Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition

Journal of Hematology & Oncology, Journal Year: 2025, Volume and Issue: 18(1)

Published: Jan. 13, 2025

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, signaling molecules that interact promote growth therapeutic resistance. Elucidating the intricate interactions between cells TME crucial in understanding progression challenges. A critical process induced by epithelial-mesenchymal transition (EMT), wherein epithelial acquire mesenchymal traits, which enhance their motility invasiveness progression. By targeting various components TME, novel investigational strategies aim disrupt TME's contribution EMT, thereby improving efficacy, addressing resistance, offering a nuanced approach therapy. This review scrutinizes key players emphasizing avenues therapeutically components. Moreover, article discusses implications for resistance mechanisms highlights current toward modulation along with potential caveats.

Language: Английский

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Enhancing precision in cancer treatment: the role of gene therapy and immune modulation in oncology

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 11

Published: Jan. 13, 2025

Gene therapy has long been a cornerstone in the treatment of rare diseases and genetic disorders, offering targeted solutions to conditions once considered untreatable. As field advances, its transformative potential is now expanding into oncology, where personalized therapies address immune-related complexities cancer. This review highlights innovative therapeutic strategies, including gene replacement, silencing, oncolytic virotherapy, CAR-T cell therapy, CRISPR-Cas9 editing, with focus on their application both hematologic malignancies solid tumors. CRISPR-Cas9, revolutionary tool precision medicine, enables precise editing cancer-driving mutations, enhancing immune responses disrupting tumor growth mechanisms. Additionally, emerging approaches target ferroptosis—a regulated, iron-dependent form death—offering new possibilities for selectively inducing death resistant cancers. Despite significant breakthroughs, challenges such as heterogeneity, evasion, immunosuppressive microenvironment (TME) remain. To overcome these barriers, novel like dual-targeting, armored cells, combination checkpoint inhibitors ferroptosis inducers are being explored. rise allogeneic “off-the-shelf” offers scalable more accessible options. The regulatory landscape evolving accommodate advancements, frameworks RMAT (Regenerative Medicine Advanced Therapy) U.S. ATMP (Advanced Therapy Medicinal Products) Europe fast-tracking approval therapies. However, ethical considerations surrounding CRISPR-based editing—such off-target effects, germline ensuring equitable access—remain at forefront, requiring ongoing oversight. Advances non-viral delivery systems, lipid nanoparticles (LNPs) exosomes, improving safety efficacy By integrating innovations addressing concerns, poised revolutionize cancer treatment, providing durable, effective,

Language: Английский

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Engineering strategies to safely drive CAR T-cells into the future

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: June 19, 2024

Chimeric antigen receptor (CAR) T-cell therapy has proven a breakthrough in cancer treatment the last decade, giving unprecedented results against hematological malignancies. All approved CAR products, as well many being assessed clinical trials, are generated using viral vectors to deploy exogenous genetic material into T-cells. Viral have long-standing history gene delivery, and thus underwent iterations of optimization improve their efficiency safety. Nonetheless, capacity integrate semi-randomly host genome makes them potentially oncogenic via insertional mutagenesis dysregulation key cellular genes. Secondary cancers following administration appear be rare adverse event. However several cases documented few years put spotlight on this issue, which might been underestimated so far, given relatively recent deployment therapies. Furthermore, initial successes obtained malignancies not yet replicated solid tumors. It is now clear that further enhancements needed allow T-cells increase long-term persistence, overcome exhaustion cope with immunosuppressive tumor microenvironment. To aim, variety genomic engineering strategies under evaluation, most relying CRISPR/Cas9 or other editing technologies. These approaches liable introduce unintended, irreversible alterations product cells. In first part review, we will discuss non-viral used for generation T-cells, whereas second focus non-gene engineering, particular regard advantages, limitations, Finally, critically analyze different combinations, delineating superior safety profile production next-generation T-cell.

Language: Английский

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CAR-T cell therapy in Multiple Myeloma: current status and future challenges

Blood Cancer Journal, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 26, 2024

The treatment of multiple myeloma has changed dramatically in recent years, with huge strides forward made the field. Chimeric antigen receptor T-cell therapy targeting B cell maturation (BCMA) is now widely approved relapsed refractory patients and moving into earlier lines. In this review, we discuss evidence underpinning current regulatory approvals consider mechanisms through which CAR-T efficacy could be improved. These include tackling BCMA-loss, harnessing immunosuppressive tumour microenvironment, manufacturing concerns including potential role other cellular sources, safety issues such as cytokine release syndrome neurotoxicity, optimal patient selection.

Language: Английский

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From ex vivo to in vivo chimeric antigen T cells manufacturing: new horizons for CAR T-cell based therapy

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

Published: Jan. 4, 2025

Abstract In the past decades, Chimeric Antigen Receptor (CAR)-T cell therapy has achieved remarkable success, leading to approval of six therapeutic products for haematological malignancies. Recently, potential this also been demonstrated in non-tumoral diseases. Currently, manufacturing process produce clinical-grade CAR-T cells is complex, time-consuming, and highly expensive. It involves multiple steps, including collection T from patients or healthy donors, vitro engineering expansion, finally reinfusion into patients. Therefore, despite impressive clinical outcomes, ex vivo makes out reach many cancer Direct could be a more rapid solution able circumvent both complexity costs associated with manufactured cells. This novel approach allows completely eliminate manipulation expansion while producing populations directly vivo. To date, several studies have feasibility reprogramming, by employing injectable viral- nanocarrier-based delivery platforms tumour animal models. Additionally, production might reduce incidence, at least severity, systemic toxicities frequently occurring produced cells, such as cytokine release syndrome immune effector cell-associated neurotoxicity syndrome. review, we highlight challenges current protocols review latest progresses emerging field therapy, comparing various so far investigated. Moreover, offer an overview advantages deriving reprogramming other types, Natural Killer macrophages, CAR constructs.

Language: Английский

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Alloreactive-free CAR-VST therapy: a step forward in long-term tumor control in viral context

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 15, 2025

CAR-T cell therapy has revolutionized immunotherapy but its allogeneic application, using various strategies, faces significant challenges including graft-versus-host disease and graft rejection. Recent advances Virus Specific T cells to generate CAR-VST have demonstrated potential for enhanced persistence antitumor efficacy, positioning CAR-VSTs as a promising alternative conventional in an setting. This review provides comprehensive overview of development, emphasizing strategies mitigate immunogenicity, such specialized TCR, approaches improve therapeutic against host immune responses. In this review, we discuss the production methods explore optimization enhance their functionality, activation profiles, memory persistence, exhaustion resistance. Emphasis is placed on unique dual specificity both antiviral responses, along with in-depth examination preclinical clinical outcomes. We highlight how these contribute efficacy durability settings, offering new perspectives broad applications. By focusing key mechanisms that enable address autologous challenges, highlights strategy developing effective therapies.

Language: Английский

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The Evolving Landscape in Multiple Myeloma: From Risk Stratification to T Cell-Directed Advanced Therapies

Cancers, Journal Year: 2025, Volume and Issue: 17(3), P. 525 - 525

Published: Feb. 5, 2025

Multiple myeloma is biologically and clinically a complex heterogeneous disease which develops late in life, with the median age at time of initial diagnosis being 66 years. In 1975, Durie Salmon developed first broadly adopted staging system multiple myeloma, ensuing decades, risk stratification tools have improved now incorporate different parameters to better predict prognosis guide treatment decisions. The International Staging System (ISS) was initially 2005, revised 2015 (R-ISS), again 2022 (R2-ISS). Tremendous progress has been achieved therapy over past 25 years approval immunomodulatory drugs, proteasome inhibitors, anti-CD38 monoclonal antibodies, resulting major paradigm shift. dysfunction innate adaptive immune system, especially T cell repertoire, represents hallmark evolution time, supporting need for additional therapeutic approaches activate host’s overcome immunosuppressive tumor microenvironment. Novel cell-directed therapies include chimeric antigen receptor (CAR) bispecific antibodies that leverage system’s cells recognize attack cells. Second-generation anti-BCMA CAR bind BCMA or GPRC5D onto CD3 on cell’s surface are currently available relapsed/refractory myeloma. Despite impressive results obtained approved treatments, remains incurable, almost all patients eventually relapse. Moreover, extramedullary plasma leukemia represent an unmet medical require strategies improve outcome. this review, we provide overview

Language: Английский

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Clinical Proof-of-Concept of a Non-Gene Editing Technology Using miRNA-Based shRNA to Engineer Allogeneic CAR T-Cells

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1658 - 1658

Published: Feb. 15, 2025

With the success of chimeric antigen receptor (CAR) T-cell therapy in B-cell malignancies, efforts are being made to extend this other malignancies and broader patient populations. However, limitations associated with time-consuming highly personalized manufacturing autologous CAR T-cells remain. Allogeneic approaches may overcome these challenges but require further engineering reduce their alloreactivity. As a means prevent graft-versus-host disease (GvHD) allogeneic T-cells, we have selected micro RNA (miRNA)-based short hairpin (shRNA) targeting CD3ζ which efficiently downregulates expression (TCR) below detection level. We generated anti-B-cell maturation (CYAD-211) that co-express an anti-CD3ζ miRNA-based shRNA within construct inhibited TCR-mediated signaling vitro GvHD vivo. CYAD-211 was subsequently evaluated Phase-I clinical trial (NCT04613557), patients relapsed or refractory multiple myeloma. No signs were observed despite evidence engraftment, demonstrating efficient downregulation TCR. Our data provide proof concept non-gene-edited technology can generate fully functional without any GvHD. is needed improve persistence long-term activity.

Language: Английский

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Key Challenges in CAR T-Cell Therapy Access in Community Oncology

JAMA Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

This Viewpoint discusses the need to bring chimeric antigen receptor T-cell (CAR-T) therapy community oncology, which will allow an uninterrupted continuum of care for patients.

Language: Английский

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A chimeric antigen receptor tailored to integrate complementary activation signals potentiates the antitumor activity of NK cells

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: March 6, 2025

Chimeric antigen receptors (CARs) are synthetic that reprogram the target specificity and functions of CAR-expressing effector cells. The design CAR constructs typically includes an extracellular antigen-binding moiety, hinge (H), transmembrane (TM), intracellular signaling domains. Conventional primarily designed for T cells but have been directly adopted other cells, including natural killer (NK) without tailored optimization. Given benefits CAR-NK over CAR-T in terms safety, off-the-shelf utility, escape, there is increasing emphasis on tailoring them to NK cell activation mechanisms. We first taken a stepwise approach modifying components such as combination order H, TM, domains achieve Functionality NK-tailored CARs were evaluated vitro vivo model CD19-expressing lymphoma, along with their expression properties found NK-CAR driven by synergistic NKG2D 2B4 rather than DNAM-1 induces potent Further, more effective CAR-mediated cytotoxicity was observed following sequential DAP10, not domain despite capacity TM recruit endogenous DAP10 signaling. Accordingly, incorporating 2B4, CD3ζ coupled CD8α H CD28 identified most promising candidate improve cytotoxicity. This provided antitumor activity conventional T-CAR when delivered both vivo. Hence, receptor-based hold great promise future potentially significant therapeutic benefits.

Language: Английский

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