Challenges in the Treatment of Glioblastoma by Chimeric Antigen Receptor T-Cell Immunotherapy and Possible Solutions

Zhang, Peng; Zhang, Yang; Ji, Nan

doi:10.3389/fimmu.2022.927132

Cited by 7 publications

(7 citation statements)

References 128 publications

(189 reference statements)

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“…The canonical "second generation" CAR recognizes target antigen by an extracellular single chain fragment of variable region (scFv) antibody that is composed of the variable domains of the antibody heavy (VH) and light (VL) chains tethered together by a short flexible linker in the order VH-VL or VL-VH (16,17). A hinge region physically connects the scFv to the transmembrane domain and is usually derived from the IgG1 CH2-CH3 region, the extracellular part of CD28 or from the hinge domain of the CD8a molecule (18).…”

Section: Modifying the Carmentioning

confidence: 99%

Fine-tuning the antigen sensitivity of CAR T cells: emerging strategies and current challenges

Harrer,

Li,

Kaljanac

et al. 2023

Front. Immunol.

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Chimeric antigen receptor (CAR) T cells are “living drugs” that specifically recognize their target antigen through an antibody-derived binding domain resulting in T cell activation, expansion, and destruction of cognate target cells. The FDA/EMA approval of CAR T cells for the treatment of B cell malignancies established CAR T cell therapy as an emerging pillar of modern immunotherapy. However, nearly every second patient undergoing CAR T cell therapy is suffering from disease relapse within the first two years which is thought to be due to downregulation or loss of the CAR target antigen on cancer cells, along with decreased functional capacities known as T cell exhaustion. Antigen downregulation below CAR activation threshold leaves the T cell silent, rendering CAR T cell therapy ineffective. With the application of CAR T cells for the treatment of a growing number of malignant diseases, particularly solid tumors, there is a need for augmenting CAR sensitivity to target antigen present at low densities on cancer cells. Here, we discuss upcoming strategies and current challenges in designing CARs for recognition of antigen low cancer cells, aiming at augmenting sensitivity and finally therapeutic efficacy while reducing the risk of tumor relapse.

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Section: Modifying the Carmentioning

confidence: 99%

Fine-tuning the antigen sensitivity of CAR T cells: emerging strategies and current challenges

Harrer,

Li,

Kaljanac

et al. 2023

Front. Immunol.

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“…Recent advances in T-cell immunotherapy and the prominent success of CAR-T-cell therapy in treating hematological malignancies have encouraged attempts to utilize these promising novel therapeutics in treating brain malignancies [ 13 , 14 ]. Despite the challenges encountered in CAR-T-cell immunotherapy for glioma, such as tumor heterogeneity, the tumor immunosuppressive microenvironment, and CAR-T-cell persistence, clinical trials have revealed significant potential for CAR-T-cell immunotherapy in treating glioma [ 15 ]. Some patients have experienced tumor shrinkage and an extended survival period [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Despite the challenges encountered in CAR-T-cell immunotherapy for glioma, such as tumor heterogeneity, the tumor immunosuppressive microenvironment, and CAR-T-cell persistence, clinical trials have revealed significant potential for CAR-T-cell immunotherapy in treating glioma [ 15 ]. Some patients have experienced tumor shrinkage and an extended survival period [ 15 , 16 ]. Notably, a patient with CAR-T targeting the antigen IL13Ra2 achieved complete remission for up to 7.5 months, marking the first instance of CAR-T treatment achieving complete remission in a solid tumor [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Expression of Interleukin-13 Receptor Alpha 2 in Brainstem Gliomas

Li,

Xiao,

Wang

et al. 2024

Cancers

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The objective of this study was to investigate IL13Ra2 expression in brainstem glioma (BSG) and its correlation with key markers, functions, and prognostic implications, evaluating its therapeutic potential. A total of 80 tumor samples from BSG patients were analyzed. Multiplex immunofluorescence was used to examine six markers—IL13Ra2, H3.3K27M, CD133, Ki67, HLA-1, and CD4—establishing relationships between IL13Ra2 and these markers. Survival analysis, employing Kaplan–Meier and Cox proportional hazard regression models, encompassed 66 patients with complete follow-up. RNA-Seq data from a previously published study involving 98 patients were analyzed using the DESeq2 library to determine differential gene expression between groups. Gene Ontology (GO) enrichment and single-sample gene set enrichment analysis (ssGSEA) via the clusterProfiler library were used to delineate the gene functions of differentially expressed genes (DEGs). Nearly all the BSG patients displayed varying IL13Ra2 expression, with 45.0% (36/80) exhibiting over a 20% increase. Elevated IL13Ra2 levels were notably observed in pontine gliomas, diffuse intrinsic pontine gliomas (DIPGs), H3F3A-mutant gliomas, and WHO IV gliomas. IL13Ra2 expression was strongly correlated with H3.3K27M mutant protein, Ki67, and CD133. Patients with IL13Ra2 expression >20% showed shorter overall survival compared to those with ≤20% IL13Ra2 expression. The Cox proportional hazard regression model identified H3F3A mutations, rather than IL13Ra2 expression, as an independent prognostic factor. Analysis of RNA-Seq data from our prior cohort confirmed IL13Ra2’s correlation with H3.3, CD133, and Ki67 levels. Widespread IL13Ra2 expression in BSG, particularly elevated in the H3F3A mutant group, was strongly correlated with H3F3A mutations, increased proliferation, and heightened tumor stemness. IL13Ra2 represents a promising therapeutic target for BSGs, potentially benefiting patients with H3K27M mutations, DIPGs, WHO Grade IV, and pontine location-specific BSGs, particularly those with H3K27M mutations.

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“…GBM is the most malignant tumour in adults, accounting for 48.6% of all malignant primary central nervous system tumors. 1 Although comprehensive treatment regimens, such as surgery, immunotherapy, and targeted therapy have been applied in clinical practice, the prognosis of patients with GBM is still poor. 2 Clinical studies have shown that the five-year survival rate is less than 10%, and the median survival time is less than 15 months.…”

Section: Introductionmentioning

confidence: 99%

VSIG4 Silencing Inhibits Glioblastoma Growth by Regulating the JAK2/STAT3 Pathway

Zheng¹,

Mao²,

Tang³

et al. 2023

NDT

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Background Glioblastoma (GBM) is the most common malignant primary brain tumour in adults. VSIG4 has been identified to be associated with GBM. We aimed to determine the downstream regulatory mechanisms of VSIG4 in GBM. Methods Differential expression of VSIG4 was analysed using GEPIA. The expression of VSIG4 was assessed by RT-qPCR and its downstream genes were screened by transcriptome sequencing. The expression of pyroptosis-related proteins and the JAK2/STAT3 pathway was measured by Western blotting. GBM cell viability, migration, and invasion were detected using CCK-8, scratch, and Transwell assays. The levels of pyroptosis-related factors were measured using ELISA. The effect of VSIG4 on GBM tumour growth in vivo was explored by constructing a xenograft tumour model. Results VSIG4 expression was upregulated in GBM. Functionally, silencing of VSIG4 inhibited proliferation, invasion, and migration of U251 and LN229 cells, and promoted pyroptosis. Mechanically, transcriptome sequencing revealed that the JAK2/STAT3 pathway might be a downstream regulator of VSIG4. Further studies proved that silencing of VSIG4 enhanced the expression of p-JAK2 and p-STAT3, and the JAK2/STAT3 pathway inhibitor relieved the suppression of VSIG4 silencing on GBM cell viability, invasion, and migration. Furthermore, in vivo experiments further validated that knockdown of VSIG4 inhibited the growth of GBM tumors. Conclusion In GBM, silencing VSIG4 promoted pyroptosis and inhibited tumor progression by regulating the JAK2/STAT3 signaling pathway.

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Challenges in the Treatment of Glioblastoma by Chimeric Antigen Receptor T-Cell Immunotherapy and Possible Solutions

Cited by 7 publications

References 128 publications

Fine-tuning the antigen sensitivity of CAR T cells: emerging strategies and current challenges

Fine-tuning the antigen sensitivity of CAR T cells: emerging strategies and current challenges

Expression of Interleukin-13 Receptor Alpha 2 in Brainstem Gliomas

VSIG4 Silencing Inhibits Glioblastoma Growth by Regulating the JAK2/STAT3 Pathway

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