CAR T Cell Therapy’s Potential for Pediatric Brain Tumors

Abstract

Malignant central nervous system tumors are the leading cause of cancer death in children. Progress in high-throughput molecular techniques has increased the molecular understanding of these tumors, but the outcomes are still poor. Even when efficacious, surgery, radiation, and chemotherapy cause neurologic and neurocognitive morbidity. Adoptive cell therapy with autologous CD19 chimeric antigen receptor T cells (CAR T) has demonstrated remarkable remission rates in patients with relapsed refractory B cell malignancies. Unfortunately, tumor heterogeneity, the identification of appropriate target antigens, and location in a growing brain behind the blood–brain barrier within a specific suppressive immune microenvironment restrict the efficacy of this strategy in pediatric neuro-oncology. In addition, the vulnerability of the brain to unrepairable tissue damage raises important safety concerns. Recent preclinical findings, however, have provided a strong rationale for clinical trials of this approach in patients. Here, we examine the most important challenges associated with the development of CAR T cell immunotherapy and further present the latest preclinical strategies intending to optimize genetically engineered T cells’ efficiency and safety in the field of pediatric neuro-oncology.

The Implementation of Chimeric Antigen Receptor (CAR) T-cell Therapy in Pediatric Patients: Where Did We Come From, Where Are We Now, and Where are We Going?

“…Even within an individual tumor, or between patients with the same type of tumor, the expression levels or even presence/absence of specific antigens may vary. 134 These challenges, as well as some of the means by which they may be overcome have recently been discussed in a pair of excellent review articles. 130,131 Despite these limitations, some early evidence of success in pediatric clinical trials has been seen.…”

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

“…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 ].…”

Chemoimmunotherapy Administration Protocol Design for the Treatment of Leukemia through Mathematical Modeling and In Silico Experimentation

“…Porter et al [ 7 ] detected, also by means of flow cytometry and qPCR, persistence of CAR-T cells in the range of 14 to 49 months in the four patients who achieved CR (complete response). However, we have identified that recent studies are leaning to the side of CAR-T cells long-term persistence as new generations of these cells are being developed [ 11 , 45 , 46 , 47 ].…”