Abstract
Simple SummaryT cells that are genetically engineered to express chimeric antigen receptors constitute an effective new therapy with curative potential for patients with hematological tumors. The value of chimeric antigen receptor T cells in childhood brain tumors, the leading cause of cancer death in children, is less clear. In this context, the main obstacles for these engineered T cells remain how to find them, allow them to infiltrate, and induce them to remain active in the tumor site. Here, we discuss recent progress in the field and examine future directions for realizing the potential of this therapy.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.
Highlights
Primary brain tumors constitute the most common solid neoplasms in children and have overtaken leukemia as the leading cause of death by cancer in childhood [1]
A pool of five tumorassociated antigens (B7-H3, GD2, ILR13α2, HER2, and EPHA2) has, been identified in pediatric brain tumors (PBTs), mostly as a result of research on adult GBM [38,40,41,42] These antigens have recently been ranked according to their abundance across a panel of 49 patient-derived orthotopic xenograft (PDOX) samples, including medulloblastomas, atypical teratoid/rhabdoid tumors (ATRTs), ependymomas, and high-grade gliomas (HGGs)
While promising preclinical studies have already led to the implementation of several clinical trials in children with brain tumors, the current clinical data indicate that the efficacy of chimeric antigen receptors (CARs) T cells used as a monotherapy is not especially effective in solid tumors
Summary
Primary brain tumors constitute the most common solid neoplasms in children and have overtaken leukemia as the leading cause of death by cancer in childhood [1]. In the current WHO guidelines, PBT diagnoses and prognoses differ with WHO grade and histologic as well as molecular classification (Table 1) [2] This combined histomolecular approach allows for a much more accurate diagnosis and, has recently translated into novel therapeutic options for this population of patients, including targeted therapies. PBTs harbor a small subpopulation of self-renewing cells that are considered responsible for tumor initiation, maintenance, and recurrence [27] It is essential for the antigen target of CARs to be expressed on this subset in addition to the tumor bulk to prevent immune escape. CD19-specific CAR T cells induce B cell aplasia with subsequent hypogammaglobulinemia that is effectively manageable with immunoglobulin replacement therapy [37]
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