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Despite these advances, durable remission remains limited by disease relapse, with antigen escape emerging as one of the principal mechanisms of therapeutic resistance. This review comprehensively summarizes the biologic mechanisms underlying antigen escape and highlights emerging engineering strategies designed to overcome immune evasion and improve long\u2010term CAR T\u2010cell efficacy. We discuss both irreversible and reversible resistance pathways, including genetic alterations, alternative splicing, lineage plasticity, trogocytosis, epigenetic repression, and tumor microenvironment\u2010mediated antigen modulation. Particular emphasis is placed on clinically relevant examples such as CD19 loss in B\u2010ALL and BCMA dysregulation in multiple myeloma. The review further examines next\u2010generation approaches developed to prevent antigen\u2010negative relapse, including dual\u2010 and multi\u2010target CAR constructs, logic\u2010gated systems, pharmacologic enhancement of antigen density, epitope spreading, and TCR\u2010mimic CAR platforms targeting intracellular antigens. In addition, we evaluate the major translational and biologic challenges associated with these advanced strategies, including structural complexity, manufacturing barriers, toxicity control, tumor heterogeneity, and limited long\u2010term clinical validation. Finally, we discuss future perspectives involving single\u2010cell and multi\u2010omic technologies, computational modeling, and universal modular CAR systems that may enable the development of safer, more adaptable, and precision\u2010guided cellular immunotherapies for hematologic malignancies.<\/jats:p>","DOI":"10.1111\/ejh.70252","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T01:52:33Z","timestamp":1782957153000},"page":"1136-1158","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Outsmarting Antigen Escape: Next\u2010Generation\n                    <scp>CAR<\/scp>\n                    T Cell Engineering Strategies for Durable Remissions in Hematologic Malignancies"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9347-8456","authenticated-orcid":false,"given":"Amr Ali Mohamed","family":"Abdelgawwad El\u2010Sehrawy","sequence":"first","affiliation":[{"name":"Internal Medicine, Diabetes, Endocrinology and Metabolism Mansoura University  Mansoura Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Islam","family":"Alfreahat","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy Al\u2010Ahliyya Amman University  Aman Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurillo","family":"Bobokulov","sequence":"additional","affiliation":[{"name":"Department of Urology Samarkand State Medical University  Samarkand Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quvonch","family":"Tursunov","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences Termez University of Economics and Service  Termez Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulnora","family":"Shakhmurova","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences National Pedagogical University of Uzbekistan Named After Nizami  Tashkent Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajashree","family":"Panigrahi","sequence":"additional","affiliation":[{"name":"Department of Microbiology IMS and SUM Hospital, Siksha \u2018O\u2019 Anusandhan  Bhubaneswar Odisha India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rswl Mahmoud","family":"Hashem","sequence":"additional","affiliation":[{"name":"Department of Tqnyat Altkhdyr College Altqnyat Altbyh, The Islamic University  Najaf Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeraj","family":"Bainsal","sequence":"additional","affiliation":[{"name":"University Institute of Pharma Sciences, Chandigarh University  Mohali Punjab India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1583116"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.70201"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-025-01737-8"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.70348"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1650568"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/mps8050108"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1054-1"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-025-03697-y"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14041078"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.113392"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-025-01744-9"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1557405"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-003351"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-3784"},{"issue":"1","key":"e_1_2_14_16_1","article-title":"MON\u2010312 Lewis Y Antigen as a Novel Target for CAR (Chimeric Antigen Receptor) T\u2010Cell Therapy in Patients With Neuroendocrine Prostate Cancer","volume":"9","author":"Kulakowska W. 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