RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Cellular Therapy for Children with Central Nervous System Tumors: Mining and Mapping the Correlative Data.

PURPOSE OF REVIEW: Correlative studies should leverage clinical trial frameworks to conduct biospecimen analyses that provide insight into the bioactivity of the intervention and facilitate iteration toward future trials that further improve patient outcomes. In pediatric cellular immunotherapy trials, correlative studies enable deeper understanding of T cell mobilization, durability of immune activation, patterns of toxicity, and early detection of treatment response. Here, we review the correlative science in adoptive cell therapy (ACT) for childhood central nervous system (CNS) tumors, with a focus on existing chimeric antigen receptor (CAR) and T cell receptor (TCR)-expressing T cell therapies. RECENT FINDINGS: We highlight long-standing and more recently understood challenges for effective alignment of correlative data and offer practical considerations for current and future approaches to multi-omic analysis of serial tumor, serum, and cerebrospinal fluid (CSF) biospecimens. We highlight the preliminary success in collecting serial cytokine and proteomics from patients with CNS tumors on ACT clinical trials.

Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study.

Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked the power to integrate molecular and clinical findings. The different proposed molecular group structures also highlighted a need to reach consensus on a robust and relevant classification system. We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical, and genomic features of patients and samples from these pineal tumor groups were annotated. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1 (n = 96), PB-miRNA2 (n = 23), PB-MYC/FOXR2 (n = 34), and PB-RB1 (n = 25). A final molecularly distinct group, designated PPTID (n = 43), comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease groups, laying the groundwork for future studies as well as routine use in tumor diagnostic classification and clinical trial stratification.

Phase 1 study of pomalidomide in children with recurrent, refractory, and progressive central nervous system tumors: A Pediatric Brain Tumor Consortium trial.

BACKGROUND: Central nervous system (CNS) malignancies are the most common solid tumors among children, and novel therapies are needed to help improve survival. Pomalidomide is an immunomodulatory agent that displays antiangiogenic and cytotoxic activity, making it an appropriate candidate to explore in pediatric CNS tumors. METHODS: A phase 1 first in pediatric trial of pomalidomide was conducted in children with recurrent, progressive, and refractory CNS tumors. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) when given orally once daily for 21 consecutive days of a 28-day cycle. Once the MTD was established, 12 additional patients were enrolled on expansion cohorts based on age and steroid use. RESULTS: Twenty-nine children were enrolled and 25 were evaluable for dose-limiting toxicity (DLT). The MTD was 2.6 mg/m2 (dose level 2). Four DLTs were observed in three patients at dose level 3 (3.4 mg/m2 ) includeding grade 3 diarrhea, grade 3 thrombocytopenia, grade 3 lung infection, and grade 4 neutropenia. The most common adverse events were grade 1 and 2 myelosuppression. One patient with an oligodendroglioma had stable disease for nine cycles, and a second patient with an anaplastic pleomorphic xanthoastrocytoma achieved a sustained partial response. Immunologic analyses suggested that pomalidomide triggers immunomodulation. CONCLUSIONS: The MTD of pomalidomide is 2.6 mg/m2 . It was well tolerated, and immune correlates showed a serum immune response. These data led to an industry-sponsored phase 2 trial of pomalidomide monotherapy in children with recurrent brain tumors (NCT03257631).

A phase I trial of the CDK 4/6 inhibitor palbociclib in pediatric patients with progressive brain tumors: A Pediatric Brain Tumor Consortium study (PBTC-042).

BACKGROUND: Disruption of cell-cycle regulators is a potential therapeutic target for brain tumors in children and adolescents. The aim of this study was to determine the maximum tolerated dose (MTD) and describe toxicities related to palbociclib, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in pediatric patients with progressive/refractory brain tumors with intact retinoblastoma protein. METHODS: Palbociclib was administered orally starting at 50 mg/m2 daily for the first 21 days of a 28-day course. Dose escalation was according to the Rolling-6 statistical design in less heavily (stratum I) and heavily pretreated (stratum II) patients, and MTD was determined separately for each group. Pharmacokinetic studies were performed during the first course, and pharmacodynamic studies were conducted to evaluate relationships between drug levels and toxicities. RESULTS: A total of 21 patients were enrolled on stratum I and 14 patients on stratum II. The MTD for both strata was 75 mg/m2 . Palbociclib absorption (mean Tmax between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and 19.5 h) were assessed. The most common toxicity was myelosuppression. Higher palbociclib exposure was associated with grade 3/4 neutropenia and leukopenia. Dose limiting toxicities included grade 4 neutropenia and grade 3 thrombocytopenia and dehydration. No patients had an objective response to palbociclib therapy. CONCLUSIONS: Palbociclib was safely administered to children and adolescents at a dosage of 75 mg/m2 for 21 consecutive days followed by seven days of rest in both strata. Future studies will establish its optimal utilization in pediatric patients with brain tumors.

Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study.

Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.

Medulloblastoma rendered susceptible to NK-cell attack by TGFß neutralization.

BACKGROUND: Medulloblastoma (MB), the most common pediatric brain cancer, presents with a poor prognosis in a subset of patients with high risk disease, or at recurrence, where current therapies are ineffective. Cord blood (CB) natural killer (NK) cells may be promising off-the-shelf effector cells for immunotherapy due to their recognition of malignant cells without the need for a known target, ready availability from multiple banks, and their potential to expand exponentially. However, they are currently limited by immune suppressive cytokines secreted in the MB tumor microenvironment including Transforming Growth Factor ß (TGF-ß). Here, we address this challenge in in vitro models of MB. METHODS: CB-derived NK cells were modified to express a dominant negative TGF-ß receptor II (DNRII) using retroviral transduction. The ability of transduced CB cells to maintain function in the presence of medulloblastoma-conditioned media was then assessed. RESULTS: We observed that the cytotoxic ability of nontransduced CB-NK cells was reduced in the presence of TGF-ß-rich, medulloblastoma-conditioned media (21.21 ± 1.19% killing at E:T 5:1 in the absence vs. 14.98 ± 2.11% in the presence of medulloblastoma-conditioned media, n = 8, p = 0.02), but was unaffected in CB-derived DNRII-transduced NK cells (21.11 ± 1.84% killing at E:T 5:1 in the absence vs. 21.81 ± 3.37 in the presence of medulloblastoma-conditioned media, n = 8, p = 0.85. We also observed decreased expression of CCR2 in untransduced NK cells (mean CCR2 MFI 826 ± 117 in untransduced NK + MB supernatant from mean CCR2 MFI 1639.29 ± 215 in no MB supernatant, n = 7, p = 0.0156), but not in the transduced cells. Finally, we observed that CB-derived DNRII-transduced NK cells may protect surrounding immune cells by providing a cytokine sink for TGF-ß (decreased TGF-ß levels of 610 ± 265 pg/mL in CB-derived DNRII-transduced NK cells vs. 1817 ± 342 pg/mL in untransduced cells; p = 0.008). CONCLUSIONS: CB NK cells expressing a TGF-ß DNRII may have a functional advantage over unmodified NK cells in the presence of TGF-ß-rich MB, warranting further investigation on its potential applications for patients with medulloblastoma.

Heterogeneity within the PF-EPN-B ependymoma subgroup.

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

A pediatric brain tumor consortium phase II trial of capecitabine rapidly disintegrating tablets with concomitant radiation therapy in children with newly diagnosed diffuse intrinsic pontine gliomas.

BACKGROUND: We conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG). PATIENTS AND METHODS: Children 3-17 years with newly diagnosed DIPG were eligible. Capecitabine, 650 mg/m2 /dose BID (maximum tolerated dose [MTD] in children with concurrent radiation), was administered for 9 weeks starting the first day of RT. Following a 2-week break, three courses of capecitabine, 1,250 mg/m2 /dose BID for 14 days followed by a 7-day rest, were administered. As prospectively designed, 10 evaluable patients treated at the MTD on the phase I trial were included in the phase II analyses. The design was based on comparison of the PFS distribution to a contemporary historical control (n = 140) with 90% power to detect a 15% absolute improvement in the 1-year PFS with a type-1 error rate, α = 0.10. RESULTS: Forty-four patients were evaluable for the phase II objectives. Capecitabine and RT was well tolerated with low-grade palmar plantar erythrodyesthesia, increased alanine aminotransferase, cytopenias, and vomiting the most commonly reported toxicities. Findings were significant for earlier progression with 1-year PFS of 7.21% (SE = 3.47%) in the capecitabine-treated cohort versus 15.59% (SE = 3.05%) in the historical control (P = 0.007), but there was no difference for overall survival (OS) distributions (P = 0.30). Tumor enhancement at diagnosis was associated with shorter PFS and OS. Capecitabine was rapidly absorbed and converted to its metabolites. CONCLUSION: Capecitabine did not improve the outcome for children with newly diagnosed DIPG.

Anaplastic Ependymoma in a Child With Sickle Cell Anemia: A Case Report Highlighting Treatment Challenges for Young Children With Central Nervous System Tumors and Underlying Vasculopathy.

A 3-year-old boy with sickle cell anemia (SCA) presented with progressive daily emesis and was found to have an anaplastic ependymoma. Radiation therapy and chemotherapy are usually employed after subtotal resections of anaplastic ependymomas, although the benefits from chemotherapy are unclear. To mitigate the risks of adjuvant treatment in this patient at risk for SCA-associated vasculopathy, renal impairment, and other end-organ damage, proton beam irradiation without chemotherapy was chosen. Scheduled packed red blood cell transfusions were instituted to maintain sickle hemoglobin levels less than 30%. This case highlights treatment complexities for malignant brain tumors in patients predisposed to treatment-related adverse effects.

Pediatric Brain Tumors: Current Knowledge and Therapeutic Opportunities.

Great progress has been made in many areas of pediatric oncology. However, tumors of the central nervous system (CNS) remain a significant challenge. A recent explosion of data has led to an opportunity to understand better the molecular basis of these diseases and is already providing a foundation for the pursuit of rationally chosen therapeutics targeting relevant molecular pathways. The molecular biology of pediatric brain tumors is shifting from a singular focus on basic scientific discovery to a platform upon which insights are being translated into therapies.

An open-label, two-stage, phase II study of bevacizumab and lapatinib in children with recurrent or refractory ependymoma: a collaborative ependymoma research network study (CERN).

Co-expression of ERBB2 and ERBB4, reported in 75% of pediatric ependymomas, correlates with worse overall survival. Lapatinib, a selective ERBB1 and ERBB2 inhibitor has produced prolonged disease stabilization in patients with ependymoma in a phase I study. Bevacizumab exposure in ependymoma xenografts leads to ablation of tumor self-renewing cells, arresting growth. Thus, we conducted an open-label, phase II study of bevacizumab and lapatinib in children with recurrent ependymomas. Patients ≤ 21 years of age with recurrent ependymoma received lapatinib orally twice daily (900 mg/m(2)/dose to the first 10 patients, and then 700 mg/m(2)/dose) and bevacizumab 10 mg/kg intravenously on days 1 and 15 of a 28-day course. Lapatinib serum trough levels were analyzed prior to each course. Total and phosphorylated VEGFR2 expression was measured in peripheral blood mononuclear cells (PBMCs) before doses 1 and 2 of bevacizumab and 24-48 h following dose 2 of bevacizumab. Twenty-four patients with a median age of 10 years (range 2-21 years) were enrolled; 22 were eligible and 20 evaluable for response. Thirteen had anaplastic ependymoma. There were no objective responses; 4 patients had stable disease for ≥ 4 courses (range 4-14). Grade 3 toxicities included rash, elevated ALT, and diarrhea. Grade 4 toxicities included peri-tracheostomy hemorrhage (n = 1) and elevated creatinine phosphokinase (n = 1). The median lapatinib pre-dose trough concentration was 3.72 µM. Although the combination of bevacizumab and lapatinib was well tolerated in children with recurrent ependymoma, it proved ineffective.

WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.

WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling.

Transcriptomic observations of intra and extracellular immunotherapy targets for pediatric brain tumors.

OBJECTIVES: Despite surgical resection, chemoradiation, and targeted therapy, brain tumors remain a leading cause of cancer-related death in children. Immunotherapy has shown some promise and is actively being investigated for treating childhood brain tumors. However, a critical step in advancing immunotherapy for these patients is to uncover targets that can be effectively translated into therapeutic interventions. METHODS: In this study, our team performed a transcriptomic analysis across pediatric brain tumor types to identify potential targets for immunotherapy. Additionally, we assessed components that may impact patient response to immunotherapy, including the expression of genes essential for antigen processing and presentation, inhibitory ligands and receptors, interferon signature, and overall predicted T cell infiltration. RESULTS: We observed distinct expression patterns across tumor types. These included elevated expression of antigen genes and antigen processing machinery in some tumor types while other tumors had elevated inhibitory checkpoint receptors, known to be associated with response to checkpoint inhibitor immunotherapy. CONCLUSION: These findings suggest that pediatric brain tumors exhibit distinct potential for specific immunotherapies. We believe our findings can guide investigators in their assessment of appropriate immunotherapy classes and targets in pediatric brain tumors.

Sluggish cognitive tempo in survivors of pediatric brain tumors.

The presence of neurocognitive late effects in survivors of pediatric brain tumors is well established. However, there remains some debate about how best to conceptualize these deficits. Sluggish cognitive tempo (SCT) is a proposed conceptual framework that has been used to describe a subset of children with ADHD who exhibit a particular profile characterized by lethargy, day dreaming and staring, and poor organization. Previous work has suggested that survivors of leukemia exhibit a similar profile, but it has not yet been examined in survivors of pediatric brain tumors. A sample of 65 survivors of pediatric brain tumors, 25 survivors of leukemia and 50 community controls completed the Child Behavior Checklist, with four items used to measure SCT. Survivors completed additional measures of neurocognitive functioning. Survivors of brain tumors demonstrated significantly greater symptoms of SCT than survivors of leukemia or controls. SCT was associated with attention problems and working memory deficits and the presence of a VP-shunt. Results provided conditional support for the presence of SCT in survivors of brain tumors, with further research needed to determine the clinical utility of the framework.

Long-term efficacy and toxicity of bevacizumab-based therapy in children with recurrent low-grade gliomas.

BACKGROUND: Because definitive resection or radiotherapy for pediatric low-grade gliomas (LGGs) may be associated with severe and permanent adverse effects, medical management has taken a significant role. Bevacizumab-based therapy has demonstrated encouraging responses; however, longer-term toxicity, response durability and alternative dosing regimens have not been evaluated. PROCEDURE: This was a retrospective review of children with multiply recurrent, progressive LGGs treated with bevacizumab-based therapy and followed for at least 12 months after treatment completion. Toxicity was uniformly graded and imaging was centrally reviewed. RESULTS: All fourteen patients had failed at least two prior treatment regimens; six had dissemination. Patients received initial bevacizumab-based therapy at a median age of 5.3 years (range, 1-12 years). Median treatment duration was 12 months (range, 1-24 months). 12 patients had an objective response; 2 had stable disease. Median time to maximum response was 9 weeks (range, 7-17 weeks). No patients progressed on therapy, although 13/14 progressed after stopping bevacizumab at a median of 5 months. Four patients were re-treated with bevacizumab and all again responded or stabilized. Alternative dosing strategies were effective, including bevacizumab monotherapy and prolonging the dosing interval to 3 weeks. High-grade bevacizumab-related toxicities consisted of grade 3 proteinuria (n = 2), primary inflammatory arthritis (n = 1), and somnolence (n = 1). Toxicities resolved within 6 months of treatment cessation except one case of hypertension. CONCLUSIONS: Bevacizumab-based therapy is successful at inducing rapid LGG response. Patients progressing off-therapy may be successfully re-treated with bevacizumab. Nearly all tumors progress once treatment is discontinued. Toxicities are not insignificant but usually reversible.

Why haven't we solved intracranial pediatric ependymoma? Current questions and barriers to treatment advances.

Pediatric intracranial ependymoma has seen a recent exponential expansion of biological findings, rapidly dividing the diagnosis into several subgroups, each with specific molecular and clinical characteristics. While such subdivision may complicate clinical conclusions from historical trials, this knowledge also provides an opportunity for interrogating the major clinical and biological questions preventing near-term translation into effective therapy for children with ependymoma. In this article, we briefly review some of the most critical clinical questions facing both patient management and the construct of future trials in childhood ependymoma, as well as explore some of the current barriers to efficient translation of preclinical discovery to the clinic.

Safety of Tumor Treating Fields (TTFields) therapy in pediatric patients with malignant brain tumors: Post-marketing surveillance data.

There is an unmet need to develop effective and tolerable treatments for pediatric patients with malignant central nervous system tumors. This is especially essential for pediatric patients with aggressive brain tumors such as high-grade gliomas, which have a typical survival rate of under 2 years. Tumor Treating Fields (TTFields) are locoregional, noninvasive electric fields that produce an antimitotic effect on cancerous cells when applied to the skin via arrays. TTFields therapy (200 kHz) is currently approved in adult patients with newly diagnosed glioblastoma (GBM), with temozolomide, and recurrent GBM as monotherapy. Positive preclinical and clinical data have encouraged off-label use of TTFields therapy in pediatric patients with brain tumors, and this study aims to explore the safety of TTFields therapy in pediatric patients (0-18 years of age) based on data from an unsolicited post-marketing surveillance safety database. The real-world data reported here demonstrate that TTFields therapy has a favorable safety profile for pediatric patients with brain tumors, with no new safety signals observed. Findings from this study warrant further research into the efficacy of TTFields therapy, as well as its potential impact on the quality of life in pediatric patients.

Co-transducing B7H3 CAR-NK cells with the DNR preserves their cytolytic function against GBM in the presence of exogenous TGF-ß.

Cord blood (CB)-derived natural killer (NK) cells that are genetically engineered to express a chimeric antigen receptor (CAR) are an attractive off-the-shelf therapy for the treatment of cancer, demonstrating a robust safety profile in vivo. For poor prognosis brain tumors such as glioblastoma multiforme (GBM), novel therapies are urgently needed. Although CAR-T cells demonstrate efficacy in preclinical GBM models, an off-the-shelf product may exhibit unwanted side effects like graft-versus-host disease. Hence, we developed an off-the-shelf CAR-NK cell approach using a B7H3 CAR and showed that CAR-transduced NK cells have robust cytolytic activity against GBM cells in vitro. However, transforming growth factor (TGF)-ß within the tumor microenvironment has devastating effects on the cytolytic activity of both unmodified and CAR-transduced NK cells. To overcome this potent immune suppression, we demonstrated that co-transducing NK cells with a B7H3 CAR and a TGF-ß dominant negative receptor (DNR) preserves cytolytic function in the presence of exogenous TGF-ß. This study demonstrates that a novel DNR and CAR co-expression strategy may be a promising therapeutic for recalcitrant CNS tumors like GBM.