PMID- 38187393 OWN - NLM STAT- MEDLINE DCOM- 20240109 LR - 20240402 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Lymphodepletion - an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle. PG - 1303935 LID - 10.3389/fimmu.2023.1303935 [doi] LID - 1303935 AB - Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T) therapies as it maximizes engraftment, efficacy and long-term survival of CAR-T. Its main modes of action are the depletion and modulation of endogenous lymphocytes, conditioning of the microenvironment for improved CAR-T expansion and persistence, and reduction of tumor load. However, most LD regimens provide a broad and fairly unspecific suppression of T-cells as well as other hematopoietic cells, which can also lead to severe side effects, particularly infections. We reviewed 1271 published studies (2011-2023) with regard to current LD strategies for approved anti-CD19 CAR-T products for large B cell lymphoma (LBCL). Fludarabine (Flu) and cyclophosphamide (Cy) (alone or in combination) were the most commonly used agents. A large number of different schemes and combinations have been reported. In the respective schemes, doses of Flu and Cy (range 75-120mg/m2 and 750-1.500mg/m2) and wash out times (range 2-5 days) differed substantially. Furthermore, combinations with other agents such as bendamustine (benda), busulfan or alemtuzumab (for allogeneic CAR-T) were described. This diversity creates a challenge but also an opportunity to investigate the impact of LD on cellular kinetics and clinical outcomes of CAR-T. Only 21 studies explicitly investigated in more detail the influence of LD on safety and efficacy. As Flu and Cy can potentially impact both the in vivo activity and toxicity of CAR-T, a more detailed analysis of LD outcomes will be needed before we are able to fully assess its impact on different T-cell subsets within the CAR-T product. The T2EVOLVE consortium propagates a strategic investigation of LD protocols for the development of optimized conditioning regimens. CI - Copyright (c) 2023 Lickefett, Chu, Ortiz-Maldonado, Warmuth, Barba, Doglio, Henderson, Hudecek, Kremer, Markman, Nauerth, Negre, Sanges, Staber, Tanzi, Delgado, Busch, Kuball, Luu and Jager. FAU - Lickefett, Benno AU - Lickefett B AD - Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria. FAU - Chu, Lulu AU - Chu L AD - Cell Therapy Clinical Pharmacology and Modeling, Takeda, Boston, MA, United States. FAU - Ortiz-Maldonado, Valentin AU - Ortiz-Maldonado V AD - Department of Hematology, Hospital Clinic de Barcelona, Barcelona, Spain. FAU - Warmuth, Linda AU - Warmuth L AD - Institut fur Med. Mikrobiologie, Immunologie und Hygiene, Technische Universitat Munich, Munich, Germany. FAU - Barba, Pere AU - Barba P AD - Hematology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain. FAU - Doglio, Matteo AU - Doglio M AD - Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy. FAU - Henderson, David AU - Henderson D AD - Bayer Aktiengesellschaft (AG), Business Development & Licensing & Open Innovation (OI), Pharmaceuticals, Berlin, Germany. FAU - Hudecek, Michael AU - Hudecek M AD - Lehrstuhl fur Zellulare Immuntherapie, Medizinische Klinik und Poliklinik II, Universitatsklinikum Wurzburg, Wurzburg, Germany. FAU - Kremer, Andreas AU - Kremer A AD - ITTM S.A. (Information Technology for Translational Medicine), Esch-sur-Alzette, Luxembourg. FAU - Markman, Janet AU - Markman J AD - Cell Therapy Clinical Pharmacology and Modeling, Takeda, Boston, MA, United States. FAU - Nauerth, Magdalena AU - Nauerth M AD - Institut fur Med. Mikrobiologie, Immunologie und Hygiene, Technische Universitat Munich, Munich, Germany. FAU - Negre, Helene AU - Negre H AD - Institut de Recherches Internationales Servier, Suresnes, France. FAU - Sanges, Carmen AU - Sanges C AD - Lehrstuhl fur Zellulare Immuntherapie, Medizinische Klinik und Poliklinik II, Universitatsklinikum Wurzburg, Wurzburg, Germany. FAU - Staber, Philipp B AU - Staber PB AD - Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria. FAU - Tanzi, Rebecca AU - Tanzi R AD - Institut de Recherches Internationales Servier, Suresnes, France. FAU - Delgado, Julio AU - Delgado J AD - Department of Hematology, Hospital Clinic de Barcelona, Barcelona, Spain. FAU - Busch, Dirk H AU - Busch DH AD - Institut fur Med. Mikrobiologie, Immunologie und Hygiene, Technische Universitat Munich, Munich, Germany. FAU - Kuball, Jurgen AU - Kuball J AD - Legal and Regulatory Affairs Committee of the European Society for Blood and Marrow Transplantation, Leiden, Netherlands. FAU - Luu, Maik AU - Luu M AD - Lehrstuhl fur Zellulare Immuntherapie, Medizinische Klinik und Poliklinik II, Universitatsklinikum Wurzburg, Wurzburg, Germany. FAU - Jager, Ulrich AU - Jager U AD - Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20231222 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Receptors, Chimeric Antigen) RN - 0 (Adaptor Proteins, Signal Transducing) RN - 3A189DH42V (Alemtuzumab) RN - 0 (Antibodies) RN - 8N3DW7272P (Cyclophosphamide) SB - IM MH - *Receptors, Chimeric Antigen/genetics MH - Adaptor Proteins, Signal Transducing MH - Alemtuzumab MH - Antibodies MH - Cyclophosphamide MH - Cell- and Tissue-Based Therapy PMC - PMC10770848 OTO - NOTNLM OT - CAR-T cells OT - conditioning OT - efficacy OT - lymphodepletion OT - optimization OT - toxicity COIS- MH and ML: inventors on patents related to CAR T- cell therapy filed by the University of Wurzburg. MH is listed as an inventor on patent applications and granted patents related to CAR-T technologies that have been filed by the Fred Hutchinson Cancer Research Center, Seattle, WA and by the University of Wurzburg, Wurzburg, Germany. MH is a co-founder and equity owner of T-CURX GmbH, Wurzburg, Germany. MH received honoraria from Celgene/BMS, Janssen, Kite/Gilead. VO-M: Travel grants: Kite, Celgene-BMS, Novartis, Roche, Takeda & Janssen; Consultant or advisory fees: Kite, Celgene-BMS, Miltenyi Biomedicine, Pfizer, Novartis & Janssen; Honoraria: Kite, Celgene-BMS & Janssen; Employment: Hospital Clinic de Barcelona. UJ: consultant and advisory fees from Novartis, BMS, Gilead, Janssen, Roche, Honoraria from Miltenyi Biomedicine. DB: research projects with Juno/BMS and Repairon Immuno GmbH; consultant and advisory fees from BMS and Immatics. JD: Employment: Hospital Clinic de Barcelona. DH is an employee and shareholder of Bayer AG. HN and RT: are employees of Servier IRIS. PB: Advisory Board and consultancy from Allogene, Amgen, BMS/Celgene, Kite/Gilead, Incyte, Miltenyi Biomedicine, Novartis, Nektar, Pfizer and Pierre FabreKite/Gilead, Incyte, Miltenyi Biomedicine, Novartis, Nektar, Pfizer and Pierre Fabre. JK: Received grants form Novartis, Miltenyi Biotech and Gadeta. JK is inventor and receives revenues on multiple patents on CAR T and TEG engineering. LC was employed by Takeda. AK was employed by ITTM S.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2024/01/08 06:41 MHDA- 2024/01/09 06:42 PMCR- 2023/01/01 CRDT- 2024/01/08 04:41 PHST- 2023/09/28 00:00 [received] PHST- 2023/12/05 00:00 [accepted] PHST- 2024/01/09 06:42 [medline] PHST- 2024/01/08 06:41 [pubmed] PHST- 2024/01/08 04:41 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1303935 [doi] PST - epublish SO - Front Immunol. 2023 Dec 22;14:1303935. doi: 10.3389/fimmu.2023.1303935. eCollection 2023.