New Era of Immunotherapy in Pediatric Brain Tumors: Chimeric Antigen Receptor T-Cell Therapy.

Wan-Tai Wu,Yi-Yen Lee,Chun-Fu Lin,Wen-Ying Lin,Hsin-Hui Wang,Yi-Wei Chen,Szu-Hsien Wu

doi:10.3390/ijms22052404

Abstract

Immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy, immune checkpoint inhibitors, cancer vaccines, and dendritic cell therapy, has been incorporated as a fifth modality of modern cancer care, along with surgery, radiation, chemotherapy, and target therapy. Among them, CAR T-cell therapy emerges as one of the most promising treatments. In 2017, the first two CAR T-cell drugs, tisagenlecleucel and axicabtagene ciloleucel for B-cell acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL), respectively, were approved by the Food and Drug Administration (FDA). In addition to the successful applications to hematological malignancies, CAR T-cell therapy has been investigated to potentially treat solid tumors, including pediatric brain tumor, which serves as the leading cause of cancer-associated death for children and adolescents. However, the employment of CAR T-cell therapy in pediatric brain tumors still faces multiple challenges, such as CAR T-cell transportation and expansion through the blood–brain barrier, and identification of the specific target antigen on the tumor surface and immunosuppressive tumor microenvironment. Nevertheless, encouraging outcomes in both clinical and preclinical trials are coming to light. In this article, we outline the current propitious progress and discuss the obstacles needed to be overcome in order to unveil a new era of treatment in pediatric brain tumors.

Highlights

Introduction of Pediatric Brain TumorsPrimary malignant central nervous system (CNS) tumors, including medulloblastomas, ependymomas, astrocytomas, and germ cell tumors, serve as the second most common pediatric malignancies, just after hematological cancers [1]
The targeted antigens of Chimeric antigen receptor (CAR) T cells should be tremendously expressed on cancer cells but not on normal tissues to have the highest efficacy [52]
It has been revealed that B7-H3 CAR T cells, by producing IFNg, TNFa, and IL-2, can have antitumor effects in xenograft models [55]

Summary

Introduction of Pediatric Brain Tumors

Primary malignant central nervous system (CNS) tumors, including medulloblastomas, ependymomas, astrocytomas, and germ cell tumors, serve as the second most common pediatric malignancies, just after hematological cancers [1]. 3. Application of CAR T-Cell Therapy, from Hematological Malignancies to Pediatric Brain Tumors In 2012, the first child received CD19-targeted CAR-T therapy for her relapsed B-cell acute lymphoblastic leukemia exhibited complete remission and no refractory or relapse for more than five years [26]. Application of CAR T-Cell Therapy, from Hematological Malignancies to Pediatric Brain Tumors In 2012, the first child received CD19-targeted CAR-T therapy for her relapsed B-cell acute lymphoblastic leukemia exhibited complete remission and no refractory or relapse for more than five years [26] This finding opened up a new era of CAR-T therapy for malignancies. Many clinical trials have exhibited that CAR T-cell therapy targeting GD2 is well tolerated in neuroblastoma, and we discuss this further below [21,63,65]

Identifications of Further Antigens

Prevention of Tumor Antigens Escape

Other Ongoing Clinical Trials

Limitations of CAR T-Cell Therapy in CNS Tumors