Bispecific T-Cell Engagers and Chimeric Antigen Receptor T-Cell Therapies in Glioblastoma: An Update

Current Oncology, Journal Year: 2023, Volume and Issue: 30(9), P. 8501 - 8549

Published: Sept. 15, 2023

Glioblastoma is the most common malignant primary brain tumor in adults. The prognosis extremely poor even with standard treatment of maximal safe resection, radiotherapy, and chemotherapy. Recurrence inevitable within months, options are very limited. Chimeric antigen receptor T-cell therapy (CART) bispecific engagers (TCEs) two emerging immunotherapies that can redirect T-cells for tumor-specific killing have shown remarkable success hematological malignancies been under extensive study application glioblastoma. While there multiple clinical trials showing preliminary evidence safety efficacy CART, TCEs still early stages testing, preclinical studies promising results. However, shared challenges need to be addressed future, including route delivery, escape, immunosuppressive microenvironment, toxicity resulting from limited choice antigens. Efforts underway optimize design both these treatments find ideal combination overcome challenges. In this review, we describe work has performed as well novel approaches glioblastoma other solid tumors may applicable future.

Language: Английский

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Tumor endothelial cell autophagy is a key vascular‐immune checkpoint in melanoma

EMBO Molecular Medicine, Journal Year: 2023, Volume and Issue: 15(12)

Published: Nov. 27, 2023

Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show autophagy ablation in TECs boosts antitumor immunity by supporting infiltration effector function of T-cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss TEC leads to transcriptional expression immunostimulatory/inflammatory phenotype driven heightened NF-kB STING signaling. line, single-cell transcriptomic datasets from patients disclose enriched InflammatoryHigh /AutophagyLow correlation with clinical immunotherapy, responders exhibit increased presence inflamed vessels interfacing infiltrating CD8+ T-cells. Mechanistically, STING-dependent is not critical for immunomodulatory effects ablation, since NF-kB-driven inflammation remains functional STING/ATG5 double knockout TECs. Hence, our study identifies as a principal vascular anti-inflammatory mechanism dampening immunity.

Language: Английский

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Targeting vascular normalization: a promising strategy to improve immune–vascular crosstalk in cancer immunotherapy

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Dec. 15, 2023

Blood vessels are a key target for cancer therapy. Compared with the healthy vasculature, tumor blood extremely immature, highly permeable, and deficient in pericytes. The aberrantly vascularized microenvironment is characterized by hypoxia, low pH, high interstitial pressure, immunosuppression. efficacy of chemotherapy, radiotherapy, immunotherapy affected abnormal vessels. Some anti-angiogenic drugs show vascular normalization effects addition to targeting angiogenesis. Reversing state creates normal microenvironment, essential various treatments, specifically immunotherapy. In addition, immune cells molecules involved regulation Therefore, combining may increase reduce risk adverse reactions. this review, we discussed structure, function, formation elaborated on role immunosuppressive Finally, described clinical challenges associated combination normalization, highlighted future research directions therapeutic area.

Language: Английский

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Insights gained from single-cell analysis of chimeric antigen receptor T-cell immunotherapy in cancer

Military Medical Research, Journal Year: 2023, Volume and Issue: 10(1)

Published: Nov. 8, 2023

Abstract Advances in chimeric antigen receptor (CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies. However, progress is still hindered as benefit only available for a fraction patients. A lack understanding CAR-T behaviors vivo at the single-cell level impedes their more extensive application practice. Mounting evidence suggests that sequencing techniques can help perfect design, guide gene-based T modification, and optimize manufacturing conditions, all them are essential long-term immunosurveillance favorable outcomes. The information generated by employing these methods also potentially informs our numerous complex factors dictate therapeutic efficacy toxicities. In this review, we discuss reasons why immunotherapy fails practice what field has learned since milestone technologies. We further outline recent advances analyses immunotherapy. Specifically, provide an overview studies focusing on target antigens, CAR-transgene integration, preclinical research applications, then how it will affect future therapy.

Language: Английский

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EGFRVIII and EGFR targeted chimeric antigen receptor T cell therapy in glioblastoma

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Sept. 19, 2024

Glioblastoma is the most common primary brain tumor. Although there have been significant advances in surgical techniques, chemo and immunotherapies, radiation therapy, outcomes continue to be devastating for these patients with minimal improvements survival. Chimeric antigen receptor T cell therapy a revolutionary approach that new pillar treatment of cancer. CAR has produced remarkable results hematological malignancies; however, multiple limitations currently prevent it from being first-line especially solid tumors. Epidermal growth factor classically amplified glioblastoma, variant, EGFR variant III, expressed on making an exciting potential target therapy. preclinical potential, clinical data heterogeneous. In this review, we assess state field EGFR-targeted cells.

Language: Английский

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Modulation of blood-tumor barrier transcriptional programs improves intratumoral drug delivery and potentiates chemotherapy in GBM

Science Advances, Journal Year: 2025, Volume and Issue: 11(9)

Published: Feb. 26, 2025

Efficient drug delivery to glioblastoma (GBM) is a major obstacle as the blood-brain barrier (BBB) and blood-tumor (BTB) prevent passage of majority chemotherapies into brain. Here, we identified transcriptional 12-gene signature associated with BTB in GBM. We CDH5 core molecule this set confirmed its expression GBM vasculature using transcriptomics immunostaining patient specimens. The indirubin-derivative, 6-bromoindirubin acetoxime (BIA), down-regulates other genes, causing endothelial disruption vitro murine xenograft models. Treatment BIA increased intratumoral cisplatin accumulation potentiated DNA damage by targeting repair pathways. Last, an injectable nanoparticle formulation, PPRX-1701, significantly improved efficacy Our work reveals potential targets bifunctional properties modulator potentiator chemotherapy, supporting further development.

Language: Английский

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Immune Cell Interplay in the Fight Against GBM

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 817 - 817

Published: Feb. 26, 2025

Despite multimodal therapies, the treatment of glioblastoma remains challenging. In addition to very complex mechanisms cancer cells, including specialized phenotypes that enable them proliferate, invade tissues, and evade immunosurveillance, they exhibit a pronounced resistance chemo- radiotherapy. More advanced tumors create hypoxic environment supports their proliferation survival, while robust angiogenesis ensures constant supply nutrients. GBM, these structures are contribute creation maintenance highly immunosuppressive microenvironment promotes tumor growth immune escape. addition, high accumulation tumor-infiltrating leukocytes other expression checkpoint molecules, low mutational burden, i.e., number neoantigens, hallmarks GBM challenge therapeutic approaches. Here, we review exploits support potential treatments. These include new chemotherapeutics, treating fields, small compounds targeting or blockers tyrosine kinases inhibit cell survival. focus on immunotherapies such as blockade in particular vaccination with dendritic cells CAR-T which can either kill directly bypass immunosuppression by modulating boosting patient's own response.

Language: Английский

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Multi-omic landscape of human gliomas from diagnosis to treatment and recurrence

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

Gliomas are among the most lethal cancers, with limited treatment options. To uncover hallmarks of therapeutic escape and tumor microenvironment (TME) evolution, we applied spatial proteomics, transcriptomics, glycomics to 670 lesions from 310 adult pediatric patients. Single-cell analysis shows high B7H3+ cell prevalence in glioblastoma (GBM) pleomorphic xanthoastrocytoma (PXA), while gliomas, including cases, express targetable antigens less than 50% cells, potentially explaining trial failures. Longitudinal samples isocitrate dehydrogenase (IDH)-mutant gliomas reveal recurrence driven by tumor-immune reorganization, shifting T-cell vasculature-associated myeloid cell-enriched niches microglia CD206+ macrophage-dominated tumors. Multi-omic integration identified N-glycosylation as best classifier grade, immune transcriptome predicted GBM survival. Provided a community resource, this study opens new avenues for glioma targeting, classification, outcome prediction, baseline TME composition across all stages.

Language: Английский

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Inhibition of VEGF signaling prevents exhaustion and enhances anti-leukemia efficacy of CAR-T cells via Wnt/β-catenin pathway

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 30, 2025

Current challenges in Chimeric Antigen Receptor (CAR) -T cell therapy for hematological cancers include T exhaustion and limited persistence, which contribute to cancer relapse. The effects of Axitinib, a VEGFR inhibitor, on the biological functions CAR-T cells vitro vivo were investigated by comparing pre-treated ex with as well utilizing B-ALL mouse model. Real-time quantitative PCR Western blotting employed detect expression molecules related differentiation, exhaustion, Wnt pathway cells. Flow cytometry was used assess changes activation, apoptosis, proliferation, cytokine secretion. flow expression. Bioluminescence imaging, cytometry, immunohistochemistry (IHC) analysis evaluate tumor burden mice receiving different treatments, while hematoxylin eosin (H&E) staining monitor histological liver spleen mice. Axitinib treatment notably reduced terminal differentiation both under tonic signaling antigen exposure scenarios. Furthermore, pretreated demonstrated enhanced anti-tumor efficacy prolonged survival vivo. Mechanistically, upregulated Wnt/β-catenin Using agonists/inhibitors could respectively mimic or counteract differentiation. treated can inhibit VEGFR2 pathway. anti-VEGFR2 antibody activate prevent exhaustion. confers resistance modulating

Language: Английский

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The Potential Use of Digital Twin Technology for Advancing CAR-T Cell Therapy

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(5), P. 321 - 321

Published: April 30, 2025

CAR-T cell therapy is a personalized immunotherapy that has shown promising results in treating hematologic cancers. However, its therapeutic efficacy solid cancers often limited by tumor evasion mechanisms, resistance pathways, and an immunosuppressive microenvironment. These challenges highlight the need for advanced predictive models to better capture intricate interactions between cells tumors enhance their potential. Digital Twins represent transformative approach optimizing providing virtual representation of therapy-tumor trajectory using high-dimensional patient data. In this review, we first define outline fundamental steps development. We then explore critical parameters required designing CAR-T-specific Twins. examine published case studies demonstrating few applications addressing key therapy, including impact on clinical trials manufacturing processes. Finally, discuss limitations associated with integrating into therapy. As Twin technology continues evolve, potential through precision modeling real-time adaptation could redefine landscape cancer treatment.

Language: Английский

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