<![CDATA[Background: Chimeric Antigen Receptor T-cell (CAR T-cell) therapy targeting CD19 on B-cells has emerged as a promising treatment for B-cell malignancies such as B-Acute Lymphoblastic Leukemia (B-ALL) and Diffuse Large B-cell Lymphoma (DLBCL). Despite its success, resistance mechanisms, including immune checkpoint inhibitors, persistent antigen stimulation, T-cell exhaustion, antigen loss, lineage switch, tumor heterogeneity, impaired death receptor signalling, and the tumor microenvironment, pose significant challenges. Understanding these mechanisms is crucial to advancing CAR T-cell therapy and improving its efficacy.Methods: This literature review was conducted by analyzing peer-reviewed articles and clinical trials focusing on CAR T-cell therapy for B-ALL and DLBCL. Key mechanisms of resistance were identified, and their biological underpinnings were evaluated to highlight trends and potential strategies for overcoming resistance. Sources included PubMed, Science Direct, Google Scholar, and Google database using keywords such as ‘CD19,’ ‘CAR T-cell,’ ‘B-ALL,’ and ‘DLBCL’. Most articles were published within the past five years and were selected from journals with a high impact factor, and some older publications were included for foundational and theoretical insights.Results: The review identifies multiple resistance mechanisms, including persistent antigen stimulation leading to T-cell exhaustion, immune checkpoint inhibitors suppressing effector functions, and tumor intrinsic factors like antigen loss and lineage switch. The role of the tumor microenvironment, with its immunosuppressive components, also contributes significantly to treatment failure. These findings underscore the complexity of resistance pathways and the need for combinatory and innovative approaches to enhance therapeutic outcomes.Conclusions: Resistance to CAR T-cell therapy presents a significant challenge in treating B-cell malignancies. Addressing these mechanisms requires further research into combination therapies, multi-antigen targeting, and tumor microenvironment modulation. These strategies have the potential to optimize CAR T-cell efficacy and improve patient survival rates]]>
