Optimizing T Cell-Based Therapy for Glioblastoma

Karachi, Aida; Dastmalchi, Farhad; Nazarian, Saina; Huang, Jianping; Sayour, Elias; Jin, Linchun; Yang, Changlin; Mitchell, Duane A.; Rahman, Maryam

doi:10.3389/fimmu.2021.705580

Cited by 11 publications

(12 citation statements)

References 89 publications

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“…Tumor antigen loss after the infiltration of CAR-T cells into the tumor site represents a common mechanism of immune escape and resistance to CAR-T cell therapy [ 16 , 90 , 92 , 93 ]. Therefore, designing multivalent CARs could contribute to the success of the therapy.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Site-Specific Considerations on Engineered T Cells for Malignant Gliomas

et al. 2022

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Immunotherapy has revolutionized cancer treatment. Despite the recent advances in immunotherapeutic approaches for several tumor entities, limited response has been observed in malignant gliomas, including glioblastoma (GBM). Conversely, one of the emerging immunotherapeutic modalities is chimeric antigen receptors (CAR) T cell therapy, which demonstrated promising clinical responses in other solid tumors. Current pre-clinical and interventional clinical studies suggest improved efficacy when CAR-T cells are delivered locoregionally, rather than intravenously. In this review, we summarize possible CAR-T cell administration routes including locoregional therapy, systemic administration with and without focused ultrasound, direct intra-arterial drug delivery and nanoparticle-enhanced delivery in glioma. Moreover, we discuss published as well as ongoing and planned clinical trials involving CAR-T cell therapy in malignant glioma. With increasing neoadjuvant and/or adjuvant combinatorial immunotherapeutic concepts and modalities with specific modes of action for malignant glioma, selection of administration routes becomes increasingly important.

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Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Site-Specific Considerations on Engineered T Cells for Malignant Gliomas

et al. 2022

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“…In addition, preferential infiltration of Vγ9Vδ2 T cells in the GBM patient tissues was also observed ( 26 ). Because pre-existing T cells are not sufficient to eradicate tumors, interest in adoptive cell therapy has gained traction ( 144 ). However, adoptive therapy using in vitro expanded conventional T cells has shown low effectiveness ( 145 ).…”

Section: The Role Of γδ T Cells In Brain Diseasesmentioning

confidence: 99%

γδ T Cells in Brain Homeostasis and Diseases

2022

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γδ T cells are a distinct subset of T cells expressing γδ T cell receptor (TCR) rather than αβTCR. Since their discovery, the critical roles of γδ T cells in multiple physiological systems and diseases have been investigated. γδ T cells are preferentially located at mucosal surfaces, such as the gut, although a small subset of γδ T cells can circulate the blood. Additionally, a subset of γδ T cells reside in the meninges in the central nervous system. Recent findings suggest γδ T cells in the meninges have critical roles in brain function and homeostasis. In addition, several lines of evidence have shown γδ T cells can infiltrate the brain parenchyma and regulate inflammatory responses in multiple diseases, including neurodegenerative diseases. Although the importance of γδ T cells in the brain is well established, their roles are still incompletely understood due to the complexity of their biology. Because γδ T cells rapidly respond to changes in brain status and regulate disease progression, understanding the role of γδ T cells in the brain will provide critical information that is essential for interpreting neuroimmune modulation. In this review, we summarize the complex role of γδ T cells in the brain and discuss future directions for research.

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“…Mechanistically, GBM tumour cell kynurenine production activates the aryl hydrocarbon receptor (AHR) on TAMs, decreasing NFKβ signalling and thereby promoting an M2-like phenotype, leading to cytotoxic CD8+ T cell dysfunction [ 275 ]. Dysfunctional T cells are defined by the loss of effector function, including the loss of cytotoxicity and the decreased secretion of inflammatory cytokines such as TNFα and IFNγ [ 276 ] which, in turn, decrease M1 TAM polarisation, perpetuating the low inflammatory microenvironment characteristic of this disease. Further, the increased expression of Arg-1 by M2 macrophages is able to directly suppress T cell function within the microenvironment through the arginase-mediated depletion of arginine, which induces the down-regulation of the T cell CD3ζ chain [ 277 ].…”

Section: Activating the Immune Response As A Potential Therapeutic Option In Dmgsmentioning

confidence: 99%

“…In addition to targeting the upstream activation of the inflammatory response through modulation of the TAM phenotype switch, augmentation of T cell activation by employing CAR T therapy is another potential therapeutic avenue aimed at beneficially altering the DMG tumour microenvironment. In CAR T therapy, peripherally circulating T cells are primed against antigens by ex vivo co-culturing with antigen-loaded dendritic cells or, alternately, are modified with a CAR gene, arming these cytolytic T cells with a receptor that can recognize a surface protein on tumour cells [ 276 ]. These cells are then expanded in culture before being infused into patients as an adoptive T cell transfer [ 278 ].…”

Section: Activating the Immune Response As A Potential Therapeutic Option In Dmgsmentioning

confidence: 99%

“…The primary hurdle to successful CAR T cell therapy is the engraftment of cells, involving both the sufficient migration of the transferred cells to within the tumour microenvironment and the sustained activation of their anti-tumour responses [ 276 ]. One approach to improve engraftment is the pre-conditioning of patients with chemotherapy to induce lymphopenia, with this approach currently in the recruitment stage of a phase I clinical trial within the setting of DMGs (NCT03396575).…”

Section: Activating the Immune Response As A Potential Therapeutic Option In Dmgsmentioning

confidence: 99%

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Therapeutic Targets in Diffuse Midline Gliomas—An Emerging Landscape

Hayden

Holliday

Lehmann

et al. 2021

Cancers

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Diffuse midline gliomas (DMGs) are invariably fatal pediatric brain tumours that are inherently resistant to conventional therapy. In recent years our understanding of the underlying molecular mechanisms of DMG tumorigenicity has resulted in the identification of novel targets and the development of a range of potential therapies, with multiple agents now being progressed to clinical translation to test their therapeutic efficacy. Here, we provide an overview of the current therapies aimed at epigenetic and mutational drivers, cellular pathway aberrations and tumor microenvironment mechanisms in DMGs in order to aid therapy development and facilitate a holistic approach to patient treatment.

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Optimizing T Cell-Based Therapy for Glioblastoma

Cited by 11 publications

References 89 publications

Site-Specific Considerations on Engineered T Cells for Malignant Gliomas

Site-Specific Considerations on Engineered T Cells for Malignant Gliomas

γδ T Cells in Brain Homeostasis and Diseases

Therapeutic Targets in Diffuse Midline Gliomas—An Emerging Landscape

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