These major barriers to effective CAR-T therapy in AML are discussed and emerging engineering strategies developed to address them are summarized, including approaches to improve targeting precision, reinforce CAR-T cell functional fitness, and remodel the suppressive immune niche.
Abstract
Acute myeloid leukemia (AML) remains a difficult disease to treat, especially in patients with relapsed or refractory disease. While chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment landscape of several B-cell malignancies, its clinical efficacy in AML has been substantially more limited. This limited efficacy reflects not only challenges in CAR design, but also the complex biological and immunological barriers inherent to AML. Insufficient target specificity, pronounced leukemic heterogeneity, and an immunosuppressive bone marrow microenvironment collectively impair CAR-T cell recognition, persistence, and effector function, thereby restricting both therapeutic efficacy and safety. In this review, we discuss these major barriers and summarize emerging engineering strategies developed to address them, including approaches to improve targeting precision, reinforce CAR-T cell functional fitness, and remodel the suppressive immune niche. Together, these insights may help clarify the key barriers to effective CAR-T therapy in AML and inform future strategies for its optimization.
Next-generation engineering strategies are being designed to overcome the obstacles that constrain CAR-T-cell efficacy in solid tumors and to guide the development of safer and more effective therapeutic platforms.
Ziyan Kong, Jinke Wang· Frontiers in Immunology· 0 citations
Acute myeloid leukemia is a clonal malignant disease that arises from hematopoietic stem cells and is characterized by high genetic heterogeneity. AML has a poor prognosis, with a low 5-year survival rate, and is typically treated with chemotherapy. The management of AML, particularly for cases that are relapsed or refractory to conventional chemotherapy and transplantation, remains a formidable clinical challenge. This comprehensive review systematically evaluates the current landscape of cellular immunotherapeutic strategies for AML. We focus on the mechanisms of action, recent clinical progress, and persistent challenges associated with a range of adoptive cell therapies. These include natural killer cell-based infusions, and engineered approaches such as chimeric antigen receptor-T, CAR-NK, and CAR-macrophage therapies. Furthermore, we examine the roles of tumor-infiltrating lymphocytes and cytokine-induced killer cells. Our analysis synthesizes evidence from preclinical studies and clinical trials to assess the potential of these modalities in inducing durable antileukemic responses. We conclude that while cellular immunotherapies represent a transformative frontier in AML treatment, their broad application is currently constrained by target antigen heterogeneity, a complex tumor microenvironment, and significant toxicities. Finally, this review discusses strategic innovations necessary to overcome these barriers, highlighting directions for future research aimed at enhancing the efficacy and safety of these promising treatments for AML patients.
The biological mechanisms underlying resistance to CAR-T therapy in solid tumors are examined and emerging combination strategies designed to enhance tumor recognition, trafficking, persistence, and antitumor activity are critically evaluated.
Wei Cheng, Mei-Lan Liu, Yu-Hua Diao et al.· Cancer Biome and Targeted Th...· 0 citations
Breast cancer is one of the most common malignancies worldwide and remains a leading cause of cancer-related mortality. Over the past decades, advances in multimodal treatment have significantly improved patient survival. However, disease recurrence, metastatic progression, and therapeutic resistance continue to limit long-term outcomes, underscoring the need for more effective therapies. Among emerging immunotherapeutic approaches, chimeric antigen receptor T (CAR-T) cell therapy has attracted considerable attention. CAR-T therapy has achieved remarkable success in hematologic malignancies, prompting its investigation in breast cancer. However, translating this success to solid tumors remains challenging because of fundamental biological differences between hematologic and solid malignancies. Major barriers include antigen heterogeneity, limited tumor trafficking and infiltration, an immunosuppressive tumor microenvironment, and therapy-related toxicities. Numerous preclinical and clinical studies are currently evaluating CAR-T cell therapy in solid tumors, including breast cancer. These efforts incorporate next-generation CAR designs and novel engineering strategies with the goal of reproducing the clinical success achieved in hematologic malignancies. Although the available clinical evidence is still largely limited to early-phase trials, current findings suggest that CAR-T therapy in breast cancer is feasible and generally well tolerated. Most reported adverse events have been low-grade inflammatory toxicities, whereas severe neurotoxicity and dose-limiting toxicities have been infrequent. Despite this favorable safety profile, clinical responses remain modest, with stable disease representing the most common outcome and durable objective responses being uncommon. These findings underscore the need to overcome the major biological barriers that continue to limit CAR-T cell therapy in solid tumors. This review summarizes recent advances in CAR-T cell engineering, discusses the major target antigens investigated to date, provides a comprehensive overview of the available clinical evidence, and examines the key biological and clinical challenges that must be addressed to improve future therapeutic outcomes.
Ahmad Farajzadeh, Mahmoud Mahmoudi, Soroush Yazdani et al.· International Immunopharmaco...· 0 citations
Background Chimeric antigen receptor T-cell therapy has changed the treatment landscape of relapsed or refractory hematological malignancies, but primary non-response and post-infusion relapse remain frequent clinical problems. In aggressive B-cell lymphomas, acute leukemias, and multiple myeloma, treatment failure is often driven by overlapping mechanisms rather than a single resistance pathway. These include antigen loss or reduced antigen density, impaired immune recognition, defective inflammatory signaling, checkpoint-mediated suppression, metabolic stress, and limited effector-cell persistence within suppressive disease niches. Main Body Genome engineering has become an important tool for both identifying and addressing these resistance mechanisms. CRISPR-based functional screening, single-cell perturbation approaches, and multi-omics profiling allow immune escape and tumor microenvironment-mediated resistance to be defined more functionally, rather than inferred only from correlative datasets. These insights can inform the design of CAR-T and CAR-NK therapies through multi-target or logic-gated receptors, checkpoint or exhaustion-pathway editing, cytokine-supported and armored constructs, metabolic fitness enhancement, and selected multiplex-editing strategies. In parallel, CAR-NK cells, universal allogeneic CAR-T products, and stem-cell-derived platforms may provide additional options in relapse-prone or heavily pretreated patients, particularly when autologous T-cell fitness, manufacturing feasibility, or repeat dosing is a concern. Conclusion A resistance-guided approach may help align engineered cellular therapy design with the dominant mechanisms of treatment failure in high-risk hematological malignancies. Rather than simply increasing engineering complexity, future CAR-T and CAR-NK development should link each modification to a measurable resistance mechanism, a feasible biomarker, and a clinically testable benefit. Prospective validation, genomic safety assessment, manufacturing consistency, and long-term monitoring will be essential before resistance-matched cellular immunotherapy can be broadly integrated into clinical practice.
Shi-Qi Cai, Yang Tan, Qian Yang et al.· Frontiers in Genome Editing· 0 citations
Continued efforts to identify highly specific target antigens, optimize manufacturing processes, enhance safety, and integrate CAR-T therapy with complementary immunotherapeutic approaches are expected to improve clinical outcomes and broaden the application of CAR-T therapy to T-cell malignancies and potentially other solid and hematologic cancers.
H. Hetta, Fawaz E Alanazi, Mahmoud H. El-Maghrabey et al.· Journal of Pharmaceutical In...· 0 citations
