Assuntos
Leucemia Megacarioblástica Aguda , Humanos , Leucemia Megacarioblástica Aguda/imunologia , Leucemia Megacarioblástica Aguda/genética , Leucemia Megacarioblástica Aguda/patologia , Camundongos , Animais , Criança , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Imunoterapia Adotiva , Feminino , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/imunologia , Proteínas de Fusão Oncogênica/metabolismoAssuntos
Antineoplásicos , Imunoconjugados , Leucemia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Leucemia/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
The CBFA2T3-GLIS2 (C/G) fusion is a product of a cryptic translocation primarily seen in infants and early childhood and is associated with dismal outcome. Here, we demonstrate that the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML) and induces highly aggressive leukemia in xenograft models. Interrogating the transcriptome of C/G-CB cells and primary C/G AML identified a library of C/G-fusion-specific genes that are potential targets for therapy. We developed chimeric antigen receptor (CAR) T cells directed against one of the targets, folate receptor α (FOLR1), and demonstrated their preclinical efficacy against C/G AML using in vitro and xenograft models. FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns for toxicity that must be addressed for the clinical application of this therapy. Our findings underscore the role of the endothelial niche in promoting leukemic transformation of C/G-transduced CB HSPCs. Furthermore, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy.
Assuntos
Receptor 1 de Folato , Imunoterapia Adotiva , Leucemia Megacarioblástica Aguda , Proteínas de Fusão Oncogênica , Animais , Criança , Pré-Escolar , Humanos , Lactente , Modelos Animais de Doenças , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Leucemia Megacarioblástica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Linfócitos T , Transcriptoma , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: We previously identified mesothelin (MSLN) as highly expressed in a significant fraction of acute myeloid leukemia (AML) but entirely silent in normal hematopoiesis, providing a promising antigen for immunotherapeutic targeting that avoids hematopoietic toxicity. Given that T cells genetically modified to express chimeric antigen receptors (CAR) are effective at eradicating relapsed/refractory acute lymphocytic leukemia, we developed MSLN-directed CAR T cells for preclinical evaluation in AML. EXPERIMENTAL DESIGN: The variable light (VL) and heavy (VH) sequences from the MSLN-targeting SS1P immunotoxin were used to construct the single-chain variable fragment of the standard CAR containing 41-BB costimulatory and CD3Zeta stimulatory domains. The preclinical efficacy of MSLN CAR T cells was evaluated against AML cell lines and patient samples expressing various levels of MSLN in vitro and in vivo. RESULTS: We demonstrate that MSLN is expressed on the cell surface of AML blasts and leukemic stem cell-enriched CD34+CD38- subset, but not on normal hematopoietic stem and progenitor cells (HSPC). We further establish that MSLN CAR T cells are highly effective in eliminating MSLN-positive AML cells in cell line- and patient-derived xenograft models. Importantly, MSLN CAR T cells can target and eradicate CD34+CD38- cells without impacting the viability of normal HSPCs. Finally, we show that CAR T-cell functionality can be improved by inhibition of the ADAM17 metalloprotease that promotes shedding of MSLN. CONCLUSIONS: These findings demonstrate that MSLN is a viable target for CAR T-cell therapy in AML and that inhibiting MSLN shedding is a promising approach to improve CAR T-cell efficacy.
Assuntos
Imunoterapia Adotiva/métodos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , Mesotelina/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos/uso terapêutico , Adolescente , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
Background Blunt cerebrovascular injury (BCVI) is associated with increased stroke and mortality risk. However, the most appropriate follow-up strategy remains uncertain. Purpose To better understand the natural history of BCVI and help define the most optimal timing and length of follow-up imaging. Materials and Methods In this retrospective HIPAA-compliant study, data from all patients treated for BCVI at a level I trauma center between April 1, 2005, and June 30, 2015, were reviewed. For patients with at least one follow-up study, time-to-event analysis was performed to assess the trend in injury evolution. Association of injury grade and injury evolution was also assessed. The Fisher exact test and multivariable logistic regression were used to evaluate association of the number of injured vessels, vessel grade, and vessel type (internal carotid artery, vertebral artery) with BCVI-associated stroke. Results A total of 1204 patients (800 men; mean age ± standard deviation, 45 years ± 22) with 1604 vessel injuries were evaluated. High-grade (grades 3-5) injuries were less likely to resolve (hazard ratio [HR], 0.2; P < .001) than low-grade injuries. High-grade injuries were more likely to progress than low-grade injuries (HR, 3.3; P = .005). Of the injuries that improved or resolved (343 of 419 [81.9%]), 76% (259 of 343) changed within 30 days after the initial injury, and the remaining 24% (84 of 343) changed between 30 and 90 days. Of the injuries that progressed (46 of 419 [11.0%]), 87% (40 of 46) changed within 90 days. Beyond 90 days, no improvement or resolution occurred, and only 1.4% (six of 419) of injuries progressed. Higher injury grade (adjusted odds ratio, 2.0 per one-grade increase [95% confidence interval {CI}: 1.6, 2.4]; P < .001), carotid injuries versus vertebral artery injuries (49 of 420 [11.7%] vs 35 of 667 [5.2%]; P < .001), and increasing number of vessels injured per patient (adjusted odds ratio, 1.6 per one-vessel increase [95% CI: 1.3, 2.2]; P < .001) were associated with increased risk for BCVI-related stroke. Conclusion Most blunt cerebrovascular injury-related changes occurred within 30 days; changes rarely occurred beyond 90 days. Follow-up imaging is therefore unlikely to be helpful beyond 90 days. © RSNA, 2020 See also the editorial by Talbott in this issue.