Immunotherapy for pediatric brain tumors

Landi, Daniel; Thompson, Eric M.; Ashley, David M.

doi:10.20517/2347-8659.2018.35

Cited by 9 publications

(12 citation statements)

References 96 publications

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“…At this point in time, the option of immunotherapy is not available to the subset of PCA patients whose tumors are difficult to eradicate. Understanding the immune environment in which pediatric brain tumors exist is a first step to identifying effective immune-based therapies for these diseases [30]. As no matched normal brain tissue is collected as part of the surgical procedure, we did not compare cytokine expression between tumor cells and their non-tumor counterparts for each patient.…”

Section: Discussionmentioning

confidence: 99%

“…Currently, we are aware of the benefits of immunotherapy for various malignancies [28,29]. Here, treatment leverages the high specificity of the immune system to target and eliminate neoplastic cells while leaving healthy cells undamaged [30]. Extrapolating this concept into CNS malignancies, a thorough understanding of the immune environment of brain tumors will be a requisite to identify effective immune-based treatments [30].…”

Section: Introductionmentioning

confidence: 99%

“…Here, treatment leverages the high specificity of the immune system to target and eliminate neoplastic cells while leaving healthy cells undamaged [30]. Extrapolating this concept into CNS malignancies, a thorough understanding of the immune environment of brain tumors will be a requisite to identify effective immune-based treatments [30]. For the purposes of this study, the authors postulate that immunotherapy may be helpful for the subset of therapeutically difficult PCAs.…”

Section: Introductionmentioning

confidence: 99%

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Cytokines in Pediatric Pilocytic Astrocytomas: A Clinico-Pathological Study

et al. 2021

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Pilocytic astrocytomas (PCA) are WHO Grade I tumors with a favorable prognosis. Surgical resection is usually curative. Nonetheless, progressive and/or metastatic disease occurs in 20% of patients. For these patients, treatment options are limited. The role of the immune system in PCA has not previously been reported. We hypothesize that the circulating cytokines contribute to tumorigenicity in PCA. This is an exploratory study with a focus on the identification of circulating cerebrospinal (CSF) cytokines associated with PCA. The primary objective is to demonstrate that CSF cytokines will be differentially expressed in the subset of PCAs that are difficult to treat in comparison to their surgically amendable counterparts. This is a single-institution, retrospective study of prospectively collected data. Patients with a confirmed histological diagnosis of PCA who have simultaneous intraoperative CSF sampling are included. Cerebrospinal fluid samples are subjected to multiplex cytokine profiling. Patient-derived PCA lines from selected patients in the same study cohort are cultured. Their cell culture supernatants are collected and interrogated using the sample multiplex platform as the CSF. A total of 8 patients are recruited. There were two patients with surgically difficult tumors associated with leptomeningeal involvement. Multiplex profiling of the cohort’s CSF samples showed elevated expressions of IFN-γ, IL-2, IL-12p70, IL-1β, IL-4, and TNF-α in these two patients in comparison to the remaining cohort. Next, primary cell lines derived from the same PCA patients demonstrated a similar trend of differential cytokine expression in their cell culture supernatant in vitro. Although our findings are preliminary at this stage, this is the first study in pediatric PCAs that show cytokine expression differences between the two groups of PCA with different clinical behaviors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cytokines in Pediatric Pilocytic Astrocytomas: A Clinico-Pathological Study

et al. 2021

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“…In adult glioma, higher numbers of infiltrating CD8+ T cells are associated with longer survival 102 . Pediatric brain tumors are generally immunologically “cold” and lack T cell infiltration 103 , 104 . Tumor neoantigens, activating cytokines, the tumor vasculature, and integrins all contribute to T cell homing 5 ; brain tumors have a unique extracellular matrix that prevents T cell migration 105 .…”

Section: Immunotherapymentioning

confidence: 99%

Epigenomics and immunotherapeutic advances in pediatric brain tumors

et al. 2021

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Brain tumors are the leading cause of childhood cancer-related deaths. Similar to adult brain tumors, pediatric brain tumors are classified based on histopathological evaluations. However, pediatric brain tumors are often histologically inconsistent with adult brain tumors. Recent research findings from molecular genetic analyses have revealed molecular and genetic changes in pediatric tumors that are necessary for appropriate classification to avoid misdiagnosis, the development of treatment modalities, and the clinical management of tumors. As many of the molecular-based therapies developed from clinical trials on adults are not always effective against pediatric brain tumors, recent advances have improved our understanding of the molecular profiles of pediatric brain tumors and have led to novel epigenetic and immunotherapeutic treatment approaches currently being evaluated in clinical trials. In this review, we focus on primary malignant brain tumors in children and genetic, epigenetic, and molecular characteristics that differentiate them from brain tumors in adults. The comparison of pediatric and adult brain tumors highlights the need for treatments designed specifically for pediatric brain tumors. We also discuss the advancements in novel molecularly targeted drugs and how they are being integrated with standard therapy to improve the classification and outcomes of pediatric brain tumors in the future.

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“…Chemotherapy and radiation are the standard of care, but survival benefits are slim with high risks of side effects and decreased quality of life during and after treatment 1 . Immunotherapeutic approaches have had limited success due to the low mutational burden and immunosuppressive microenvironment of pediatric brain tumors, such that adaptive immune interventions including checkpoint blockade are ineffective 2 . Recent efforts to molecularly profile pHGGs have discovered conserved mutations unique to the pediatric age range and anatomical locations 3 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic inhibition of lysine specific demethylase-1 (LSD1) as a therapeutic and immune-sensitization strategy in diffuse intrinsic pontine glioma (DIPG)

Bailey

Romero²,

Becher³

et al. 2019

Preprint

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BackgroundDiffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor. Mutations in the H3 histone tail (H3.1/3.3-K27M) are a feature of DIPG, potentially rendering them therapeutically sensitive to small-molecule inhibition of chromatin modifiers. Pharmacological inhibition of lysine specific demethylase-1 (LSD1) shows promise in pediatric cancers such as Ewing’s sarcoma, but has not been investigated in DIPG, which was the aim of our study.MethodsPatient-derived DIPG cell lines and pediatric high-grade glioma (pHGG) datasets were used to evaluate effects of several LSD1 inhibitors on selective cytotoxicity and immune gene expression. Immune cell cytotoxicity was assessed in DIPG cells treated with LSD1 inhibitors and informatics platforms were used to determine immune infiltration of pHGG and impact on survival.ResultsSelective cytotoxicity and an immunogenic gene signature was established in DIPG lines using several clinically-relevant LSD1 inhibitors. Pediatric high-grade glioma patient sequencing data demonstrated survival benefit using this LSD1-dependent gene signature. On-target binding of catalytic LSD1 inhibitors was confirmed in DIPG and pre-treatment of DIPG with these inhibitors increased lysis by natural killer (NK) cells. CIBERSORT analysis of patient data confirmed NK infiltration is beneficial to patient survival while CD8 T-cells are negatively prognostic. Catalytic LSD1 inhibitors are non-perturbing to NK cells while scaffolding LSD1 inhibitors are toxic to NK cells and do not induce the gene signature in DIPG cells.ConclusionsLSD1 inhibition using catalytic inhibitors are both selectively cytotoxic and promote an immune gene signature that is associated with NK cell killing, representing a therapeutic opportunity for pHGG.Key pointsLSD1 inhibition using several clinically relevant compounds is selectively cytotoxic in DIPG.An LSD1-controlled gene signature predicts survival in pediatric high-grade glioma patients.LSD1 inhibition enhances NK cell cytotoxicity against DIPG with correlative genetic biomarkers.Importance of the studyThis is the first study to evaluate inhibition of LSD1 in a uniformly lethal type of pediatric brain tumor: DIPG. We demonstrate selective cytotoxicity of several clinically relevant compounds against patient derived DIPG cells, and identify an immune gene signature that is upregulated in DIPG cells by catalytic inhibitors of LSD1. This immune gene signature is predictive of prognosis in pHGG, consistent with the rationale of promoting this signature through LSD1 inhibition. NK cell killing of DIPG is enhanced by LSD1 inhibition, providing functional confirmation of this gene signature, and represents the first report of LSD1 inhibition promoting NK cell cytotoxicity of cancer cells. Given the poor prognosis of pHGGs and lack of effective treatments, our results suggest use of LSD1 inhibition as a single agent or in combination with NK cell therapy may be a safe and efficacious strategy.

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Immunotherapy for pediatric brain tumors

Cited by 9 publications

References 96 publications

Cytokines in Pediatric Pilocytic Astrocytomas: A Clinico-Pathological Study

Cytokines in Pediatric Pilocytic Astrocytomas: A Clinico-Pathological Study

Epigenomics and immunotherapeutic advances in pediatric brain tumors

Pharmacologic inhibition of lysine specific demethylase-1 (LSD1) as a therapeutic and immune-sensitization strategy in diffuse intrinsic pontine glioma (DIPG)

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