Glioblastoma (GBM) is the most common primary malignant brain cancer, and is currently incurable. Chimeric Antigen Receptor (CAR) T-cells have shown promise in GBM treatment. While we have shown that combinatorial targeting of two glioma antigens offsets antigen escape and enhances T-cell effector functions, the inter-patient variability in surface antigen expression between patients hinders the clinical impact of targeting two antigen pairs. This study addresses targeting 3 antigens using a single CAR T-cell product for broader application. We analyzed the surface expression of 3 targetable glioma antigens (HER2, IL13Rα2 and EphA2) in 15 primary GBM samples. Accordingly, we created a trivalent T-cell product armed with three CAR molecules specific for these validated targets encoded by a single universal (U) tricistronic transgene (UCAR T-cells). Our data showed that co-targeting HER2, IL13Rα2 and EphA2 could overcome inter-patient variability by a tendency to capture near 100% of tumor cells in most tumors tested in this cohort. UCAR T-cells made from GBM patients’ blood uniformly expressed all three CAR molecules with distinct antigen specificity. UCAR T-cells mediated robust immune synapses with tumor targets forming more polarized microtubule organizing centers (MTOC) and exhibited improved cytotoxicity and cytokine release over best monospecific and bispecific CAR T-cells per patient tumor profile. Lastly, low doses of UCAR T-cells controlled established autologous GBM patient derived xenografts (PDX) and improved survival of treated animals. UCAR T-cells can overcome antigenic heterogeneity in GBM and lead to improved treatment outcomes.

Purpose of Review: This review will discuss the challenges facing chimeric antigen receptor (CAR)-T cell application for solid tumors and opportunities to overcome these obstacles. In addition, this review will examine therapies that are in development for pediatric solid tumors. Recent Findings: The similar success of CAR-T cell treatment for hematological malignancies has not been observed in solid tumors because of the hostile tumor microenvironment and tumor heterogeneity. Most strategies developed to combat these limitations emphasize combinatorial techniques that still require further testing. Preliminary results of multiple clinical trials, including GD2- and HER2-CAR-T cells, are encouraging but must be reproduced and validated on a larger scale. Summary: CAR-T cell application in solid tumors remains challenging, and most research is in development. Several clinical trials are ongoing for pediatric solid tumors. Early results are promising but demonstrate the need for CAR-T cell modification to prevent tumor recurrence.

Pharmacogenomics (PGx) is a growing field within precision medicine. Testing can help predict adverse events and sub-therapeutic response risks of certain medications. To date, the US FDA lists over 280 drugs which provide biomarker-based dosing guidance for adults and children. At Arkansas Children’s Hospital (ACH), a clinical PGx laboratory-based test was developed and implemented to provide guidance on 66 pediatric medications for genotype-guided dosing. This PGx test consists of 174 single nucleotide polymorphisms (SNPs) targeting 23 clinically actionable PGx genes or gene variants. Individual genotypes are processed to provide per-gene discrete results in star-allele and phenotype format. These results are then integrated into EPIC- EHR. Genomic indicators built into EPIC-EHR provide the source for clinical decision support (CDS) for clinicians, providing genotype-guided dosing.

Purpose Central nervous system (CNS) embryonal tumors are a diverse group of malignant tumors typically affecting pediatric patients that recently have been better defined, and this paper describes evolution of a unique type of embryonal tumor at relapse. Methods Two pediatric patients with CNS embryonal tumors with EWSR1-PLAGL1 rearrangements treated at Arkansas Children’s Hospital with histopathologic and molecular data are described. Results These two patients at diagnosis were classified as CNS embryonal tumors with EWSR1-PLAGL1 rearrangements based on histologic appearance and molecular data. At relapse both patient’s disease was reclassified as atypical teratoid rhabdoid tumor (ATRT) based on loss of INI-1, presence of SMARCB1 alterations, and methylation profiling results. Conclusion CNS embryonal tumors with EWSR1-PLAGL1 rearrangements acquire or include a population of cells with SMARCB1 alterations that are the component that predominate at relapse, suggesting treatment aimed at this disease component at diagnosis should be considered.

High-grade glial tumors represent the most morbid form of brain cancer