Dual targeting of CD19 and CD22 with bicistronic CAR-T cells in patients with relapsed/refractory large B-cell lymphoma

Claire Roddie, Lazaros J. Lekakis, Maria A.V. Marzolini, Aravind Ramakrishnan, Yiyun Zhang, Yanqing Hu, Vijay G.R. Peddareddigari, Nushmia Khokhar, Robert Chen, Silvia Basilico, Meera Raymond, Frederick Arce Vargas, Kevin Duffy, Wolfram Brugger, Maeve A. O'Reilly, Leigh Wood, David C. Linch, Karl S. Peggs, Carlos Bachier, Elizabeth Lihua BuddeConnie Lee Batlevi, Nancy Bartlett, David Irvine, Eleni Tholouli, Wendy Osborne, Kirit M. Ardeshna, Martin A. Pule

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in relapsed/refractory LBCL (NCT03289455). End points include toxicity (primary) and response rates (secondary). Fifty-two patients received AUTO3 and 48/52 received pembrolizumab. Median age was 59 years (range, 27-83), 46/52 had stage III/ IV disease and median follow-up was 21.6 months. AUTO3 was safe; grade 1-2 and grade 3 cytokine release syndrome affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), and hemophagocytic lymphohistiocytosis affected 2 patients. Outpatient administration was tested in 20 patients, saving a median of 14 hospital days per patient. Overall response rates were 66% (48.9%, complete response [CR]; 17%, partial response). Median duration of remission (DOR) for CR patients was not reached and for all responding patients was 8.3 months (95% confidence interval [CI]: 3.0-not evaluable). 54.4% (CI: 32.8-71.7) of CR patients and 42.6% of all responding patients were projected to remain progression-free at ≥12 months. AUTO3 ± pembrolizumab for relapsed/refractory LBCL was safe and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation–AUTO3, engineered for superior expansion in vivo, and selection of CAR binders active at low antigen densities.

Original languageEnglish
Pages (from-to)2470-2482
Number of pages13
Issue number20
StatePublished - May 18 2023


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