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1.
Cell ; 187(10): 2521-2535.e21, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38697107

RESUMEN

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.


Asunto(s)
Inmunoterapia , Lípidos , ARN , Microambiente Tumoral , Animales , Perros , Femenino , Humanos , Ratones , Antígenos de Neoplasias/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Línea Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Glioblastoma/terapia , Glioblastoma/inmunología , Glioma/terapia , Glioma/inmunología , Inmunoterapia/métodos , Ratones Endogámicos C57BL , Neoplasias/terapia , Neoplasias/inmunología , ARN/química , ARN/uso terapéutico , ARN Mensajero/metabolismo , ARN Mensajero/genética , Lípidos/química
2.
J Pediatr Nurs ; 28(3): 243-8, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-22999994

RESUMEN

Successful strategies for recruitment and retention (R & R) in pediatric trials are needed. The purpose of our study was to analyze the effectiveness of R&R in a trial for children with hepatitis C. Recruitment strategies were (1) Initial (months 0-12) and (2) extra effort (months 13-18). Initial strategies enrolled 70/114 (61%) of patients. Extra effort strategies included: (1) radio broadcasts, (2) contact with adult hepatologists, (3) dissemination of study material and (4) modification of the exclusion criteria. The overall retention rate was 84% at 2 years. Lessons learned will be valuable in designing future pediatric trials.


Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Selección de Paciente , Polietilenglicoles/uso terapéutico , Niño , Humanos , Radio , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/uso terapéutico , Proyectos de Investigación
3.
Neurosurgery ; 92(1): 68-74, 2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-36156532

RESUMEN

BACKGROUND: Levetiracetam is commonly used as a prophylactic antiseizure medication in patients undergoing surgical resection of brain tumors. OBJECTIVE: To quantitate side effects experienced in patients treated with 1 week vs 6 weeks of prophylactic levetiracetam using validated measures for neurotoxicity and depression. METHODS: Patients undergoing surgical resection of a supratentorial tumor with no seizure history were randomized within 48 hours of surgery to receive prophylactic levetiracetam for the duration of either 1 or 6 weeks. Patients were given oral levetiracetam extended release 1000 mg during the first part of this study. Owing to drug backorder, patients enrolled later in this study received levetiracetam 500 mg BID. The primary outcome was the change in the neurotoxicity score 6 weeks after drug initiation. The secondary outcome was seizure incidence. RESULTS: A total of 81 patients were enrolled and randomized to 1 week (40 patients) or 6 weeks (41 patients) of prophylactic levetiracetam treatment. The neurotoxicity score slightly improved in the overall cohort between baseline and reassessment. There was no significant difference between groups in neurotoxicity or depression scores. Seizure incidence was low in the entire cohort of patients with 1 patient in each arm experiencing a seizure during the follow-up period. CONCLUSION: The use of prophylactic levetiracetam did not result in significant neurotoxicity or depression when given for either 1 week or 6 weeks. The incidence of seizure after craniotomy for tumor resection is low regardless of duration of therapy.


Asunto(s)
Anticonvulsivantes , Neoplasias Encefálicas , Humanos , Levetiracetam/efectos adversos , Anticonvulsivantes/efectos adversos , Estudios Prospectivos , Convulsiones/etiología , Convulsiones/prevención & control , Convulsiones/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico
4.
medRxiv ; 2023 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-36993772

RESUMEN

Messenger RNA (mRNA) has emerged as a remarkable tool for COVID-19 prevention but its use for induction of therapeutic cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Herein, we develop a facile approach for substantially enhancing immunogenicity of tumor-derived mRNA in lipid-particle (LP) delivery systems. By using mRNA as a molecular bridge with ultrapure liposomes and foregoing helper lipids, we promote the formation of 'onion-like' multi-lamellar RNA-LP aggregates (LPA). Intravenous administration of RNA-LPAs mimics infectious emboli and elicits massive DC/T cell mobilization into lymphoid tissues provoking cancer immunogenicity and mediating rejection of both early and late-stage murine tumor models. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for toll-like receptor engagement, RNA-LPAs stimulate intracellular pathogen recognition receptors (RIG-I) and reprogram the TME thus enabling therapeutic T cell activity. RNA-LPAs were safe in acute/chronic murine GLP toxicology studies and immunologically active in client-owned canines with terminal gliomas. In an early phase first-in-human trial for patients with glioblastoma, we show that RNA-LPAs encoding for tumor-associated antigens elicit rapid induction of pro-inflammatory cytokines, mobilization/activation of monocytes and lymphocytes, and expansion of antigen-specific T cell immunity. These data support the use of RNA-LPAs as novel tools to elicit and sustain immune responses against poorly immunogenic tumors.

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