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However, a critical void exists in therapeutic options for patients with high-risk diseases who are resistant to the current CLL therapies, underscoring the urgency for adoptive immunotherapies in these patients. The diminished CAR T-cell efficacy within CLL can be traced to factors such as compromised T-cell fitness due to persistent antigenic stimulation inherent to CLL. Resistance mechanisms encompass tumor-related factors like antigen escape, CAR T-cell-intrinsic factors like T-cell exhaustion, and a suppressive tumor microenvironment (TME). New strategies to combat CAR T-cell resistance include the concurrent administration of therapies that augment CAR T-cell endurance and function, as well as the engineering of novel CAR T-cells targeting different antigens. Moreover, the concept of \u201carmored\u201d CAR T-cells, armed with transgenic modulators to modify both CAR T-cell function and the tumor milieu, is gaining traction. Beyond this, the development of readily available, allogeneic CAR T-cells and natural killer (NK) cells presents a promising countermeasure to innate T-cell defects in CLL patients. In this review, we explore the role of CAR T-cell therapy in CLL, the intricate tapestry of resistance mechanisms, and the pioneering methods studied to overcome resistance.<\/jats:p>","DOI":"10.20517\/cdr.2023.100","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T03:28:43Z","timestamp":1715657323000},"update-policy":"https:\/\/doi.org\/10.20517\/oae.crossmark.policy","source":"Crossref","is-referenced-by-count":4,"title":["Advancing CAR T-cell therapy for chronic lymphocytic leukemia: exploring resistance mechanisms and the innovative strategies to overcome them"],"prefix":"10.20517","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5093-1634","authenticated-orcid":true,"given":"Azra","family":"Borogovac","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5292-8298","authenticated-orcid":true,"given":"Tanya","family":"Siddiqi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"8410","published-online":{"date-parts":[[2024,5,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201607485"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/nejmra1706169"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022018893"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023020197"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021014960"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-05-787366"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019002936"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/jco.19.03237"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01052-8"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1056\/nejm200012283432602"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-01-546150"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830230705"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1084\/jem.181.5.1653"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0102-70"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.75"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.11.063"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.684642"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20192203"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2014.215"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1517\/14712598.2015.1046430"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1914347"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1103849"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04390-6"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2017.72.8519"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1200\/jco.20.01467"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-179529"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtct.2021.10.005"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1097\/hs9.0000000000000988"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-185076"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-180858"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.183459"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-15-1020"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-08-665547"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.5ru0817-315r"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1709866"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021010930"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1097\/cji.0000000000000169"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21168-6"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001150"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.13562"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1054-1"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s11899-011-0106-x"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.2174\/138161212801227023"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0221-9"},{"key":"B45","unstructured":"Herrmann F, Lochner A, Philippen H, Jauer B, R\u00fchl H. 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