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CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial

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Shaun Cordoba, Shimobi Onuoha, Simon Thomas, Daniela Soriano Pignataro, Rachael Hough, Sara Ghorashian, Ajay Vora, Denise Bonney, Paul Veys, Kanchan Rao, Giovanna Lucchini, Robert Chiesa, Jan Chu, Liz Clark, Mei Mei Fung, Koval Smith, Carlotta Peticone, Muhammad Al-Hajj, Vania Baldan, Mathieu Ferrari & 16 more Saket Srivastava, Ram Jha, Frederick Arce Vargas, Kevin Duffy, William Day, Paul Virgo, Lucy Wheeler, Jeremy Hancock, Farzin Farzaneh, Sabine Domning, Yiyun Zhang, Nushmia Z. Khokhar, Vijay G.R. Peddareddigari, Robert Wynn, Martin Pule, Persis J. Amrolia

Original languageEnglish
Pages (from-to)1797-1805
Number of pages9
JournalNature Medicine
Issue number10
Early online date12 Oct 2021
E-pub ahead of print12 Oct 2021
PublishedOct 2021

Bibliographical note

Funding Information: M.P. is supported by the University College London Hospital, National Institute of Health Research Biomedical Research Centre. This work was supported by National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children. P.J.A. was the chief investigator of the study and is a recipient of an NIHR Research Professorship. The study was funded by Autolus PLC who provided the study drug AUTO3. The authors thank the patients who participated in this study and their families. Publisher Copyright: © 2021, The Author(s).

King's Authors


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.

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