PMID- 36821767 OWN - NLM STAT- MEDLINE DCOM- 20230522 LR - 20240324 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 141 IP - 20 DP - 2023 May 18 TI - Dual targeting of CD19 and CD22 with bicistronic CAR-T cells in patients with relapsed/refractory large B-cell lymphoma. PG - 2470-2482 LID - 10.1182/blood.2022018598 [doi] AB - 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. CI - (c) 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. FAU - Roddie, Claire AU - Roddie C AUID- ORCID: 0000-0002-4901-5858 AD - Cancer Institute, University College London, London, United Kingdom. AD - Department of Haematology, University College London Hospital, London, United Kingdom. FAU - Lekakis, Lazaros J AU - Lekakis LJ AD - Department of Hematology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL. FAU - Marzolini, Maria A V AU - Marzolini MAV AD - Department of Haematology, University College London Hospital, London, United Kingdom. FAU - Ramakrishnan, Aravind AU - Ramakrishnan A AD - Department of Hematology, St David's South Austin Medical Center, Austin, TX. FAU - Zhang, Yiyun AU - Zhang Y AD - Department of Haematology, Autolus Ltd, London, United Kingdom. FAU - Hu, Yanqing AU - Hu Y AD - Department of Haematology, Autolus Ltd, London, United Kingdom. FAU - Peddareddigari, Vijay G R AU - Peddareddigari VGR AD - Department of Haematology, Autolus Ltd, London, United Kingdom. FAU - Khokhar, Nushmia AU - Khokhar N AD - Department of Haematology, Autolus Ltd, London, United Kingdom. FAU - Chen, Robert AU - Chen R AD - Department of Haematology, Autolus Ltd, London, United Kingdom. FAU - Basilico, Silvia AU - Basilico S AD - Department of Haematology, Autolus Ltd, London, United Kingdom. FAU - Raymond, Meera AU - Raymond M AD - Department of Haematology, Autolus Ltd, London, United Kingdom. FAU - Vargas, Frederick Arce AU - Vargas FA AD - Department of Haematology, Autolus Ltd, London, United Kingdom. FAU - Duffy, Kevin AU - Duffy K AD - Department of Haematology, Autolus Ltd, London, United Kingdom. FAU - Brugger, Wolfram AU - Brugger W AD - Department of Haematology, Autolus Ltd, London, United Kingdom. FAU - O'Reilly, Maeve A AU - O'Reilly MA AD - Department of Haematology, University College London Hospital, London, United Kingdom. FAU - Wood, Leigh AU - Wood L AD - Department of Haematology, University College London Hospital, London, United Kingdom. FAU - Linch, David C AU - Linch DC AD - Cancer Institute, University College London, London, United Kingdom. FAU - Peggs, Karl S AU - Peggs KS AD - Cancer Institute, University College London, London, United Kingdom. AD - Department of Haematology, University College London Hospital, London, United Kingdom. FAU - Bachier, Carlos AU - Bachier C AD - Department of Hematology, Methodist Hospital, San Antonio, TX. FAU - Budde, Elizabeth Lihua AU - Budde EL AUID- ORCID: 0000-0003-1464-5494 AD - Department of Hematology, City of Hope National Medical Centre, Duarte, CA. FAU - Lee Batlevi, Connie AU - Lee Batlevi C AUID- ORCID: 0000-0002-9036-9463 AD - Department of Hematology, Memorial Sloan Kettering Cancer Center, New York, NY. FAU - Bartlett, Nancy AU - Bartlett N AUID- ORCID: 0000-0001-8470-394X AD - Department of Hematology, Washington University School of Medicine, St Louis, MO. FAU - Irvine, David AU - Irvine D AD - Department of Haematology, Queen Elizabeth University Hospital, Glasgow, United Kingdom. FAU - Tholouli, Eleni AU - Tholouli E AD - Department of Haematology, Manchester Royal Infirmary, Manchester, United Kingdom. FAU - Osborne, Wendy AU - Osborne W AD - Department of Haematology, Freeman Hospital, Newcastle, United Kingdom. FAU - Ardeshna, Kirit M AU - Ardeshna KM AD - Department of Haematology, University College London Hospital, London, United Kingdom. FAU - Pule, Martin A AU - Pule MA AUID- ORCID: 0000-0002-8347-9867 AD - Cancer Institute, University College London, London, United Kingdom. AD - Department of Haematology, Autolus Ltd, London, United Kingdom. LA - eng SI - ClinicalTrials.gov/NCT03289455 GR - DH_/Department of Health/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Receptors, Chimeric Antigen) RN - 0 (Antigens, CD19) RN - 0 (CD22 protein, human) RN - 0 (Sialic Acid Binding Ig-like Lectin 2) SB - IM CIN - Blood. 2023 May 18;141(20):2410-2411. PMID: 37200062 MH - Humans MH - Middle Aged MH - *Receptors, Chimeric Antigen MH - Neoplasm Recurrence, Local MH - *Lymphoma, Large B-Cell, Diffuse/drug therapy MH - Immunotherapy, Adoptive MH - T-Lymphocytes MH - Antigens, CD19 MH - Sialic Acid Binding Ig-like Lectin 2 PMC - PMC10646794 COIS- Conflict-of-interest disclosure: M.A.P. owns stock in and is employed by Autolus Therapeutics and is an inventor on patents licensed to Autolus Therapeutics, for which he receives a share of revenues. C.L.B. consults and serves on the advisory board for BMS, Seattle Genetics, Kite, Karyopharm, TG Therapeutics, ADC Therapeutics, AbbVie, Genentech, and Treeline Bioscience; receives research fundings from Epizyme, Autolus Therapeutics, Roche, and Vincerx; and received honoraria from Dava Oncology, TouchIME, and Medscape. W.O. reports fees from Roche, Takeda, Pfizer, Servier, Kite Gilead, MSD, Novartis, Beigene, AstraZeneca, Syneos, Autolus, Kyowa Kirin, AbbVie, Incyte, BMS/Celgene, and Janssen. K.S.P. is a shareholder and consultant of Autolus Therapeutics. E.T. receives speaker fees from and serves in the advisory boards for Novartis, Kite/Gilead, Janssen, and BMS/Celgene. D.I. receives speaker fees from Kite/Gilead. The remaining authors declare no competing financial interests. EDAT- 2023/02/24 06:00 MHDA- 2023/05/22 06:42 PMCR- 2023/02/26 CRDT- 2023/02/23 15:03 PHST- 2023/02/09 00:00 [accepted] PHST- 2022/10/11 00:00 [received] PHST- 2023/05/22 06:42 [medline] PHST- 2023/02/24 06:00 [pubmed] PHST- 2023/02/23 15:03 [entrez] PHST- 2023/02/26 00:00 [pmc-release] AID - S0006-4971(23)00486-X [pii] AID - 10.1182/blood.2022018598 [doi] PST - ppublish SO - Blood. 2023 May 18;141(20):2470-2482. doi: 10.1182/blood.2022018598.