CAR T Cell Therapy in Glioblastoma: Overcoming Challenges Related to Antigen Expression

Luksik, Andrew S.; Yazigi, Eli; Shah, P.; Jackson, Christopher M.

doi:10.3390/cancers15051414

Cited by 27 publications

(21 citation statements)

References 116 publications

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“…MSN is part of the ERM (ezrin, radixin, moesin) protein family, playing a role in cytoskeletal rearrangement and cellular morphology, potentially influencing cell motility and invasion in mesenchymal GBM. METRNL, which is implicated in immunometabolic responses, could contribute to the unique inflammatory microenvironment of the mesenchymal subtype [29]. Finally, LITAF (lipopolysaccharide-induced tumor necrosis factor-alpha factor), with its role in inflammatory response regulation, may reflect the mesenchymal subtype's pro-inflammatory traits.…”

Section: Resultsmentioning

confidence: 99%

Genetic Optimization in Uncovering Biologically Meaningful Gene Biomarkers for Glioblastoma Subtypes

Paplomatas,

Douroumi,

Vlamos

et al. 2024

BioMedInformatics

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Background: Glioblastoma multiforme (GBM) is a highly aggressive brain cancer known for its challenging survival rates; it is characterized by distinct subtypes, such as the proneural and mesenchymal states. The development of targeted therapies is critically dependent on a thorough understanding of these subtypes. Advances in single-cell RNA-sequencing (scRNA-seq) have opened new avenues for identifying subtype-specific gene biomarkers, which are essential for innovative treatments. Methods: This study introduces a genetic optimization algorithm designed to select a precise set of genes that clearly differentiate between the proneural and mesenchymal GBM subtypes. By integrating differential gene expression analysis with gene variability assessments, our dual-criterion strategy ensures the selection of genes that are not only differentially expressed between subtypes but also exhibit consistent variability patterns. This approach enhances the biological relevance of identified biomarkers. We applied this algorithm to scRNA-seq data from GBM samples, focusing on the discovery of subtype-specific gene biomarkers. Results: The application of our genetic optimization algorithm to scRNA-seq data successfully identified significant genes that are closely associated with the fundamental characteristics of GBM. These genes show a strong potential to distinguish between the proneural and mesenchymal subtypes, offering insights into the molecular underpinnings of GBM heterogeneity. Conclusions: This study introduces a novel approach for biomarker discovery in GBM that is potentially applicable to other complex diseases. By leveraging scRNA-seq data, our method contributes to the development of targeted therapies, highlighting the importance of precise biomarker identification in personalized medicine.

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Section: Resultsmentioning

confidence: 99%

Genetic Optimization in Uncovering Biologically Meaningful Gene Biomarkers for Glioblastoma Subtypes

Paplomatas,

Douroumi,

Vlamos

et al. 2024

BioMedInformatics

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“…Different ongoing clinical trials are currently testing conventional CAR T cells and recently also NK-92 cells to target different TAAs in GBM [43][44][45]. For example, clinical trials targeting the epidermal growth factor receptor variant III (EGFRvIII) showed promising outcome [46][47][48] but replicable responses were challenging to be obtained [47].…”

Section: Discussionmentioning

confidence: 99%

RevCAR-expressing immune effector cells for targeting of Fn14-positive glioblastoma

Saleh,

Mitwasi,

R. Loureiro

et al. 2024

Cancer Gene Ther

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In recent studies, we have established the unique adapter chimeric antigen receptor (CAR) platform RevCAR which uses, as an extracellular CAR domain, a peptide epitope instead of an antibody domain. RevCAR adapters (termed RevCAR target modules, RevTMs) are bispecific antibodies that enable the reversible ON/OFF switch of the RevCAR system, improving the safety compared to conventional CARs. Here, we describe for the first time its use for retargeting of both T and NK-92 cells. In addition, we describe the development and preclinical validation of a novel RevTM for targeting of the fibroblast growth factor-inducible 14 (Fn14) surface receptor which is overexpressed on Glioblastoma (GBM) cells, and therefore serves as a promising target for the treatment of GBM. The novel RevTM efficiently redirects RevCAR modified T and NK-92 cells and leads to the killing of GBM cells both in vitro and in vivo. Tumor cell killing is associated with increased IL-2, TNF-α and/or IFN-γ secretion. Hence, these findings give an insight into the complementary potential of both RevCAR T and NK-92 systems as a safe and specific immunotherapeutic approach against GBM.

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“…B7-H3 inhibits T-cell activation and proliferation, driving tumor immune evasion via diverse signaling pathways [ 123 ]. Aberrant upregulation across cancers, especially in more than half of glioblastoma cases, makes it a promising therapeutic target [ 124 ].…”

Section: Main Textmentioning

confidence: 99%

From glioma gloom to immune bloom: unveiling novel immunotherapeutic paradigms-a review

Regmi,

Wang,

Liu

et al. 2024

J Exp Clin Cancer Res

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In tumor therapeutics, the transition from conventional cytotoxic drugs to targeted molecular therapies, such as those targeting receptor tyrosine kinases, has been pivotal. Despite this progress, the clinical outcomes have remained modest, with glioblastoma patients' median survival stagnating at less than 15 months. This underscores the urgent need for more specialized treatment strategies. Our review delves into the progression toward immunomodulation in glioma treatment. We dissect critical discoveries in immunotherapy, such as spotlighting the instrumental role of tumor-associated macrophages, which account for approximately half of the immune cells in the glioma microenvironment, and myeloid-derived suppressor cells. The complex interplay between tumor cells and the immune microenvironment has been explored, revealing novel therapeutic targets. The uniqueness of our review is its exhaustive approach, synthesizing current research to elucidate the intricate roles of various molecules and receptors within the glioma microenvironment. This comprehensive synthesis not only maps the current landscape but also provides a blueprint for refining immunotherapy for glioma, signifying a paradigm shift toward leveraging immune mechanisms for improved patient prognosis.

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CAR T Cell Therapy in Glioblastoma: Overcoming Challenges Related to Antigen Expression

Cited by 27 publications

References 116 publications

Genetic Optimization in Uncovering Biologically Meaningful Gene Biomarkers for Glioblastoma Subtypes

Genetic Optimization in Uncovering Biologically Meaningful Gene Biomarkers for Glioblastoma Subtypes

RevCAR-expressing immune effector cells for targeting of Fn14-positive glioblastoma

From glioma gloom to immune bloom: unveiling novel immunotherapeutic paradigms-a review

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