Conditionally replicative adenovirus as a therapy for malignant peripheral nerve sheath tumors.

Oncolytic adenoviruses (Ads) stand out as a promising strategy for the targeted infection and lysis of tumor cells, with well-established clinical utility across various malignancies. This study delves into the therapeutic potential of oncolytic Ads in the context of neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs). Specifically, we evaluate conditionally replicative adenoviruses (CRAds) driven by the cyclooxygenase 2 (COX2) promoter, as selective agents against MPNSTs, demonstrating their preferential targeting of MPNST cells compared with non-malignant Schwann cell control. COX2-driven CRAds, particularly those with modified fiber-knobs exhibit superior binding affinity toward MPNST cells and demonstrate efficient and preferential replication and lysis of MPNST cells, with minimal impact on non-malignant control cells. In vivo experiments involving intratumoral CRAd injections in immunocompromised mice with human MPNST xenografts significantly extend survival and reduce tumor growth rate compared with controls. Moreover, in immunocompetent mouse models with MPNST-like allografts, CRAd injections induce a robust infiltration of CD8+ T cells into the tumor microenvironment (TME), indicating the potential to promote a pro-inflammatory response. These findings underscore oncolytic Ads as promising, selective, and minimally toxic agents for MPNST therapy, warranting further exploration.

Revealing Pan-Histology Immunomodulatory Targets in Pediatric Central Nervous System Tumors.

BACKGROUND: The application of immunotherapy for pediatric CNS malignancies has been limited by the poorly understood immune landscape in this context. The aim of this study was to uncover the mechanisms of immune suppression common among pediatric brain tumors. METHODS: We apply an immunologic clustering algorithm validated by The Cancer Genome Atlas Project to an independent pediatric CNS transcriptomic dataset. Within the clusters, the mechanisms of immunosuppression are explored via tumor microenvironment deconvolution and survival analyses to identify relevant immunosuppressive genes with translational relevance. RESULTS: High-grade diseases fall predominantly within an immunosuppressive subtype (C4) that independently lowers overall survival time and where common immune checkpoints (e.g., PDL1, CTLA4) are less relevant. Instead, we identify several alternative immunomodulatory targets with relevance across histologic diseases. Specifically, we show how the mechanism of EZH2 inhibition to enhance tumor immunogenicity in vitro via the upregulation of MHC class 1 is applicable to a pediatric CNS oncologic context. Meanwhile, we identify that the C3 (inflammatory) immune subtype is more common in low-grade diseases and find that immune checkpoint inhibition may be an effective way to curb progression for this subset. CONCLUSIONS: Three predominant immunologic clusters are identified across pediatric brain tumors. Among high-risk diseases, the predominant immune cluster is associated with recurrent immunomodulatory genes that influence immune infiltrate, including a subset that impacts survival across histologies.

Characterizing Immune-Mediated Cytopenias After Allogeneic Hematopoietic Cell Transplantation for Pediatric Nonmalignant Disorders.

Immune-mediated cytopenias (IMC)-isolated or combined hemolytic anemia, thrombocytopenia, or neutropenia-are increasingly recognized as serious complications after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant disorders (NMD). However, IMC incidence, duration, response to therapy, and risk factors are not well defined. This retrospective chart review identified cases of IMC with serologic confirmation among patients who underwent HCT for NMD at a single institution between 2010 and 2017. IMC after HCT for NMD in a large pediatric cohort (n = 271) was common with a cumulative incidence of 18%, identified at a median of 136 days after HCT. Treatment included prolonged immune suppression (>3 months) in 58% of all IMC cases, 91% when multiple cell lines were affected. Multiple therapeutic agents were used for the majority affected, and median time to resolution of IMC was 118 days from diagnosis. Fine-Gray competing risk multivariate regression analysis identified a combined risk factor of younger age (<3 years) and inherited metabolic disorder, as well as hemoglobinopathy (at any age) associated with 1-year incidence of IMC (P < .01). We expand these findings with the observation of declining donor T-lymphoid chimerism from day 60 to 100 and lower absolute CD4+ counts at day 100 (P < .01), before median onset of IMC, for patients with IMC compared to those without. In this cohort, 4 deaths (8%) were associated with IMC, including 2 requiring second transplantation for secondary graft failure. Although the pathogenesis of IMC post-HCT for NMD remains elusive, further research may identify approaches to prevent and better treat this HCT complication.

Concurrent Subcutaneous Panniculitis-like T-Cell Lymphoma and B-Cell Acute Lymphoblastic Leukemia in 2 Pediatric Patients.

Subcutaneous panniculitis-like T-cell lymphoma is a cutaneous lymphoma characterized by CD8+ T-cell infiltrate in the subcutis that is rare in children. Acute lymphoblastic lymphoma is the most common pediatric malignancy and often presents with fevers and pancytopenia. Herein, we report 2 pediatric patients presenting with subcutaneous panniculitis-like T-cell lymphoma and B-cell acute lymphoblastic lymphoma, distinct hematologic malignancies arising from different lymphoid lineages, with no identifiable germline cancer predisposition.