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

• Published in: Nature medicine Vol. 26; no. 2; pp. 270 - 280
• Main Authors: Brudno, Jennifer N, Lam, Norris, Vanasse, Danielle, Yueh-wei, Shen, Rose, Jeremy J, Rossi, John, Xue, Allen, Bot, Adrian, Scholler Nathalie, Mikkilineni Lekha, Roschewski, Mark, Dean, Robert, Cachau Raul, Youkharibache Philippe, Patel Rashmika, Hansen, Brenna, Stroncek, David F, Rosenberg, Steven A, Gress, Ronald E, Kochenderfer, James N
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 01.02.2020
• Subjects: Antigens; B-cell lymphoma; Binding; Blood; Blood levels; CD19 antigen; Cell therapy; Chimeric antigen receptors; Cytokines; Domains; Feasibility studies; Immunogenicity; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Patients; Remission; Safety; Toxicity; Transmembrane domains
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-019-0737-3

Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are an 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-human clinical trial of T cells expressing the new 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 blood levels of CAR T cells, anti-lymphoma activity, second infusions and immunogenicity. All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z T cells obtained complete remission. Hu19-CD828Z T cells had clinical anti-lymphoma activity similar to that of T cells expressing FMC63-28Z, an anti-CD19 CAR tested previously by our group, which 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, whereas 50% of patients who received FMC63-28Z T cells experienced this degree of toxicity (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 from patients who received Hu19-CD828Z T cells than in blood from those who received FMC63-28Z T cells, which could explain the lower level of neurologic toxicity associated 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.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 murine binding domains.