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This review addresses persistent challenges such as antigen escape, T-cell exhaustion, and limited efficacy in acute myeloid leukemia (AML) and T-cell leukemias. It summarizes human trials and progress since 2015, emphasizing innovations from the past two years, including multi-target and next-generation CAR designs, combination approaches, and allogeneic options to improve safety, access, and durability of responses.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/emerging-applications-of-car-t-cell-therapy-in-overcoming-resistance-and-expanding-targets-in-hematologic-malignancies-insights-from-recent-research/356844/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/emerging-applications-of-car-t-cell-therapy-in-overcoming-resistance-and-expanding-targets-in-hematologic-malignancies-insights-from-recent-research/356844.png","ImageObject",300,407,{"name":92,"@type":93},"Cart","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What major limitations of CAR-T therapy are addressed in this review?","Question",{"text":112,"@type":113},"The review highlights antigen escape, T-cell exhaustion, and limited effectiveness in acute myeloid leukemia (AML) and T-cell leukemias.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What strategies does the review discuss to overcome resistance?",{"text":117,"@type":113},"It discusses multi-target CARs, next-generation constructs, and combination strategies, including approaches intended to counter inhibitory signals in the microenvironment.",{"name":119,"@type":110,"acceptedAnswer":120},"How does the article propose improving safety and access to CAR-T therapy?",{"text":121,"@type":113},"It explores ways to increase both safety and accessibility, including allogeneic CAR-T options and proposals involving CRISPR-enhanced CARs and synthetic biology-based allogeneic systems.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},356844,1790207715,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":52,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},18829141979164,"https://eur-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Current Treatment Options in Oncology (2026) 27:28  \n[https://doi.org/10.1007/s1](https://doi.org/10.1007/s1) 1864-025-01371-z  \nREVIEW  \nEmerging Applications of CAR-T Cell Therapy in Overcoming Resistance and Expanding Targets in Hematologic Malignancies:  \nInsights from Recent Research  \nIraj Alipourfard1 · Zahra Shafaghat2 · Saber Saharkhiz3 · Marzieh Ramezani Farani4 · Salar Bakhtiyari5  \nReceived: 11 April 2025 / Accepted: 28 October 2025 © The Author(s) 2025  \nAbstract  \nChimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment outcomes of patients with hematologic malignancies, including B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM) . However, issues such as antigen escape, T-cell exhaustion, and the limited efficacy of CAR-T cells in acute myeloid leukemia (AML) and T-cell leukemias still persist. This review aims to summarize human trials and achievements from 2015 with a focus on the innovations within the last two years. We discuss strategies to overcome resistance, including multi-target CARs, next-generation constructs, and combination strategies to treat resistant cancers. We also explore the ways to increase safety and access, including allogeneic CAR-T options. In this article, we propose CRISPR-enhanced CARs and synthetic biology-based allogeneic systems to enhance the efficacy and accessibility of CAR-T therapy with the aim of moving the field of oncology towards durable cures.  \nKeywords CAR-T therapy · Hematologic malignancies · Allogenic CAR-T · Multi-target CARs  \nIntroduction  \nThe development ofchimeric antigen receptor T-cell (CAR-T) therapy revolutionized oncology treatment by creating engineered T cells that recognize tumor antigens through CARs.  \n􀀍 Iraj Alipourfard[iraj.alipourfard@wum.edu.pl](iraj.alipourfard@wum.edu.pl)  \n1 Department of Pharmacotherapy and Pharmaceutical Care, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1b, Warsaw 02-097, Poland  \n2 Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran  \n3 Division of Neuroscience, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada  \n4 Department of Biological Sciences and Bioengineering, Nano Bio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Michuhol-gu, Incheon, Republic of Korea  \n5 Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA  \nThe outcome has been truly remarkable. The complete remission rates for relapsed/refractory B-ALL patients treated with Tisagenlecleucel range from 81 to 90%[1], and axicabtageneciloleucel resulted in a 43% overall survival rate for DLBCL patients during a 5-year follow-up period [2, 3] . The BCMAdirected CAR-T therapy idecabtagene vicleucel has shown overall response rates (ORRs) of 73% in patients with MM. The FDA has approved six CAR-T products for B-cell malignancies since 2017, which target CD19 and BCMA. However, these successes have been tempered by lingering limitations. Antigen escape, or loss of CD19 or BCMA by tumor cells, leads to disease relapse in 30–50% of B-ALL patients, usually within 18 months [1, 4] . In multiple myeloma (MM), results from BCMA CART studies show a median progression-free survival (PFS) of less than 12 months for heavily pretreated patients [5] . T-cell exhaustion, as a result of chronic antigen exposure and immune suppressive microenvironments with increased TGF-β or IL-10, also contributes to reduced effectiveness [6, 7] . Collectively, AML and T-cell leukemias have limitations due to the antigen shared with normal immunologic T cells and fratricide [8, 9]. The last ten years, from 2024 to 2025, have seen various potential inventions emerge to address these obstacles. The CARs with multiple targets, such  \nas CD19/CD22 or BCMA/GPRC5D, have been engineered to prevent antigen loss [1","cbCainRFT336Ev4A","https://ap.wps.com/l/cbCainRFT336Ev4A","pdf",1899901,"English","# Abstract\n# Introduction\n# Current Landscape of CAR-T Therapy","[{\"question\":\"What major limitations of CAR-T therapy are addressed in this review?\",\"answer\":\"The review highlights antigen escape, T-cell exhaustion, and limited effectiveness in acute myeloid leukemia (AML) and T-cell leukemias.\"},{\"question\":\"What strategies does the review discuss to overcome resistance?\",\"answer\":\"It discusses multi-target CARs, next-generation constructs, and combination strategies, including approaches intended to counter inhibitory signals in the microenvironment.\"},{\"question\":\"How does the article propose improving safety and access to CAR-T therapy?\",\"answer\":\"It explores ways to increase both safety and accessibility, including allogeneic CAR-T options and proposals involving CRISPR-enhanced CARs and synthetic biology-based allogeneic systems.\"}]","Emerging Applications of CAR-T Cell Therapy in Overcoming Resistance and Expanding Targets in Hematologic Malignancies: Insights from Recent Research | PDF",1790127631,25]