1区 · 医学
Article
作者: Peddareddigari, Vijay G R ; Baldan, Vania ; Duffy, Kevin ; Chu, Jan ; Lucchini, Giovanna ; Fung, Mei Mei ; Pule, Martin ; Zhang, Yiyun ; Khokhar, Nushmia Z ; Peticone, Carlotta ; Veys, Paul ; Amrolia, Persis J ; Domning, Sabine ; Ghorashian, Sara ; Cordoba, Shaun ; Jha, Ram ; Hough, Rachael ; Arce Vargas, Frederick ; Rao, Kanchan ; Thomas, Simon ; Chiesa, Robert ; Clark, Liz ; Hancock, Jeremy ; Wheeler, Lucy ; Bonney, Denise ; Vora, Ajay ; Al-Hajj, Muhammad ; Wynn, Robert ; Smith, Koval ; Srivastava, Saket ; Day, William ; Onuoha, Shimobi ; Ferrari, Mathieu ; Virgo, Paul ; Pignataro, Daniela Soriano ; Farzaneh, Farzin
Abstract:Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.