Chimeric Antigen Receptor T Research Articles

Calcinosis in Adult and Juvenile Dermatomyositis: Pathogenesis and Potential Therapeutic Targets.

Abstract Purpose The aim of this study was to determine the expression of Glypican-3(GPC-3) and AXL in hepatocellular carcinomas (HCCs). Methods A total of 140 patients diagnosed with HCC were included in this study. All patients had undergone radical surgery and had complete clinical information. Formalin-fixed paraffin-embedded tissue blocks of HCC from these patients were collected, and the expression levels of GPC-3 and AXL were detected by immunohistochemical (IHC) staining. Results Immunohistochemical analysis showed that GPC-3 and AXL were diffusely expressed in HCCs. The positive expression rate of GPC-3 was 77.1% (108/140) and that of AXL was 85.7% (120/140). Additionally, the proportion of cases with positive expression for either GPC-3 or AXL is 93.6%. Conclusions The findings of this study confirm that both GPC-3 and AXL are highly expressed in HCCs tissues, and the high co-expression rate supports the development of dual-target chimeric antigen receptor T (CAR-T) cell therapy for HCC treatment.

Chimeric antigen receptor T cell therapy: a new frontier therapeutic landscape in autoimmune diseases.

CD7 Chimeric Antigen Receptor-T cell (CAR-T) therapy demonstrates efficacy in relapsed/refractory (R/R) acute T-lymphoblastic leukaemia (ALL)T-ALL/lymphoblastic lymphoma (LBL), but concerns about T-cell depletion and severe immunodeficiency persist. We compared infection rates and immune cell subsets in 60 R/R T-ALL/LBL patients receiving naturally selected CD7 CAR-T (NS7CAR-T) with 60 R/R B-ALL patients undergoing CD19 CAR-T. Infections were monitored from infusion until allogeneic haematopoietic stem cell transplantation (HSCT) or up to 3 months. Overall infection rates did not significantly differ between groups (36.67% vs. 24.56%, p = 0.24), although the incidence of early immune effector cell-associated haematotoxicity (ICAHT) grade III-IV was higher in the CD7 CAR-T group than in the CD19 CAR-T group (33.9% vs. 16.7%, p = 0.03). Post-CD7 CAR-T infusion analysis showed a significant decline in CD7(+) T cells and an increase in non-CAR-T-derived CD7(-) T cells, particularly non-CAR-T cells, which rose to a median proportion of 84.4% (range: 22.1%-99.9%) by day 28; meanwhile, CD7(-) natural killer (NK) cells approached nearly 100% following the depletion of CD7(+) NK cells. This study indicates that while CD7 CAR-T therapy significantly reduces CD7(+) T cells, it does not lead to increased short-term infection rates. The notable expansion of non-CAR-T-derived CD7(-) T and NK cells helps preserve immune function, highlighting distinct therapeutic mechanisms between CD7 CAR-T and CD19 CAR-T due to their different lineage restrictions.

Anti-BCMA CAR-T therapy in patients with progressive multiple sclerosis.

Chimeric antigen receptor T (CAR-T)-cell therapy has revolutionized the treatment of hematological malignancies, yet long-term efficacy remains constrained by antigen escape and T-cell dysfunction. Recent advances have rapidly elucidated the molecular underpinnings of antigen escape mechanisms and intrinsic T-cell dysfunction, revealing novel vulnerabilities in current CAR-T paradigms. In this review, we discuss the limitations of CAR-T-cell therapy in hematological malignancies, particularly regarding antigen escape mechanisms and T-cell dysfunction. It is noteworthy that in recent years, multi-targeted CAR-T and engineered CAR-T cells have demonstrated promising clinical efficacy in overcoming drug resistance and relapse in hematological malignancies. Here, we also discuss emerging approaches to enhance the efficacy of CAR-T-cell therapy, including advanced CAR-T-cell engineering techniques, the identification of novel therapeutic targets, and the development of multi-targeted CAR-T-cell strategies.

Nanotechnology-enhanced Chimeric Antigen Receptor-T Cell Therapy for Ovarian Cancer

Mitophagy: A key regulator of radiotherapy resistance in the tumor immune microenvironment.

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized cancer treatment but continues to face substantial quality control challenges due to cellular heterogeneity. Here, we report a multiplexed nanodevice, the Aptamer Lattice-Powered Hybrid Architecture (ALPHA), for one-step phenotypic and functional analysis of CAR-T cells. By integrating aptamers targeting CD3, CD25, and CD122 into a programmable DNA lattice scaffold, ALPHA enables rapid, wash-free, and orthogonal fluorescence activation. Within 30 min, the platform distinguishes resting from activated T cells and generates an Activation Index that strongly correlates with cytokine secretion and cytotoxic function. To directly monitor cytotoxicity, an integrated ATP-responsive aptamer detects extracellular ATP released from lysed targets, enabling real-time assessment of target cell killing. ALPHA also captured donor-dependent functional variability in CAR-T samples, consistent with conventional functional readouts. Overall, ALPHA represents a versatile and scalable tool for comprehensive quality control of engineered immune cells during manufacturing.

Large B‐cell lymphoma (LBCL) accounts for about one‐third of adult lymphoma cases. Diagnosis requires specialized hematopathology laboratories, with immunophenotypic analysis essential for confirming B‐cell lineage and identifying variants. MYC and BCL2 rearrangements indicate a poor prognosis. Staging and prognosis rely on positron emission tomography computed tomography (PET‐CT). The International Prognostic Index (IPI) aids risk stratification. PET‐CT is critical for assessing treatment response and guiding strategies. First‐line management for LBCL can be informed by interim PET to assess chemosensitivity, with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) or polatuzumab vedotin rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola‐R‐CHP) for advanced stages depending on IPI scores. Primary mediastinal B‐cell lymphoma (PMBCL) management favors R‐CHOP given every 14 days (R‐CHOP14) or dose‐adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA‐EPOCH‐R) without radiotherapy in complete responders. Elderly patients, unfit or not (≥80 years or <80 with poor fitness), need geriatric assessment to guide therapy, often R‐miniCHOP or non‐anthracycline regimens. Frail patients should have adapted treatments. Prephase corticosteroids improve performance status, and supportive treatment should be optimized. The value of central nervous system (CNS) prophylaxis remains uncertain. CNS‐IPI scores and specific anatomical sites help identify high‐risk patients; magnetic resonance imaging (MRI) and colony‐stimulating factor (CSF) analysis are recommended. Approximately 30%–40% of patients with LBCL experience relapsed or refractory disease after 1L treatment. Treatment strategies vary based on the timing of relapse (<1 year or ≥1 year). For those refractory or relapsing within <1 year and fit for therapy, chimeric antigen receptor T (CART) are the gold standard in 2L. CART in CART‐naïve patients and bispecific antibodies appear to be the best approach in 3L. Follow‐up includes clinical examination for 2 years and management for long‐term side effects, such as cardiotoxicity, osteoporosis, immune dysfunction, neurocognitive impairment, endocrine dysfunction, fatigue, neuropathy, and mental distress.

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematologic malignancies, yet its efficacy in solid tumors remains limited due to antigen heterogeneity, immunosuppressive tumor microenvironments, and therapy-associated toxicities. This review highlights advances across CAR-T generations, emphasizing co-stimulatory domains and cytokine-armed TRUCKs to enhance persistence and function. Viral (lentiviral, gamma-retroviral) and non-viral (CRISPR, transposons, mRNA electroporation) delivery systems are compared for efficiency, safety, and scalability, with CRISPR enabling multiplex edits for improved specificity. Dual-targeting CARs counter antigen heterogeneity, while hypoxia-inducible and SynNotch CARs restrict activity to tumor sites. Chemokine receptor engineering enhances infiltration, and armored CARs secreting IL-12 or checkpoint inhibitors remodel the TME. Nanobody-based CAR-T cells further expand design versatility, offering improved stability, tumor penetration, and reduced immunogenicity compared with single-chain variable fragment constructs. Safety innovations include iCasp9 Suicide switches, dasatinib-controlled activation, and cytokine blockade. Clinical trials of bispecific CAR-Ts show promise, yet challenges Like manufacturing complexity and off-target effects persist. Integrating AI-driven design and Personalized neoantigen targeting may unlock CAR-T 2.0 for solid tumors, pending scalable production and regulatory harmonization.

CD70-Targeted Radiotheranostics: Now and Future.

Animal models in preclinical evaluation of CAR-T cell therapy: Advantages and limitations.

Despite the success of chimeric antigen receptor-T (CAR-T) in hematological malignancies, challenges persist, including limited efficacy in solid tumors, on-off tumor toxicity, and CAR-T cell persistence. Cellular mechanics profoundly influence cell behavior and function, yet the biophysical aspects of CAR-T cells remain underexplored. Here, we investigate various CAR molecules incorporating CD19 or CD123 recognition domains. We assess their in vitro cytotoxicity against cancer cells expressing CD19 and/or CD123 and evaluate their in vivo efficacy in mouse models. Notably, single-specific CAR-T cells targeting CD19 or CD123 exhibit potent cytotoxicity, while dual-target CAR-T cells─arranged in parallel or in crossing series─yield optimal outcomes in animal experiments. Through atomic force microscopy (AFM), we uncover a negative correlation between the binding forces of CAR-T cells and antigens and the efficacy of CAR-T therapy in animal experiments in our five dual CAR-expressing CAR-T cells. We proposed that lower binding forces lead to a faster CAR-T cell effect and detachment, enhancing killing efficiency. Our findings underscore the significance of binding forces in CAR-T cell function, highlighting the role of cellular mechanics in guiding the design and evaluation of CAR-T therapies.

Myocardial fibrosis is a common pathological feature in many cardiovascular diseases, yet effective targeted therapies remain elusive. Given the emerging potential of chimeric antigen receptor T (CAR-T) cell therapy in nononcological diseases and fibroblast activation protein (FAP) as a promising target, we engineered a second-generation FAP-targeted CAR construct incorporating the 4-1BB costimulatory domain to enhance therapeutic safety. Using two delivery approaches—lentiviral vectors and lipid nanoparticles (LNPs)—we generated FAP-CAR–engineered Jurkat cells as a preliminary screening model and evaluated their CAR expression, target recognition, and in vitro cytotoxic activity. These engineered cells selectively recognized and induced apoptosis in FAP-expressing cardiac myofibroblasts without triggering excessive IL-6 secretion, supporting their potential for fibrosis-selective cytotoxicity. Our findings provide key preliminary in vitro evidence supporting the design and target-specific functionality of FAP-targeted CAR constructs incorporating the 4-1BB domain, warranting further investigation in primary T cell models for cardiac fibrosis therapy.

Label-free chimeric antigen receptor T-cell expression analysis using neural networks and statistical distribution modeling.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by neurofibromas, with 5-13% of patients risk developing malignant peripheral nerve sheath tumors (MPNST). Current treatments for MPNST are largely ineffective. AXL, overexpressed in MPNST, is a potential target for Chimeric Antigen Receptor T (CAR-T) cell therapy. This study evaluates the immunophenotypes, efficacy, and safety of NF1-derived AXL-CAR-T cells in treating MPNST. AXL-CAR-T cells, containing an anti-AXL single-chain variable fragment, were derived from NF1 patients (n = 27) and healthy donors (n = 15). Immunophenotypes were characterized using CCR7, CD45RA, CD4, and CD8 markers. The cytotoxicity of CAR-T cells was tested in vitro against MPNST cells, and efficacy and safety were evaluated in an MPNST xenograft mouse model. Multiplex immunoassays and ELISA measured cytokines and granzyme b release. AXL-CAR-T cells from both NF1 patients and healthy donors had a similar partition in stem cell-like memory T cell composition and comparable ex vivo expansion. AXL-CAR-T cells from both groups effectively lysed MPNST cells in vitro. In vivo, tumor volumes in xenograft mice were significantly reduced with no on-target off-tumor toxicity. NF1 patient-derived AXL-CAR-T cells demonstrated similar quality and efficacy to those from healthy donors, supporting their potential autologous therapy for MPNST.

Patients with relapsed/refractory multiple myeloma (RRMM) who develop extramedullary disease (EMD) generally have a poor prognosis, highlighting the urgent need for new therapies. We report effectiveness outcomes and safety in patients with and without EMD from the pooled analysis of LocoMMotion and MoMMent. LocoMMotion and MoMMent-1 are prospective, noninterventional, consecutive studies assessing the evolving standard of care from 20192022 in patients with triple-class exposed RRMM. Of 302 patients, 29 had EMD per investigator discretion and only 15 patients were assessed as having true extramedullary plasmacytoma (EMP; defined as patients with ≥1 EMP lesion) by the response review committee. The 29 EMD patients received 21 unique regimens (most commonly chemotherapy-based regimens). Of the 29 patients with EMD, overall response rate (ORR) was 24.1%, median progression-free survival (PFS) was 2.66 months, median overall survival (OS) was 7.16 months, and median time to next treatment (TTNT) was 3.09 months. All responses were lower (ORR) and shorter (median PFS, OS, and TTNT) in patients with EMD vs patients without EMD. Nineteen (65.5%) patients with EMD received ≥1 subsequent lines of therapy. Of those, two (10.5%) patients received bispecific antibodies and achieved a partial response or better; three (15.8%) patients received antibody-drug conjugates (responses were unknown or not determined at data cut-off), and no patients received chimeric antigen receptorT cell therapy. These results demonstrate the urgent need for more effective novel therapies for patients with EMD and highlight the need to use clear definitions of EMD and EMD response criteria for clinical trials.

The clinical efficacy of immunotherapy in acute myeloid leukemia (AML) remains significantly limited by early relapse and treatment-associated toxicities. This review examines recent advances in antibody- and cell-based immunotherapies for AML, focusing on established targets (CD33, CD123, and CLL1) as well as emerging targets (including CD7, CD70, CD38, and FLT3). Therapeutic modalities discussed include immunoconjugates, bispecific T-cell engagers and chimeric antigen receptor T (CAR-T) cells. Furthermore, we summarize the current challenges impeding the success of immunotherapy in AML and propose strategies to enhance its efficacy. These include combination therapies, structural optimization of CAR constructs, functional enhancement of CAR-T cells, identification of novel targets, and the development of next-generation cellular therapies. Collectively, these approaches aim to offer new insights for improving immunotherapeutic outcomes in AML.

New targets and new drugs for hepatobiliary cancers.