Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
1.
Cell ; 185(10): 1745-1763.e22, 2022 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-35483375

RESUMEN

Regulatable CAR platforms could circumvent toxicities associated with CAR-T therapy, but existing systems have shortcomings including leakiness and attenuated activity. Here, we present SNIP CARs, a protease-based platform for regulating CAR activity using an FDA-approved small molecule. Design iterations yielded CAR-T cells that manifest full functional capacity with drug and no leaky activity in the absence of drug. In numerous models, SNIP CAR-T cells were more potent than constitutive CAR-T cells and showed diminished T cell exhaustion and greater stemness. In a ROR1-based CAR lethality model, drug cessation following toxicity onset reversed toxicity, thereby credentialing the platform as a safety switch. In the same model, reduced drug dosing opened a therapeutic window that resulted in tumor eradication in the absence of toxicity. SNIP CARs enable remote tuning of CAR activity, which provides solutions to safety and efficacy barriers that are currently limiting progress in using CAR-T cells to treat solid tumors.


Asunto(s)
Neoplasias , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Péptido Hidrolasas , Receptores de Antígenos de Linfocitos T , Linfocitos T/patología
2.
Nature ; 630(8016): 457-465, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38750365

RESUMEN

Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.


Asunto(s)
Antígeno CD47 , Inmunoterapia Adoptiva , Neoplasias , Linfocitos T , Animales , Femenino , Humanos , Masculino , Ratones , Antígenos de Diferenciación/inmunología , Antígenos de Diferenciación/metabolismo , Antígeno CD47/genética , Antígeno CD47/inmunología , Antígeno CD47/metabolismo , Línea Celular Tumoral , Inmunoterapia Adoptiva/métodos , Macrófagos/citología , Macrófagos/inmunología , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/trasplante , Microambiente Tumoral/inmunología , Anticuerpos/inmunología , Anticuerpos/uso terapéutico , Activación de Macrófagos
3.
STAR Protoc ; 4(4): 102709, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-37967014

RESUMEN

The central role of target antigen density on chimeric antigen receptor T cell potency highlights the need for accurate measurement of antigen levels on clinical tumor samples. Here, we present a protocol for quantifying antigen density for six cell-surface antigens on neuroblastoma cells metastatic to bone marrow. We describe steps for patient sample acquisition, flow cytometry panel development, instrument setup, and compensation and detail procedures for running clinical samples and data analysis. For complete details on the use and execution of this protocol, please refer to Heitzeneder et al. (2022).1.


Asunto(s)
Neoplasias de la Médula Ósea , Neuroblastoma , Humanos , Médula Ósea , Citometría de Flujo , Inmunoterapia , Neuroblastoma/terapia , Neoplasias de la Médula Ósea/terapia
4.
Clin Immunol ; 143(1): 22-38, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22377282

RESUMEN

Mannan-binding lectin (MBL) deficiency has been classified as a commonly occurring immune disorder, affecting approximately 30% of the human population. MBL, being part of the innate immune system, supports the recognition of infectious pathogens by binding to carbohydrate moieties expressed on microorganisms and activates the lectin pathway of the complement system. MBL2 gene polymorphisms are associated with quantitative and qualitative MBL abnormalities in the serum. The clinical impact of MBL deficiency and its association to a wide variety of diseases has been extensively studied. The picture is puzzling as the studies suggest a detrimental or beneficial or no impact of low or high MBL serum levels on disease susceptibility. In this review we attempt to extract what is relevant from the literature and address controversial issues. We finally suggest that a comprehensive understanding of the role of MBL in human diseases requires considering its context-dependency.


Asunto(s)
Predisposición Genética a la Enfermedad , Lectina de Unión a Manosa/deficiencia , Lectina de Unión a Manosa/genética , Polimorfismo de Nucleótido Simple , Genotipo , Humanos , Lectina de Unión a Manosa/sangre , Modelos Genéticos
5.
Nat Med ; 28(2): 333-344, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35027753

RESUMEN

The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2+ malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.


Asunto(s)
Neoplasias Óseas , Antígeno CD47 , Animales , Línea Celular Tumoral , Humanos , Inmunoterapia , Ratones , Recurrencia Local de Neoplasia , Fagocitosis , Microambiente Tumoral
6.
Cancer Cell ; 40(1): 53-69.e9, 2022 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-34971569

RESUMEN

Pediatric cancers often mimic fetal tissues and express proteins normally silenced postnatally that could serve as immune targets. We developed T cells expressing chimeric antigen receptors (CARs) targeting glypican-2 (GPC2), a fetal antigen expressed on neuroblastoma (NB) and several other solid tumors. CARs engineered using standard designs control NBs with transgenic GPC2 overexpression, but not those expressing clinically relevant GPC2 site density (∼5,000 molecules/cell, range 1-6 × 103). Iterative engineering of transmembrane (TM) and co-stimulatory domains plus overexpression of c-Jun lowered the GPC2-CAR antigen density threshold, enabling potent and durable eradication of NBs expressing clinically relevant GPC2 antigen density, without toxicity. These studies highlight the critical interplay between CAR design and antigen density threshold, demonstrate potent efficacy and safety of a lead GPC2-CAR candidate suitable for clinical testing, and credential oncofetal antigens as a promising class of targets for CAR T cell therapy of solid tumors.


Asunto(s)
Glipicanos/inmunología , Inmunoterapia Adoptiva , Neuroblastoma/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T/metabolismo , Animales , Línea Celular Tumoral , Glipicanos/metabolismo , Humanos , Inmunoterapia/métodos , Neuroblastoma/patología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
7.
Science ; 372(6537)2021 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-33795428

RESUMEN

T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state.


Asunto(s)
Dasatinib/farmacología , Epigénesis Genética , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Animales , Línea Celular Tumoral , Citotoxicidad Inmunológica , Regulación hacia Abajo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Epigenoma , Femenino , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Memoria Inmunológica , Activación de Linfocitos , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Masculino , Ratones , Neoplasias Experimentales/terapia , Dominios Proteicos , Estabilidad Proteica , Receptores Quiméricos de Antígenos/química , Receptores Quiméricos de Antígenos/inmunología , Transducción de Señal , Linfocitos T/metabolismo , Transcripción Genética , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Cancer Discov ; 10(5): 702-723, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32193224

RESUMEN

Insufficient reactivity against cells with low antigen density has emerged as an important cause of chimeric antigen receptor (CAR) T-cell resistance. Little is known about factors that modulate the threshold for antigen recognition. We demonstrate that CD19 CAR activity is dependent upon antigen density and that the CAR construct in axicabtagene ciloleucel (CD19-CD28ζ) outperforms that in tisagenlecleucel (CD19-4-1BBζ) against antigen-low tumors. Enhancing signal strength by including additional immunoreceptor tyrosine-based activation motifs (ITAM) in the CAR enables recognition of low-antigen-density cells, whereas ITAM deletions blunt signal and increase the antigen density threshold. Furthermore, replacement of the CD8 hinge-transmembrane (H/T) region of a 4-1BBζ CAR with a CD28-H/T lowers the threshold for CAR reactivity despite identical signaling molecules. CARs incorporating a CD28-H/T demonstrate a more stable and efficient immunologic synapse. Precise design of CARs can tune the threshold for antigen recognition and endow 4-1BBζ-CARs with enhanced capacity to recognize antigen-low targets while retaining a superior capacity for persistence. SIGNIFICANCE: Optimal CAR T-cell activity is dependent on antigen density, which is variable in many cancers, including lymphoma and solid tumors. CD28ζ-CARs outperform 4-1BBζ-CARs when antigen density is low. However, 4-1BBζ-CARs can be reengineered to enhance activity against low-antigen-density tumors while maintaining their unique capacity for persistence.This article is highlighted in the In This Issue feature, p. 627.


Asunto(s)
Receptores Quiméricos de Antígenos/metabolismo , Animales , Humanos , Ratones , Transducción de Señal
9.
Nat Med ; 26(5): 712-719, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32341579

RESUMEN

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.


Asunto(s)
Antígenos B7/inmunología , Neoplasias Encefálicas/terapia , Vacunas contra el Cáncer/administración & dosificación , Inmunoterapia Adoptiva/métodos , Tumor Rabdoide/terapia , Teratoma/terapia , Adulto , Animales , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Células Cultivadas , Preescolar , Femenino , Feto/patología , Humanos , Lactante , Inyecciones Intraventriculares , Ratones , Ratones Endogámicos NOD , Ratones SCID , Receptores Quiméricos de Antígenos/administración & dosificación , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Tumor Rabdoide/inmunología , Tumor Rabdoide/patología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/trasplante , Teratoma/inmunología , Teratoma/patología , Ensayos Antitumor por Modelo de Xenoinjerto
10.
J Natl Cancer Inst ; 111(9): 970-982, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-30698726

RESUMEN

BACKGROUND: Ewing sarcoma (EWS) manifests one of the lowest somatic mutation rates of any cancer, leading to a scarcity of druggable mutations and neoantigens. Immunotherapeutics targeting differentially expressed cell surface antigens could provide therapeutic benefit for such tumors. Pregnancy-associated plasma protein A (PAPP-A) is a cell membrane-associated proteinase produced by the placenta that promotes fetal growth by inducing insulinlike growth factor (IGF) signaling. METHODS: By comparing RNA expression of cell surface proteins in EWS (n = 120) versus normal tissues (n = 42), we comprehensively characterized the surfaceome of EWS to identify highly differentially expressed molecules. Using CRISPR/Cas-9 and anti-PAPP-A antibodies, we investigated biological roles for PAPP-A in EWS in vitro and in vivo in NSG xenograft models and performed RNA-sequencing on PAPPA knockout clones (n = 5) and controls (n = 3). All statistical tests were two-sided. RESULTS: EWS surfaceome analysis identified 11 highly differentially overexpressed genes, with PAPPA ranking second in differential expression. In EWS cell lines, genetic knockout of PAPPA and treatment with anti-PAPP-A antibodies revealed an essential survival role by regulating local IGF-1 bioavailability. MAb-mediated PAPPA inhibition diminished EWS growth in orthotopic xenografts (leg area mm2 at day 49 IgG2a control (CTRL) [n = 14], mean = 397.0, SD = 86.1 vs anti-PAPP-A [n = 14], mean = 311.7, SD = 155.0; P = .03; median OS anti-PAPP-A = 52.5 days, 95% CI = 46.0 to 63.0 days vs IgG2a = 45.0 days, 95% CI = 42.0 to 52.0 days; P = .02) and improved the efficacy of anti-IGF-1R treatment (leg area mm2 at day 49 anti-PAPP-A + anti-IGF-1R [n = 15], mean = 217.9, SD = 148.5 vs IgG2a-CTRL; P < .001; median OS anti-PAPP-A + anti-IGF1R = 63.0 days, 95% CI = 52.0 to 67.0 days vs IgG2a-CTRL; P < .001). Unexpectedly, PAPPA knockout in EWS cell lines induced interferon (IFN)-response genes, including proteins associated with antigen processing/presentation. Consistently, gene expression profiles in PAPPA-low EWS tumors were enriched for immune response pathways. CONCLUSION: This work provides a comprehensive characterization of the surfaceome of EWS, credentials PAPP-A as a highly differentially expressed therapeutic target, and discovers a novel link between IGF-1 signaling and immune evasion in cancer, thus implicating shared mechanisms of immune evasion between EWS and the placenta.


Asunto(s)
Proteína Plasmática A Asociada al Embarazo/metabolismo , Sarcoma de Ewing/inmunología , Sarcoma de Ewing/metabolismo , Escape del Tumor , Animales , Línea Celular Tumoral , Membrana Celular/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/patología , Transducción de Señal , Transcriptoma , Carga Tumoral , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología
11.
Clin Cancer Res ; 25(8): 2560-2574, 2019 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-30655315

RESUMEN

PURPOSE: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system. EXPERIMENTAL DESIGN: We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models. RESULTS: B7-H3 CAR T cells mediate significant antitumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3. CONCLUSIONS: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.


Asunto(s)
Antígenos de Neoplasias/inmunología , Antígenos B7/inmunología , Neoplasias Encefálicas/etiología , Neoplasias Encefálicas/metabolismo , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Antígenos B7/antagonistas & inhibidores , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica , Inmunoterapia Adoptiva/métodos , Ratones , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Cancer Cell ; 31(4): 476-485, 2017 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-28366678

RESUMEN

Cancer immunotherapies can be classified into agents that amplify natural immune responses (e.g., checkpoint inhibitors) versus synthetic immunotherapies designed to initiate new responses (e.g., monoclonal antibodies [mAbs], chimeric antigen receptors [CARs]). Checkpoint inhibitors mediate unprecedented benefit in some adult cancers, but have not demonstrated significant activity in pediatric cancers, likely due their paucity of neoantigens. In contrast, synthetic immunotherapies such as mAbs and CAR T cells demonstrate impressive effects against childhood cancers. Intense efforts are underway to enhance the effectiveness of pediatric cancer immunotherapies through improved engineering of synthetic immunotherapies and by combining these with agents designed to amplify immune responses.


Asunto(s)
Inmunoterapia/métodos , Neoplasias/terapia , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD19/genética , Antígenos CD19/inmunología , Humanos , Mutación , Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos/genética , Receptores de Antígenos/inmunología , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología
13.
Cancer Cell ; 32(3): 295-309.e12, 2017 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-28898695

RESUMEN

We developed an RNA-sequencing-based pipeline to discover differentially expressed cell-surface molecules in neuroblastoma that meet criteria for optimal immunotherapeutic target safety and efficacy. Here, we show that GPC2 is a strong candidate immunotherapeutic target in this childhood cancer. We demonstrate high GPC2 expression in neuroblastoma due to MYCN transcriptional activation and/or somatic gain of the GPC2 locus. We confirm GPC2 to be highly expressed on most neuroblastomas, but not detectable at appreciable levels in normal childhood tissues. In addition, we demonstrate that GPC2 is required for neuroblastoma proliferation. Finally, we develop a GPC2-directed antibody-drug conjugate that is potently cytotoxic to GPC2-expressing neuroblastoma cells. Collectively, these findings validate GPC2 as a non-mutated neuroblastoma oncoprotein and candidate immunotherapeutic target.


Asunto(s)
Glipicanos/metabolismo , Inmunoterapia , Terapia Molecular Dirigida , Neuroblastoma/inmunología , Neuroblastoma/terapia , Proteínas Oncogénicas/metabolismo , Animales , Anticuerpos Antineoplásicos/metabolismo , Muerte Celular , Línea Celular Tumoral , Membrana Celular/metabolismo , Proliferación Celular , Niño , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Humanos , Ratones Endogámicos NOD , Ratones SCID , Proteína Proto-Oncogénica N-Myc/metabolismo , Neuroblastoma/genética , Neuroblastoma/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Riesgo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA