Targeting Tumor-Associated Antigen: A Promising CAR-T Therapeutic Strategy for Glioblastoma Treatment

Zhu, Gui‐Dong; Zhang, Qing; Zhang, Junwen; Liu, Fusheng

doi:10.3389/fphar.2021.661606

Cited by 10 publications

(8 citation statements)

References 105 publications

(157 reference statements)

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“…The transmembrane domain is responsible for connecting the extracellular binding domain with the intracellular signal domain and fixing it on the cell membrane. 294 , 295 The intracellular signaling region, including the CD3-zeta domain and the costimulatory domain(s), transduces the signal of antigen recognition to the cell, mediating T-cell activation. The evolution of CAR-T cells has undergone four generations.…”

Section: Cellular Immunotherapymentioning

confidence: 99%

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Wang

Sun

2022

Sig Transduct Target Ther

172

114

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Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1/PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.

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Section: Cellular Immunotherapymentioning

confidence: 99%

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Wang

Sun

2022

Sig Transduct Target Ther

172

114

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“…In GBM, there is a relative lack of TSA [ 51 ]. CAR-T targets mostly TAA, often expressed in small amounts in normal tissues [ 52 ]. Consequently, CAR-T cells invariably harm normal tissues expressing the target antigens while simultaneously eradicating tumor cells.…”

Section: Car-t Cell Therapy In Gbmmentioning

confidence: 99%

Gene Targets of CAR-T Cell Therapy for Glioblastoma

Wang

et al. 2023

Cancers

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Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood–brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM.

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“…Immunosuppressive TME [7,8,14,22,36,66,[75][76][77][78][79][80][81][82][83] • CAR-T cells that secrete cytokines or antibodies that lead to antibody-dependent cell-mediated cytotoxicity [16,32,36…”

Section: Current Challenges Potential Solutionsmentioning

confidence: 99%

“…However, PD-L1 is upregulated in TAMs and GBM cells, which leads to immune cell dysfunction through inhibition of T cells after binding PD-1 [ 79 ]. An increased expression of inhibitory ligands is, therefore, associated with worse patient outcomes due to immune escape of the tumor [ 80 , 81 ]. CLTA-4 is another inhibitory immune checkpoint expressed on T cells that binds CD80 and CD86 expressed by APCs.…”

Section: Challengesmentioning

confidence: 99%

Chimeric Antigen Receptor T Cells in Glioblastoma—Current Concepts and Promising Future

Kringel

Lamszus

Mohme

2023

Cells

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Glioblastoma (GBM) is a highly aggressive primary brain tumor that is largely refractory to treatment and, therefore, invariably relapses. GBM patients have a median overall survival of 15 months and, given this devastating prognosis, there is a high need for therapy improvement. One of the therapeutic approaches currently tested in GBM is chimeric antigen receptor (CAR)-T cell therapy. CAR-T cells are genetically altered T cells that are redirected to eliminate tumor cells in a highly specific manner. There are several challenges to CAR-T cell therapy in solid tumors such as GBM, including restricted trafficking and penetration of tumor tissue, a highly immunosuppressive tumor microenvironment (TME), as well as heterogeneous antigen expression and antigen loss. In addition, CAR-T cells have limitations concerning safety, toxicity, and the manufacturing process. To date, CAR-T cells directed against several target antigens in GBM including interleukin-13 receptor alpha 2 (IL-13Rα2), epidermal growth factor receptor variant III (EGFRvIII), human epidermal growth factor receptor 2 (HER2), and ephrin type-A receptor 2 (EphA2) have been tested in preclinical and clinical studies. These studies demonstrated that CAR-T cell therapy is a feasible option in GBM with at least transient responses and acceptable adverse effects. Further improvements in CAR-T cells regarding their efficacy, flexibility, and safety could render them a promising therapy option in GBM.

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Targeting Tumor-Associated Antigen: A Promising CAR-T Therapeutic Strategy for Glioblastoma Treatment

Cited by 10 publications

References 105 publications

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Gene Targets of CAR-T Cell Therapy for Glioblastoma

Chimeric Antigen Receptor T Cells in Glioblastoma—Current Concepts and Promising Future

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