The peculiar challenge of bringing CAR-T cells into the brain: Perspectives in the clinical application to the treatment of pediatric central nervous system tumors
Childhood malignant brain tumors remain a significant cause of death in the pediatric population, despite the use of aggressive multimodal treatments. New therapeutic approaches are urgently needed for these patients in order to improve prognosis, while reducing side effects and long-term sequelae o...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1142597/full |
| _version_ | 1797866899967574016 |
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| author | Giada Del Baldo Giada Del Baldo Francesca Del Bufalo Claudia Pinacchio Andrea Carai Concetta Quintarelli Biagio De Angelis Pietro Merli Antonella Cacchione Franco Locatelli Franco Locatelli Angela Mastronuzzi |
| author_facet | Giada Del Baldo Giada Del Baldo Francesca Del Bufalo Claudia Pinacchio Andrea Carai Concetta Quintarelli Biagio De Angelis Pietro Merli Antonella Cacchione Franco Locatelli Franco Locatelli Angela Mastronuzzi |
| author_sort | Giada Del Baldo |
| collection | DOAJ |
| description | Childhood malignant brain tumors remain a significant cause of death in the pediatric population, despite the use of aggressive multimodal treatments. New therapeutic approaches are urgently needed for these patients in order to improve prognosis, while reducing side effects and long-term sequelae of the treatment. Immunotherapy is an attractive option and, in particular, the use of gene-modified T cells expressing a chimeric antigen receptor (CAR-T cells) represents a promising approach. Major hurdles in the clinical application of this approach in neuro-oncology, however, exist. The peculiar location of brain tumors leads to both a difficulty of access to the tumor mass, shielded by the blood-brain barrier (BBB), and to an increased risk of potentially life-threatening neurotoxicity, due to the primary location of the disease in the CNS and the low intracranial volume reserve. There are no unequivocal data on the best way of CAR-T cell administration. Multiple trials exploring the use of CD19 CAR-T cells for hematologic malignancies proved that genetically engineered T cells can cross the BBB, suggesting that systemically administered CAR-T cell can be used in the neuro-oncology setting. Intrathecal and intra-tumoral delivery can be easily managed with local implantable devices, suitable also for a more precise neuro-monitoring. The identification of specific approaches of neuro-monitoring is of utmost importance in these patients. In the present review, we highlight the most relevant potential challenges associated with the application of CAR-T cell therapy in pediatric brain cancers, focusing on the evaluation of the best route of delivery, the peculiar risk of neurotoxicity and the related neuro-monitoring. |
| first_indexed | 2024-04-09T23:31:41Z |
| format | Article |
| id | doaj.art-4dd8274939b54ffea9f0c941d210bd49 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-09T23:31:41Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-4dd8274939b54ffea9f0c941d210bd492023-03-21T04:24:05ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-03-011410.3389/fimmu.2023.11425971142597The peculiar challenge of bringing CAR-T cells into the brain: Perspectives in the clinical application to the treatment of pediatric central nervous system tumorsGiada Del Baldo0Giada Del Baldo1Francesca Del Bufalo2Claudia Pinacchio3Andrea Carai4Concetta Quintarelli5Biagio De Angelis6Pietro Merli7Antonella Cacchione8Franco Locatelli9Franco Locatelli10Angela Mastronuzzi11Department of Pediatric Haematology and Oncology, and Cell and Gene Therapy Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), Rome, ItalyDepartment of Experimental Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Pediatric Haematology and Oncology, and Cell and Gene Therapy Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), Rome, ItalyDepartment of Pediatric Haematology and Oncology, and Cell and Gene Therapy Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), Rome, ItalyDepartment of Neurosciences, Neurosurgery Unit, Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), Rome, ItalyDepartment of Pediatric Haematology and Oncology, and Cell and Gene Therapy Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), Rome, ItalyDepartment of Pediatric Haematology and Oncology, and Cell and Gene Therapy Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), Rome, ItalyDepartment of Pediatric Haematology and Oncology, and Cell and Gene Therapy Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), Rome, ItalyDepartment of Pediatric Haematology and Oncology, and Cell and Gene Therapy Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), Rome, ItalyDepartment of Pediatric Haematology and Oncology, and Cell and Gene Therapy Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), Rome, ItalyDepartment of Life Sciences and Public Health, Catholic University of the Sacred Heart, Rome, ItalyDepartment of Pediatric Haematology and Oncology, and Cell and Gene Therapy Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), Rome, ItalyChildhood malignant brain tumors remain a significant cause of death in the pediatric population, despite the use of aggressive multimodal treatments. New therapeutic approaches are urgently needed for these patients in order to improve prognosis, while reducing side effects and long-term sequelae of the treatment. Immunotherapy is an attractive option and, in particular, the use of gene-modified T cells expressing a chimeric antigen receptor (CAR-T cells) represents a promising approach. Major hurdles in the clinical application of this approach in neuro-oncology, however, exist. The peculiar location of brain tumors leads to both a difficulty of access to the tumor mass, shielded by the blood-brain barrier (BBB), and to an increased risk of potentially life-threatening neurotoxicity, due to the primary location of the disease in the CNS and the low intracranial volume reserve. There are no unequivocal data on the best way of CAR-T cell administration. Multiple trials exploring the use of CD19 CAR-T cells for hematologic malignancies proved that genetically engineered T cells can cross the BBB, suggesting that systemically administered CAR-T cell can be used in the neuro-oncology setting. Intrathecal and intra-tumoral delivery can be easily managed with local implantable devices, suitable also for a more precise neuro-monitoring. The identification of specific approaches of neuro-monitoring is of utmost importance in these patients. In the present review, we highlight the most relevant potential challenges associated with the application of CAR-T cell therapy in pediatric brain cancers, focusing on the evaluation of the best route of delivery, the peculiar risk of neurotoxicity and the related neuro-monitoring.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1142597/fullpediatric brain tumorsCAR-T cellsblood-brain barrierglymphatic systemneurotoxicity |
| spellingShingle | Giada Del Baldo Giada Del Baldo Francesca Del Bufalo Claudia Pinacchio Andrea Carai Concetta Quintarelli Biagio De Angelis Pietro Merli Antonella Cacchione Franco Locatelli Franco Locatelli Angela Mastronuzzi The peculiar challenge of bringing CAR-T cells into the brain: Perspectives in the clinical application to the treatment of pediatric central nervous system tumors Frontiers in Immunology pediatric brain tumors CAR-T cells blood-brain barrier glymphatic system neurotoxicity |
| title | The peculiar challenge of bringing CAR-T cells into the brain: Perspectives in the clinical application to the treatment of pediatric central nervous system tumors |
| title_full | The peculiar challenge of bringing CAR-T cells into the brain: Perspectives in the clinical application to the treatment of pediatric central nervous system tumors |
| title_fullStr | The peculiar challenge of bringing CAR-T cells into the brain: Perspectives in the clinical application to the treatment of pediatric central nervous system tumors |
| title_full_unstemmed | The peculiar challenge of bringing CAR-T cells into the brain: Perspectives in the clinical application to the treatment of pediatric central nervous system tumors |
| title_short | The peculiar challenge of bringing CAR-T cells into the brain: Perspectives in the clinical application to the treatment of pediatric central nervous system tumors |
| title_sort | peculiar challenge of bringing car t cells into the brain perspectives in the clinical application to the treatment of pediatric central nervous system tumors |
| topic | pediatric brain tumors CAR-T cells blood-brain barrier glymphatic system neurotoxicity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1142597/full |
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