this degree of toxicity (P = 0.0017). T cells expressing Hu19-CD828Z released lower levels ofcytokines than T cells expressing FMC63-28Z. Lower levels of cytokines were detectedin blood from patients who received Hu19-CD828Z T cells than in blood from those whoreceived FMC63-28Z T cells, which could explain the lower level of neurologictoxicity associated with Hu19-CD828Z. Levels of cytokines released by CAR-expressingT cells particularly depended on the hinge and transmembrane domains included in theCAR design.
In a first-in-human, phase I trial in patients with B-cell lymphoma,CD19 CAR T cells with fully human binding domains exhibit lower neurologic toxicity,but similar clinical activity, to previously tested CD19 CAR T cells with murinebinding domains.