Current progress in CAR‑T cell therapy for tumor treatment (Review)

Chen, Lei; Xie, Ting; Wei, Bing; Di, Dalin

doi:10.3892/ol.2022.13478

Cited by 11 publications

(5 citation statements)

References 95 publications

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“…The clinical results of this study were somewhat less encouraging, with only one in fifteen patients achieving stable disease. A key limitation of CAR therapy lies in its reliance on targeting antigens that are visibly displayed on the surface of tumor cells [210]. As a result, this approach is unable to address intracellular proteins, which constitute a substantial portion of cellular proteins.…”

Section: Engineered T-cell Therapymentioning

confidence: 99%

Epigenetic and Genetic Keys to Fight HPV-Related Cancers

Folliero,

Dell’Annunziata,

Chianese

et al. 2023

Cancers

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Cervical cancer ranks as the fourth most prevalent cancer among women globally, with approximately 600,000 new cases being diagnosed each year. The principal driver of cervical cancer is the human papillomavirus (HPV), where viral oncoproteins E6 and E7 undertake the role of driving its carcinogenic potential. Despite extensive investigative efforts, numerous facets concerning HPV infection, replication, and pathogenesis remain shrouded in uncertainty. The virus operates through a variety of epigenetic mechanisms, and the epigenetic signature of HPV-related tumors is a major bottleneck in our understanding of the disease. Recent investigations have unveiled the capacity of viral oncoproteins to influence epigenetic changes within HPV-related tumors, and conversely, these tumors exert an influence on the surrounding epigenetic landscape. Given the escalating occurrence of HPV-triggered tumors and the deficiency of efficacious treatments, substantial challenges emerge. A promising avenue to address this challenge lies in epigenetic modulators. This review aggregates and dissects potential epigenetic modulators capable of combatting HPV-associated infections and diseases. By delving into these modulators, novel avenues for therapeutic interventions against HPV-linked cancers have come to the fore.

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Section: Engineered T-cell Therapymentioning

confidence: 99%

Epigenetic and Genetic Keys to Fight HPV-Related Cancers

Folliero,

Dell’Annunziata,

Chianese

et al. 2023

Cancers

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“…The target protein/antigen for these approaches does not need to be a driver of the disease, thus greatly expanding the number of cancer targets in oncology. In particular, lineage-specific antigens, such as CD19, have been successfully employed as targets for ADCs and CAR-T therapy in hematological malignancies [7], [8].…”

Section: Introductionmentioning

confidence: 99%

Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively

Raina¹,

Forbes²,

Stronk³

et al. 2023

Preprint

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While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities. Here, we describe a proof-of-concept study using novel heterobifunctional small molecules called Regulated Induced Proximity Targeting Chimeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein. Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein.

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“…In this regard, CD19-directed CAR-T cell treatment resulted in persistence of immunological memory, trafficking to the tumor sites, and antitumor activity, which led to tumor regression and, in most of the patients, complete remission [3][4][5]. Since 2017, six CAR-T cell therapies have been approved by the Food and Drug Administration (FDA) and by European Medicines Agency (EMA), among which four anti-CD19 CAR-T cells [6]. All have been approved for the treatment of hematologic malignancies, including relapsed or refractory B-ALL, diffuse large B-cell non-Hodgkin lymphoma (B-NHL), follicular lymphoma (FL), mantle cell lymphoma, and multiple myeloma.…”

Section: Introductionmentioning

confidence: 99%

Optimization and validation of in vivo flow cytometry chimeric antigen receptor T cell detection method using CD19his indirect staining

Zaninelli,

Meli,

Borleri

et al. 2023

Cytometry Pt A

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CD19‐targeted Chimeric Antigen Receptor T (CAR‐T) cell therapy has shown unprecedented results in patients with B cell relapsed/refractory acute lymphoblastic leukemia (R/R‐ALL) and B cell non‐Hodgkin lymphomas where no other curative options are available. In vivo monitoring of CAR‐T cell kinetics is fundamental to understand the correlation between CAR‐T cells expansion and persistence with treatment response and toxicity development. The aim of this study was to define a robust, sensitive, and universal method for CAR‐T cell detection using flow cytometry. We set‐up and compared with each other three assays for CD19 CAR‐T cell detection, all based on commercially available reagents. All methods used a recombinant human CD19 protein fragment recognized by the single chain variable fragment of the CAR construct. The two indirect staining assays (CD19his + APC‐conjugated anti‐histidine antibody and CD19bio + APC‐conjugated anti‐biotin antibody) showed better sensitivity and specificity compared to the direct staining with CD19‐FITC, and CD19his had a better cost‐effective profile. We validated CAR detection with CD19his with parallel quantitative real time PCR data and we could demonstrate a strong positive correlation. We also showed that CD19his staining can be easily included in a multicolor flow cytometry panel to achieve additional information about the cell phenotype of CAR‐T cell positive subpopulations. Finally, this method can be used for different anti‐CD19 CAR‐T cell products and for different sample sources. These data demonstrate that detection of CAR‐T cells by CD19his flow cytometry staining is a reliable, robust, and broadly applicable tool for in vivo monitoring of CAR‐T cells.This article is protected by copyright. All rights reserved.

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Current progress in CAR‑T cell therapy for tumor treatment (Review)

Cited by 11 publications

References 95 publications

Epigenetic and Genetic Keys to Fight HPV-Related Cancers

Epigenetic and Genetic Keys to Fight HPV-Related Cancers

Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively

Optimization and validation of in vivo flow cytometry chimeric antigen receptor T cell detection method using CD19his indirect staining

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