J Neurosurg Pediatr. 2023 Sep 8:1-8. doi: 10.3171/2023.7.PEDS22462. Online ahead of print.

ABSTRACT

OBJECTIVE: Diffuse intrinsic pontine gliomas (DIPGs) are aggressive and malignant tumors of the brainstem. Stereotactic biopsy can obtain molecular and genetic information for diagnostic and potentially therapeutic purposes. However, there is no consensus on the safety of biopsy or effect on survival. The authors aimed to characterize neurological risk associated with and the effect of stereotactic biopsy on survival among patients with DIPGs.

METHODS: A systematic review was performed in accordance with PRISMA guidelines to identify all studies examining pediatric patients with DIPG who underwent stereotactic biopsy. The search strategy was deployed in PubMed, Embase, and Scopus. The quality of studies was assessed using the Grading of Recommendations, Assessment, Development and Evaluation system, and risk of bias was evaluated with the Cochrane Risk of Bias in Nonrandomized Studies-of Interventions tool. Bibliographic, demographic, clinical, and outcome data were extracted from studies meeting inclusion criteria.

RESULTS: Of 2634 resultant articles, 13 were included, representing 192 patients undergoing biopsy. The weighted mean age at diagnosis was 7.5 years (range 0.5-17 years). There was an overall neurosurgical complication rate of 13.02% (25/192). The most common neurosurgical complication was cranial nerve palsy (4.2%, 8/192), of which cranial nerve VII was the most common (37.5%, 3/8). The second most common complication was perioperative hemorrhage (3.6%, 7/192), followed by hemiparesis (2.1%, 4/192), speech disorders (1.6%, 3/192) such as dysarthria and dysphasia, and movement disorders (1.0%, 2/192). Hydrocephalus was less commonly reported (0.5%, 1/192), and there were no complications relating to wound infection/dehiscence (0%, 0/192) or CSF leak (0%, 0/192). No mortality was specifically attributed to biopsy. Diagnostic yield of biopsy revealed a weighted mean of 97.4% (range 91%-100%). Of the studies reporting survival data, 37.6% (32/85) of patients died within the study follow-up period (range 2 weeks-48 months). The mean overall survival in patients undergoing biopsy was 9.73 months (SD 0.68, median 10 months, range 6-13 months).

CONCLUSIONS: Children with DIPGs undergoing biopsy have mild to moderate rates of neurosurgical complications and no excessive morbidity. With reasonably acceptable surgical risk and high diagnostic yield, stereotactic biopsy of DIPGs can allow for characterization of patient-specific molecular and genetic features that may influence prognosis and the development of future therapeutic strategies.

PMID:37724839 | DOI:10.3171/2023.7.PEDS22462

Oncoimmunology. 2023 Sep 12;12(1):2240670. doi: 10.1080/2162402X.2023.2240670. eCollection 2023.

ABSTRACT

BACKGROUND: Immunotherapeutic innovation is crucial for limited operability tumors. CAR T-cell therapy displayed reduced efficiency against glioblastoma (GBM), likely due to mutations underlying disease progression. Natural Killer cells (NKs) detect cancer cells despite said mutations - demonstrating increased tumor elimination potential. We developed an NK differentiation system using human pluripotent stem cells (hPSCs). Via this system, genetic modifications targeting cancer treatment challenges can be introduced during pluripotency - enabling unlimited production of modified "off-the-shelf" hPSC-NKs.

METHODS: hPSCs were differentiated into hematopoietic progenitor cells (HPCs) and NKs using our novel organoid system. These cells were characterized using flow cytometric and bioinformatic analyses. HPC engraftment potential was assessed using NSG mice. NK cytotoxicity was validated using in vitro and in vitro K562 assays and further corroborated on lymphoma, diffuse intrinsic pontine glioma (DIPG), and GBM cell lines in vitro.

RESULTS: HPCs demonstrated engraftment in peripheral blood samples, and hPSC-NKs showcased morphology and functionality akin to same donor peripheral blood NKs (PB-NKs). The hPSC-NKs also displayed potential advantages regarding checkpoint inhibitor and metabolic gene expression, and demonstrated in vitro and in vivo cytotoxicity against various cancers.

CONCLUSIONS: Our organoid system, designed to replicate in vivo cellular organization (including signaling gradients and shear stress conditions), offers a suitable environment for HPC and NK generation. The engraftable nature of HPCs and potent NK cytotoxicity against leukemia, lymphoma, DIPG, and GBM highlight the potential of this innovative system to serve as a valuable tool that will benefit cancer treatment and research - improving patient survival and quality of life.

PMID:37720687 | PMC:PMC10501168 | DOI:10.1080/2162402X.2023.2240670

Mol Cancer Ther. 2023 Sep 19. doi: 10.1158/1535-7163.MCT-23-0026. Online ahead of print.

ABSTRACT

Therapeutic resistance remains a major obstacle to successful clinical management of Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. Based on these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Since radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of ATM to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.

PMID:37723046 | DOI:10.1158/1535-7163.MCT-23-0026

Neuro Oncol. 2023 Sep 16:noad174. doi: 10.1093/neuonc/noad174. Online ahead of print.

ABSTRACT

BACKGROUND: Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy.

METHODS: We conducted a Phase 1 trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing.

RESULTS: Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n=68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n=13, range 4.7-29.7) for DIPG. The subset of n=26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p=0.006) compared to n=37 non-responders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype.

CONCLUSIONS: Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase 2/3 trials for pediatric brain tumors.

PMID:37715730 | DOI:10.1093/neuonc/noad174

Pediatr Neurol. 2023 Aug 16;148:138-141. doi: 10.1016/j.pediatrneurol.2023.08.009. Online ahead of print.

ABSTRACT

BACKGROUND: Obtaining postmortem tissue from pediatric oncology patients is critical to research and may help grieving families heal. Since 2019, the national Gift from a Child program has made significant progress in collecting postmortem tissue from pediatric patients with central nervous system tumors to advance research. This progress was at risk during the onset of the severe acute respiratory syndrome coronavirus 2 pandemic, when some autopsy programs came to a halt.

METHODS: We retrospectively reviewed autopsies of four patients treated at Memorial Sloan Kettering Cancer Center who underwent postmortem examination at Weill Cornell Medicine from June 2020 to March 2021. We collected patient demographics, Do not resuscitate status, time of death and procedure, restrictions due to the coronavirus disease 2019 (COVID-19) pandemic, and results of the tissue analysis.

RESULTS: Three of four specimens were processed within 12 hours of the time of death. Two families required interpreter services to obtain consent. In all cases, tumor aliquots were flash frozen for further study. Cell line generation was successful in one case. All families expressed gratitude both for the opportunity to participate and for the handling of the procedures.

CONCLUSIONS: Despite the sensitive nature of these cases and the challenges presented by COVID-19 restrictions, clinicians should offer the option of a rapid autopsy to caregivers of pediatric patients based on the scientific need and the positive effect it has on grieving families. This article outlines the logistic efforts required for these donations to take place and provides a framework for providers to offer rapid autopsy as an option for families through this program.

PMID:37713977 | DOI:10.1016/j.pediatrneurol.2023.08.009

Mol Cancer Ther. 2023 Sep 8. doi: 10.1158/1535-7163.MCT-23-0179. Online ahead of print.

ABSTRACT

Diffuse Intrinsic Pontine Gliomas (DIPGs) are an incurable childhood brain cancer for which novel treatments are needed. DIPGs are characterised by a mutation in the H3 histone (H3K27M), resulting in loss of H3K27 methylation and global gene dysregulation. TRX-E-009-1 is a novel anti-cancer agent with preclinical activity demonstrated against a range of cancers. We examined the anti-tumour activity of TRX-E-009-1 against DIPG neurosphere cultures and observed tumour-specific activity with IC50s ranging from 20-100 nM, while no activity was observed against normal human astrocyte cells. TRX-E-009-1 exerted its anti-proliferative effect through the induction of apoptotic pathways, with marked increases in cleaved caspase 3 and cleaved PARP levels, whilst also restoring histone H3K27me3 methylation. Co-administration of TRX-E-009-1 and the histone deacetylase (HDAC) inhibitor SAHA extended survival in DIPG orthotopic animal models. This antitumour effect was further enhanced with irradiation. Our findings indicate that TRX-E-009-1, combined with HDAC inhibition, represents a novel, potent therapy for children with DIPG.

PMID:37683275 | DOI:10.1158/1535-7163.MCT-23-0179