Facing CAR T Cell Challenges on the Deadliest Paediatric Brain Tumours

Ferreras, Cristina; Fernández, Lucía; Clares-Villa, Laura; Ibáñez-Navarro, Marta; Martín-Cortázar, Carla; Esteban-Rodríguez, Isabel; Saceda, Javier; Pérez‐Martínez, Antonio

doi:10.3390/cells10112940

Cited by 7 publications

(13 citation statements)

References 224 publications

(344 reference statements)

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“…The CAR T-cells on the other hand can also induce changes in the TME. For example, an increased production of INFg caused by the CAR T's, can induce immunostimulatory effects and inhibit the macrophages to differentiate to a M2-phenotype (78).…”

Section: Car T-cell Therapymentioning

confidence: 99%

The tumor micro-environment in pediatric glioma: friend or foe?

Messiaen,

Jacobs,

De Smet

2023

Front. Immunol.

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Brain tumors are the leading cause of morbidity and mortality related to cancer in children, where high-grade glioma harbor the worst prognosis. It has become obvious that pediatric glioma differs significantly from their adult counterparts, rendering extrapolations difficult. Curative options for several types of glioma are lacking, albeit ongoing research efforts and clinical trials. As already proven in the past, inter- and intratumoral heterogeneity plays an important role in the resistance to therapy and thus implicates morbidity and mortality for these patients. However, while less studied, the tumor micro-environment (TME) adds another level of heterogeneity. Knowledge gaps exist on how the TME interacts with the tumor cells and how the location of the various cell types in the TME influences tumor growth and the response to treatment. Some studies identified the presence of several (immune) cell types as prognostic factors, but often lack a deeper understanding of the underlying mechanisms, possibly leading to contradictory findings. Although the TME in pediatric glioma is regarded as “cold”, several treatment options are emerging, with the TME being the primary target of treatment. Therefore, it is crucial to study the TME of pediatric glioma, so that the interactions between TME, tumoral cells and therapeutics can be better understood before, during and after treatment. In this review, we provide an overview of the available insights into the composition and role of the TME across different types of pediatric glioma. Moreover, where possible, we provide a framework on how a particular TME may influence responses to conventional- and/or immunotherapy.

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Section: Car T-cell Therapymentioning

confidence: 99%

The tumor micro-environment in pediatric glioma: friend or foe?

Messiaen,

Jacobs,

De Smet

2023

Front. Immunol.

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“…The advances in the development of multi-antigen targeting CAR-T and the generation of CSC-specific CAR-T have enhanced confidence in its potential benefits in treating children with CNS tumours [ 175 , 176 , 177 ]. However, with no reports from large-scale trials and methodological challenges, such as the presence of the blood-brain barrier, the cross-expression of CSC markers in immature normal tissue, immune suppression by tumour microenvironment [ 178 , 179 ], treatment with CAR-T in targeting CSCs in paediatric CNS tumours still has a long way to go. The oncolytic virus was another potential way to target CSCs in children with CNS tumours, as an early review revealed multiple types of oncolytic viruses having the ability to kill CSCs [ 180 ].…”

Section: Clinical Significance Of Tumour Stem Cells In Tumours Of The...mentioning

confidence: 99%

Cancer Stem Cells in Tumours of the Central Nervous System in Children: A Comprehensive Review

Han

Lin

2023

Cancers

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Cancer stem cells (CSCs) are a subgroup of cells found in various kinds of tumours with stem cell characteristics, such as self-renewal, induced differentiation, and tumourigenicity. The existence of CSCs is regarded as a major source of tumour recurrence, metastasis, and resistance to conventional chemotherapy and radiation treatment. Tumours of the central nervous system (CNS) are the most common solid tumours in children, which have many different types including highly malignant embryonal tumours and midline gliomas, and low-grade gliomas with favourable prognoses. Stem cells from the CNS tumours have been largely found and reported by researchers in the last decade and their roles in tumour biology have been deeply studied. However, the cross-talk of CSCs among different CNS tumour types and their clinical impacts have been rarely discussed. This article comprehensively reviews the achievements in research on CSCs in paediatric CNS tumours. Biological functions, diagnostic values, and therapeutic perspectives are reviewed in detail. Further investigations into CSCs are warranted to improve the clinical practice in treating children with CNS tumours.

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“…The CAR‐T cell activity in the immunosuppressive TME can be inhibited by immune inhibitory ligands on the tumour cell surface, 122 which could induce T cell exhaustion, immunosuppressive cells, and immunosuppressive cytokines. 123 Major immunosuppressive cells include regulatory T cells (Treg), tumour‐associated macrophages (TAM) and myeloid‐derived suppressor cells (MDSC). Tregs secrete immunosuppressive cytokines which inhibit cytotoxic T cell function or limit the number of IL‐2 that can activate cytotoxic T cells.…”

Section: Overcoming the Immunosuppressive Microenvironmentmentioning

confidence: 99%

“…The immunosuppressive TME presents several challenges to CAR‐T cell therapy. The CAR‐T cell activity in the immunosuppressive TME can be inhibited by immune inhibitory ligands on the tumour cell surface, 122 which could induce T cell exhaustion, immunosuppressive cells, and immunosuppressive cytokines 123 . Major immunosuppressive cells include regulatory T cells (Treg), tumour‐associated macrophages (TAM) and myeloid‐derived suppressor cells (MDSC).…”

Section: Overcoming the Immunosuppressive Microenvironmentmentioning

confidence: 99%

Engineering chimeric antigen receptor T cells for solid tumour therapy

Liu

Cheng

et al. 2022

Clinical & Translational Med

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Cell‐based immunotherapy, for example, chimeric antigen receptor T (CAR‐T) cell immunotherapy, has revolutionized cancer treatment, particularly for blood cancers. However, factors such as insufficient T cell tracking, tumour heterogeneity, inhibitory tumour microenvironment (TME) and T cell exhaustion limit the broad application of CAR‐based immunotherapy for solid tumours. In particular, the TME is a complex and evolving entity, which is composed of cells of different types (e.g., cancer cells, immune cells and stromal cells), vasculature, soluble factors and extracellular matrix (ECM), with each component playing a critical role in CAR‐T immunotherapy. Thus, developing approaches to mitigate the inhibitory TME factors is critical for future success in applying CAR‐T cells for solid tumour treatment. Accordingly, understanding the bilateral interaction of CAR‐T cells with the TME is in pressing need to pave the way for more efficient therapeutics. In the following review, we will discuss TME‐associated aspects with an emphasis on T cell trafficking, ECM barriers, abnormal vasculature, solid tumour heterogenicity and immune suppressive microenvironment. We will then summarize current engineering strategies to overcome the challenges posed by the TME‐associated factors. Lastly, the future directions for engineering efficient CAR‐T cells for solid tumour therapy will be discussed.

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Facing CAR T Cell Challenges on the Deadliest Paediatric Brain Tumours

Cited by 7 publications

References 224 publications

The tumor micro-environment in pediatric glioma: friend or foe?

The tumor micro-environment in pediatric glioma: friend or foe?

Cancer Stem Cells in Tumours of the Central Nervous System in Children: A Comprehensive Review

Engineering chimeric antigen receptor T cells for solid tumour therapy

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