Background Immunotherapy with CAR T-cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class-I expression is unknown, which is critical for tumor recognition by conventional αβTCR T-cells. Methods We profiled 49 low- and high-grade pediatric brain tumor patient-derived orthotopic xenografts (PDOX) by flow analysis for the expression of five CAR targets (B7-H3, GD2, IL13Rα2, EphA2, HER2), and HLA class-I. In addition, we generated B7-H3-CAR T-cells and evaluated their antitumor activity in vitro and in vivo. Results We established an expression hierarchy for the analyzed antigens (B7-H3 = GD2 >> IL13Rα2 > HER2 = EphA2) and demonstrated that antigen expression is heterogenous. All high-grade gliomas expressed HLA class-I, but only 57.1% of other tumor subtypes had detectable expression. We then selected B7-H3 as a target for CAR T-cell therapy. B7-H3-CAR T-cells recognized tumor cells in an antigen-dependent fashion. Local or systemic administration of B7-H3-CAR T-cells induced tumor regression in PDOX and immunocompetent murine glioma models resulting in a significant survival advantage. Conclusions Our study highlights the importance of studying target antigen and HLA class-I expression in PDOX samples for the future design of immunotherapies. In addition, our results support active preclinical and clinical exploration of B7-H3-targeted CAR T-cell therapies for a broad spectrum of pediatric brain tumors.
Adoptive cellular immunotherapy using immune cells expressing chimeric antigen receptors (CARs) has shown promise, particularly for the treatment of hematological malignancies. To date, the majority of clinically evaluated CAR cell products have been derived from autologous immune cells. While this strategy can be effective it also imposes several constraints regarding logistics. This includes i) availability of center to perform leukapheresis, ii) necessity for shipment to and from processing centers, and iii) time requirements for product manufacture and clinical release testing. In addition, previous cytotoxic therapies can negatively impact the effector function of autologous immune cells, which may then affect efficacy and/or durability of resultant CAR products. The use of allogeneic CAR cell products generated using cells from healthy donors has the potential to overcome many of these limitations, including through generation of “off the shelf” products. However, allogeneic CAR cell products come with their own challenges, including potential to induce graft-versus-host-disease, as well as risk of immune-mediated rejection by the host. Here we will review promises and challenges of allogeneic CAR immunotherapies, including those being investigated in preclinical models and/or early phase clinical studies.
Infantile fibrosarcoma (IFS) is a rare pediatric cancer that typically presents early in life. Surgical resection is commonly curative; however, resection is sometimes not possible requiring additional multimodal treatment. IFS commonly harbors a fusion in one of the neurotrophic receptor tyrosine kinase (NTRK) genes. Larotrectinib, a highly selective inhibitor of tropomyosin receptor kinase (TRK), has been shown to be well tolerated and effective in children as young as 1‐month old. We report a case of IFS in a newborn treated with larotrectinib. The patient experienced a rapid clinical and radiographic response demonstrating the potential to treat newborns with larotrectinib.
Although outcomes for patients with high-risk neuroblastoma improved after the addition of a chimeric anti-GD2 monoclonal antibody (dinutuximab) as treatment for minimal residual disease, nearly half of these patients die of disease. Recent studies demonstrated efficacy of the combination of chemotherapy with anti-GD2 mAb in patients with relapsed or newly diagnosed disease. This retrospective case series describes 6 patients treated at St Jude Children’s Research Hospital with an induction regimen containing dinutuximab and chemotherapy, followed by consolidation and postconsolidation therapy. The treatment was well tolerated with expected toxicities. All patients completed induction therapy and demonstrated a clinical response. Further studies are warranted.
Stroke is the number one cause of disability and third leading cause of death in the world, costing an estimated $70 billion in the United States in 2009 1,2 . Several models of cerebral ischemia have been developed to mimic the human condition of stroke. It has been suggested that up to 80% of all strokes result from ischemic damage in the middle cerebral artery (MCA) area 3 . In the early 1990s, endothelin-1 (ET-1) 4 was used to induce ischemia by applying it directly adjacent to the surface of the MCA after craniotomy. Later, this model was modified 5 by using a stereotaxic injection of ET-1 adjacent to the MCA to produce focal cerebral ischemia. The main advantages of this model include the ability to perform the procedure quickly, the ability to control artery constriction by altering the dose of ET-1 delivered, no need to manipulate the extracranial vessels supplying blood to the brain as well as gradual reperfusion rates that more closely mimics the reperfusion in humans [5][6][7] . On the other hand, the ET-1 model has disadvantages that include the need for a craniotomy, as well as higher variability in stroke volume 8 . This variability can be reduced with the use of laser Doppler flowmetry (LDF) to verify cerebral ischemia during ET-1 infusion. Factors that affect stroke variability include precision of infusion and the batch of the ET-1 used 6 . Another important consideration is that although reperfusion is a common occurrence in human stroke, the duration of occlusion for ET-1 induced MCAO may not closely mimic that of human stroke where many patients have partial reperfusion over a period of hours to days following occlusion 9,10 . This protocol will describe in detail the ET-1 induced MCAO model for ischemic stroke in rats. It will also draw attention to special considerations and potential drawbacks throughout the procedure.
BackgroundHematopoietic stem cells mobilize to the peripheral circulation in response to stroke. However, the mechanism by which the brain initiates this mobilization is uncharacterized.MethodsAnimals underwent a murine intraluminal filament model of focal cerebral ischemia and the SDF1-A pathway was evaluated in a blinded manner via serum and brain SDF1-A level assessment, Lin−/Sca1+ cell mobilization quantification, and exogenous cell migration confirmation; all with or without SDF1-A blockade.ResultsBone marrow demonstrated a significant increase in Lin−/Sca1+ cell counts at 24 hrs (272±60%; P<0.05 vs sham). Mobilization of Lin−/Sca1+ cells to blood was significantly elevated at 24 hrs (607±159%; P<0.05). Serum SDF1-A levels were significant at 24 hrs (Sham (103±14), 4 hrs (94±20%, p = NS) and 24 hrs (130±17; p<0.05)). Brain SDF1-A levels were significantly elevated at both 4 hrs and 24 hrs (113±7 pg/ml and 112±10 pg/ml, respectively; p<0.05 versus sham 76±11 pg/ml). Following administration of an SDF1-A antibody, Lin−/Sca1+ cells failed to mobilize to peripheral blood following stroke, despite continued up regulation in bone marrow (stroke bone marrow cell count: 536±65, blood cell count: 127±24; p<0.05 versus placebo). Exogenously administered Lin−/Sca1+ cells resulted in a significant reduction in infarct volume: 42±5% (stroke alone), versus 21±15% (Stroke+Lin−/Sca1+ cells), and administration of an SDF1-A antibody concomitant to exogenous administration of the Lin−/Sca1+ cells prevented this reduction. Following stroke, exogenously administered Lin−/Sca1+ FISH positive cells were significantly reduced when administered concomitant to an SDF1-A antibody as compared to without SDF1-A antibody (10±4 vs 0.7±1, p<0.05).ConclusionsSDF1-A appears to play a critical role in modulating Lin−/Sca1+ cell migration to ischemic brain.
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