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1.
Neuro Oncol ; 24(6): 951-963, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34850166

RESUMO

BACKGROUND: Veledimex (VDX)-regulatable interleukin-12 (IL-12) gene therapy in recurrent glioblastoma (rGBM) was reported to show tumor infiltration of CD8+ T cells, encouraging survival, but also up-regulation of immune checkpoint signaling, providing the rationale for a combination trial with immune checkpoint inhibition. METHODS: An open-label, multi-institutional, dose-escalation phase I trial in rGBM subjects (NCT03636477) accrued 21 subjects in 3 dose-escalating cohorts: (1) neoadjuvant then ongoing nivolumab (1mg/kg) and VDX (10 mg) (n = 3); (2) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (10 mg) (n = 3); and (3) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (20 mg) (n = 15). Nivolumab was administered 7 (±3) days before resection of the rGBM followed by peritumoral injection of IL-12 gene therapy. VDX was administered 3 hours before and then for 14 days after surgery. Nivolumab was administered every two weeks after surgery. RESULTS: Toxicities of the combination were comparable to IL-12 gene monotherapy and were predictable, dose-related, and reversible upon withholding doses of VDX and/or nivolumab. VDX plasma pharmacokinetics demonstrate a dose-response relationship with effective brain tumor tissue VDX penetration and production of IL-12. IL-12 levels in serum peaked in all subjects at about Day 3 after surgery. Tumor IFNγ increased in post-treatment biopsies. Median overall survival (mOS) for VDX 10 mg with nivolumab was 16.9 months and for all subjects was 9.8 months. CONCLUSION: The safety of this combination immunotherapy was established and has led to an ongoing phase II clinical trial of immune checkpoint blockade with controlled IL-12 gene therapy (NCT04006119).


Assuntos
Antineoplásicos Imunológicos , Glioblastoma , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Terapia Genética , Glioblastoma/tratamento farmacológico , Glioblastoma/terapia , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Interleucina-12/genética , Nivolumabe/uso terapêutico
3.
Sci Transl Med ; 11(505)2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413142

RESUMO

Human interleukin-12 (hIL-12) is a cytokine with anticancer activity, but its systemic application is limited by toxic inflammatory responses. We assessed the safety and biological effects of an hIL-12 gene, transcriptionally regulated by an oral activator. A multicenter phase 1 dose-escalation trial (NCT02026271) treated 31 patients undergoing resection of recurrent high-grade glioma. Resection cavity walls were injected (day 0) with a fixed dose of the hIL-12 vector (Ad-RTS-hIL-12). The oral activator for hIL-12, veledimex (VDX), was administered preoperatively (assaying blood-brain barrier penetration) and postoperatively (measuring hIL-12 transcriptional regulation). Cohorts received 10 to 40 mg of VDX before and after Ad-RTS-hIL-12. Dose-related increases in VDX, IL-12, and interferon-γ (IFN-γ) were observed in peripheral blood, with about 40% VDX tumor penetration. Frequency and severity of adverse events, including cytokine release syndrome, correlated with VDX dose, reversing promptly upon discontinuation. VDX (20 mg) had superior drug compliance and 12.7 months median overall survival (mOS) at mean follow-up of 13.1 months. Concurrent corticosteroids negatively affected survival: In patients cumulatively receiving >20 mg versus ≤20 mg of dexamethasone (days 0 to 14), mOS was 6.4 and 16.7 months, respectively, in all patients and 6.4 and 17.8 months, respectively, in the 20-mg VDX cohort. Re-resection in five of five patients with suspected recurrence after Ad-RTS-hIL-12 revealed mostly pseudoprogression with increased tumor-infiltrating lymphocytes producing IFN-γ and programmed cell death protein 1 (PD-1). These inflammatory infiltrates support an immunological antitumor effect of hIL-12. This phase 1 trial showed acceptable tolerability of regulated hIL-12 with encouraging preliminary results.


Assuntos
Terapia Genética/métodos , Glioma/terapia , Interleucina-12/sangue , Corticosteroides/farmacologia , Adulto , Idoso , Dexametasona/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Glioma/sangue , Glioma/tratamento farmacológico , Glioma/mortalidade , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Interferon gama/sangue , Interleucina-12/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia
4.
Pediatr Pulmonol ; 50(2): 127-36, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24616259

RESUMO

As advances in the care of individuals with cystic fibrosis (CF) have resulted in improved survival, therapeutic regimens for treatment of CF have become increasingly complex. This high treatment burden poses challenges to chronic disease self-management, particularly amongst adolescents. The aim of this qualitative study was to understand the barriers and facilitators of adherence to chronic CF therapies as perceived by adolescents with CF and their parents. In a series of structured interviews with 18 youth and their parents, we explored issues related to daily routines, youth and parental roles regarding chronic therapy, and motivators for adherence. All interviews were audio-recorded and coded for themes and patterns. Reported barriers to adherence included time pressures, competing priorities, heightened awareness of disease trajectory, privacy concerns, and lack of perceived consequences from non-adherence. Identified facilitators for adherence included recognizing the importance of therapies, developing strong relationships with care teams, establishing structured routines, and focusing on shifting responsibilities from a parent to their adolescent child. The themes uncovered by these interviews identify areas for intervention and support by clinical programs seeking to improve adherence and self-management strategies for adolescents with CF.


Assuntos
Fibrose Cística/terapia , Motivação , Pais , Cooperação do Paciente , Autocuidado , Adolescente , Atitude Frente a Saúde , Confidencialidade , Feminino , Humanos , Entrevistas como Assunto , Masculino , Estudos de Amostragem , Tempo , Adulto Jovem
5.
Disabil Rehabil ; 33(11): 922-6, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-20812813

RESUMO

PURPOSE: We sought to examine the employment experiences in a population of adolescents and young adults with cystic fibrosis (CF). METHODS: We administered a cross-sectional survey to 68 individuals with CF, ages 16-25 years, assessing current employment experiences and perceptions of the impact of CF on these experiences. RESULTS: Forty-six percent of respondents reported working < 20 h per week. Sixty-seven percent reported disclosing their diagnosis to their employer. Only one respondent reported receiving formal job guidance in CF clinic, and only 16% reported that a clinician had discussed job-related issues with them. Only 21% reported that they completed CF therapies at work. Older respondents (ages 22-25 years) and those with a lower lung function were more likely to agree that 'balancing employment and CF care is stressful.' CONCLUSIONS: The majority of adolescents and young adults with CF report disclosing their diagnosis at work. Most do not feel that working interferes with routine CF therapies. Very few have received any formal career guidance. Age and lung disease severity are associated with increased concerns about balancing CF care and employment.


Assuntos
Fibrose Cística , Emprego , Adolescente , Adulto , Estudos Transversais , Fibrose Cística/reabilitação , Emprego/estatística & dados numéricos , Feminino , Humanos , Masculino , Orientação Vocacional , Adulto Jovem
6.
J Pediatr Psychol ; 36(2): 160-71, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20040605

RESUMO

OBJECTIVE: The aim of this study was to develop the Transition Readiness Assessment Questionnaire (TRAQ), a measure of readiness for transition from pediatric to adult healthcare for youth with special health care needs (YSHCN). METHODS: We administered TRAQ to 192 YSHCN aged 16-26 years in three primary diagnostic categories, conducted factor analysis, and assessed differences in TRAQ scores by age, gender, race, and primary diagnosis type. RESULTS: Factor analysis identified two TRAQ domains with high internal consistency: Skills for Self-Management and Skills for Self-Advocacy. Each domain had high internal consistency. In multivariate regression models, older age and a primary diagnosis of an activity limiting physical condition were associated with higher scores in Self-Management, and female gender and a primary diagnosis of an activity limiting physical condition were associated with higher scores in Self-Advocacy. CONCLUSIONS: Our initial validation study suggests the TRAQ is a useful tool to assess transition readiness in YSHCN and to guide educational interventions by providers to support transition.


Assuntos
Doença Crônica/terapia , Continuidade da Assistência ao Paciente , Avaliação das Necessidades , Defesa do Paciente , Adolescente , Adulto , Análise Fatorial , Feminino , Serviços de Saúde , Necessidades e Demandas de Serviços de Saúde , Humanos , Masculino , Análise de Regressão , Autocuidado , Autoeficácia , Fatores Sexuais
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