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1.
Breast Cancer Res ; 21(1): 119, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31703728

RESUMO

BACKGROUND: Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. METHODS: The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks). RESULTS: Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0-8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]). CONCLUSION: Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02120469. Registered 18 April 2014.

2.
J Transl Med ; 16(1): 179, 2018 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-29958537

RESUMO

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

3.
Stem Cells Int ; 2018: 5312426, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29731779

RESUMO

Background: The aim of this study was to correlate T1-weighted dynamic contrast-enhanced MRI- (DCE-MRI-) derived perfusion parameters with overall survival of recurrent high-grade glioma patients who received neural stem cell- (NSC-) mediated enzyme/prodrug gene therapy. Methods: A total of 12 patients were included in this retrospective study. All patients were enrolled in a first-in-human study (NCT01172964) of NSC-mediated therapy for recurrent high-grade glioma. DCE-MRI data from all patients were collected and analyzed at three time points: MRI#1-day 1 postsurgery/treatment, MRI#2- day 7 ± 3 posttreatment, and MRI#3-one-month follow-up. Plasma volume (Vp), permeability (Ktr), and leakage (λtr) perfusion parameters were calculated by fitting a pharmacokinetic model to the DCE-MRI data. The contrast-enhancing (CE) volume was measured from the last dynamic phase acquired in the DCE sequence. Perfusion parameters and CE at each MRI time point were recorded along with their relative change between MRI#2 and MRI#3 (Δ32). Cox regression was used to analyze patient survival. Results: At MRI#1 and at MRI#3, none of the parameters showed a significant correlation with overall survival (OS). However, at MRI#2, CE and λtr were significantly associated with OS (p < 0.05). The relative λtr and Vp from timepoint 2 to timepoint 3 (Δ32λtr and Δ32Vp) were each associated with a higher hazard ratio (p < 0.05). All parameters were highly correlated, resulting in a multivariate model for OS including only CE at MRI#2 and Δ32Vp, with an R2 of 0.89. Conclusion: The change in perfusion parameter values from 1 week to 1 month following NSC-mediated therapy combined with contrast-enhancing volume may be a useful biomarker to predict overall survival in patients with recurrent high-grade glioma.

4.
J Transl Med ; 16(1): 142, 2018 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-29843811

RESUMO

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

5.
Clin Cancer Res ; 24(1): 95-105, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29061641

RESUMO

Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease.Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain.Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease.Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95-105. ©2017 AACR.

6.
J Natl Compr Canc Netw ; 15(11): 1331-1345, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29118226

RESUMO

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias do Sistema Nervoso Central/diagnóstico , Glioma/diagnóstico , Sistema Nervoso/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Neoplasias do Sistema Nervoso Central/classificação , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Terapia Combinada/métodos , Terapia Combinada/normas , Glioma/classificação , Glioma/patologia , Glioma/terapia , Humanos , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/normas , Gradação de Tumores , Prognóstico , Radioterapia/métodos , Radioterapia/normas
7.
Clin Cancer Res ; 23(12): 2951-2960, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-27979915

RESUMO

Purpose: Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU).Experimental Design: Recurrent high-grade glioma patients underwent intracranial administration of CD-NSCs during tumor resection or biopsy. Four days later, patients began taking oral 5-FC every 6 hours for 7 days. Study treatment was given only once. A standard 3 + 3 dose escalation schema was used to increase doses of CD-NSCs from 1 × 107 to 5 × 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU. Serial blood samples were obtained to assess systemic drug concentrations as well as to perform immunologic correlative studies.Results: Fifteen patients underwent study treatment. We saw no dose-limiting toxicity (DLT) due to the CD-NSCs. There was 1 DLT (grade 3 transaminitis) possibly related to 5-FC. We did not see development of anti-CD-NSC antibodies and did not detect CD-NSCs or replication-competent retrovirus in the systemic circulation. Intracerebral microdialysis revealed that CD-NSCs produced 5-FU locally in the brain in a 5-FC dose-dependent manner. Autopsy data indicate that CD-NSCs migrated to distant tumor sites and were nontumorigenic.Conclusions: Collectively, our results from this first-in-human study demonstrate initial safety and proof of concept regarding the ability of NSCs to target brain tumors and locally produce chemotherapy. Clin Cancer Res; 23(12); 2951-60. ©2016 AACR.


Assuntos
Citosina Desaminase/genética , Terapia Genética , Glioma/tratamento farmacológico , Células-Tronco Neurais/transplante , Adolescente , Adulto , Citosina Desaminase/administração & dosagem , Citosina Desaminase/efeitos adversos , Feminino , Flucitosina/administração & dosagem , Fluoruracila/administração & dosagem , Técnicas de Transferência de Genes , Vetores Genéticos , Glioma/genética , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores
8.
N Engl J Med ; 375(26): 2561-9, 2016 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-28029927

RESUMO

A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .).


Assuntos
Linfócitos T CD8-Positivos/imunologia , Glioblastoma/terapia , Imunoterapia Adotiva , Recidiva Local de Neoplasia/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Engenharia Celular , Terapia Combinada , Humanos , Subunidade alfa2 de Receptor de Interleucina-13 , Masculino , Pessoa de Meia-Idade
9.
Neuro Oncol ; 18(8): 1137-45, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26843484

RESUMO

BACKGROUND: Despite aggressive standard of care (SOC) treatment, survival of malignant gliomas remains very poor. This Phase II, prospective, matched controlled, multicenter trial was conducted to assess the safety and efficacy of aglatimagene besadenovec (AdV-tk) plus valacyclovir (gene-mediated cytotoxic immunotherapy [GMCI]) in combination with SOC for newly diagnosed malignant glioma patients. METHODS: Treatment cohort patients received SOC + GMCI and were enrolled at 4 institutions from 2006 to 2010. The preplanned, matched-control cohort included all concurrent patients meeting protocol criteria and SOC at a fifth institution. AdV-tk was administered at surgery followed by SOC radiation and temozolomide. Subset analyses were preplanned, based on prognostic factors: pathological diagnosis (glioblastoma vs others) and extent of resection. RESULTS: Forty-eight patients completed SOC + GMCI, and 134 met control cohort criteria. Median overall survival (OS) was 17.1 months for GMCI + SOC versus 13.5 months for SOC alone (P = .0417). Survival at 1, 2, and 3 years was 67%, 35%, and 19% versus 57%, 22%, and 8%, respectively. The greatest benefit was observed in gross total resection patients: median OS of 25 versus 16.9 months (P = .0492); 1, 2, and 3-year survival of 90%, 53%, and 32% versus 64%, 28% and 6%, respectively. There were no dose-limiting toxicities; fever, fatigue, and headache were the most common GMCI-related symptoms. CONCLUSIONS: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival outcomes were most notably improved in patients with minimal residual disease after gross total resection. These data should help guide future immunotherapy studies and strongly support further evaluation of GMCI for malignant gliomas. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov NCT00589875.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Glioma/tratamento farmacológico , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Aciclovir/efeitos adversos , Aciclovir/análogos & derivados , Aciclovir/uso terapêutico , Adenoviridae , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Neoplasias Encefálicas/cirurgia , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Vetores Genéticos/uso terapêutico , Glioma/cirurgia , Humanos , Pessoa de Meia-Idade , Simplexvirus/genética , Análise de Sobrevida , Timidina Quinase/genética , Resultado do Tratamento , Valaciclovir , Valina/efeitos adversos , Valina/análogos & derivados , Valina/uso terapêutico
10.
J Natl Compr Canc Netw ; 13(10): 1191-202, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26483059

RESUMO

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.


Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Guias de Prática Clínica como Assunto , Adulto , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Metástase Neoplásica
11.
Clin Cancer Res ; 21(18): 4062-72, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26059190

RESUMO

PURPOSE: A first-in-human pilot safety and feasibility trial evaluating chimeric antigen receptor (CAR)-engineered, autologous primary human CD8(+) cytotoxic T lymphocytes (CTL) targeting IL13Rα2 for the treatment of recurrent glioblastoma (GBM). EXPERIMENTAL DESIGN: Three patients with recurrent GBM were treated with IL13(E13Y)-zetakine CD8(+) CTL targeting IL13Rα2. Patients received up to 12 local infusions at a maximum dose of 10(8) CAR-engineered T cells via a catheter/reservoir system. RESULTS: We demonstrate the feasibility of manufacturing sufficient numbers of autologous CTL clones expressing an IL13(E13Y)-zetakine CAR for redirected HLA-independent IL13Rα2-specific effector function for a cohort of patients diagnosed with GBM. Intracranial delivery of the IL13-zetakine(+) CTL clones into the resection cavity of 3 patients with recurrent disease was well-tolerated, with manageable temporary brain inflammation. Following infusion of IL13-zetakine(+) CTLs, evidence for transient anti-glioma responses was observed in 2 of the patients. Analysis of tumor tissue from 1 patient before and after T-cell therapy suggested reduced overall IL13Rα2 expression within the tumor following treatment. MRI analysis of another patient indicated an increase in tumor necrotic volume at the site of IL13-zetakine(+) T-cell administration. CONCLUSIONS: These findings provide promising first-in-human clinical experience for intracranial administration of IL13Rα2-specific CAR T cells for the treatment of GBM, establishing a foundation on which future refinements of adoptive CAR T-cell therapies can be applied.


Assuntos
Neoplasias Encefálicas/terapia , Linfócitos T CD8-Positivos/imunologia , Glioblastoma/terapia , Imunoterapia Adotiva/métodos , Subunidade alfa2 de Receptor de Interleucina-13/uso terapêutico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adulto , Idoso , Encéfalo/patologia , Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/citologia , Estudos de Viabilidade , Feminino , Glioblastoma/imunologia , Glioma/imunologia , Glioma/terapia , Antígenos HLA/química , Humanos , Inflamação , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Projetos Piloto , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , Recidiva , Resultado do Tratamento , Adulto Jovem
12.
J Natl Compr Canc Netw ; 12(11): 1517-23, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25361798

RESUMO

The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.


Assuntos
Neoplasias do Sistema Nervoso Central/secundário , Neoplasias do Sistema Nervoso Central/cirurgia , Humanos , Radiocirurgia/métodos
13.
J Neurooncol ; 118(1): 169-77, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24634191

RESUMO

Intracerebral microdialysis enables continuous measurement of changes in brain biochemistry. In this study intracerebral microdialysis was used to assess changes in cytokine levels after tumor resection and in response to treatment with temsirolimus. Brain tumor patients undergoing craniotomy participated in this non-therapeutic study. A 100 kDa molecular weight cut-off microdialysis catheter was placed in peritumoral tissue at the time of resection. Cohort 1 underwent craniotomy only. Cohort 2 received a 200 mg dose of intravenous temsirolimus 48 h after surgery. Dialysate samples were collected continuously for 96 h and analyzed for the presence of 30 cytokines. Serial blood samples were collected to measure systemic cytokine levels. Dialysate samples were obtained from six patients in cohort 1 and 4 in cohort 2. Seventeen cytokines could be recovered in dialysate samples from at least 8 of 10 patients. Concentrations of interleukins and chemokines were markedly elevated in peritumoral tissue, and most declined over time, with IL-8, IP-10, MCP-1, MIP1ß, IL-6, IL-12p40/p70, MIP1α, IFN-α, G-CSF, IL-2R, and vascular endothelial growth factor significantly (p < 0.05) decreasing over 96 h following surgery. No qualitative changes in intracerebral or serum cytokine concentrations were detected after temsirolimus administration. This is the first intracerebral microdialysis study to evaluate the time course of changes in macromolecule levels in the peritumoral microenvironment after a debulking craniotomy. Initial elevations of peritumoral interleukins and chemokines most likely reflected an inflammatory response to both tumor and surgical trauma. These findings have implications for development of cellular therapies that are administered intracranially at the time of surgery.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas , Citocinas/metabolismo , Adulto , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirurgia , Estudos de Coortes , Craniotomia , Feminino , Humanos , Masculino , Microdiálise , Pessoa de Meia-Idade , Projetos Piloto , Fatores de Tempo
14.
Stem Cells Transl Med ; 2(12): 983-92, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24167321

RESUMO

CPT-11 (irinotecan) has been investigated as a treatment for malignant brain tumors. However, limitations of CPT-11 therapy include low levels of the drug entering brain tumor sites and systemic toxicities associated with higher doses. Neural stem cells (NSCs) offer a novel way to overcome these obstacles because of their inherent tumor tropism and ability to cross the blood-brain barrier, which enables them to selectively target brain tumor sites. Carboxylesterases (CEs) are enzymes that can convert the prodrug CPT-11 (irinotecan) to its active metabolite SN-38, a potent topoisomerase I inhibitor. We have adenovirally transduced an established clonal human NSC line (HB1.F3.CD) to express a rabbit carboxylesterase (rCE) or a modified human CE (hCE1m6), which are more effective at converting CPT-11 to SN-38 than endogenous human CE. We hypothesized that NSC-mediated CE/CPT-11 therapy would allow tumor-localized production of SN-38 and significantly increase the therapeutic efficacy of irinotecan. Here, we report that transduced NSCs transiently expressed high levels of active CE enzymes, retained their tumor-tropic properties, and mediated an increase in the cytotoxicity of CPT-11 toward glioma cells. CE-expressing NSCs (NSC.CEs), whether administered intracranially or intravenously, delivered CE to orthotopic human glioma xenografts in mice. NSC-delivered CE catalyzed conversion of CPT-11 to SN-38 locally at tumor sites. These studies demonstrate the feasibility of NSC-mediated delivery of CE to glioma and lay the foundation for translational studies of this therapeutic paradigm to improve clinical outcome and quality of life in patients with malignant brain tumors.


Assuntos
Neoplasias Encefálicas/terapia , Camptotecina/análogos & derivados , Hidrolases de Éster Carboxílico/metabolismo , Glioma/terapia , Células-Tronco Neurais/enzimologia , Células-Tronco Neurais/transplante , Inibidores da Topoisomerase I/farmacologia , Adenoviridae/genética , Animais , Biotransformação , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Camptotecina/farmacocinética , Camptotecina/farmacologia , Carboxilesterase/deficiência , Carboxilesterase/genética , Hidrolases de Éster Carboxílico/genética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Vetores Genéticos , Glioma/enzimologia , Glioma/genética , Glioma/patologia , Humanos , Irinotecano , Camundongos , Camundongos Knockout , Camundongos SCID , Células-Tronco Neurais/efeitos dos fármacos , Coelhos , Fatores de Tempo , Distribuição Tecidual , Inibidores da Topoisomerase I/farmacocinética , Transdução Genética , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Natl Compr Canc Netw ; 11(9): 1114-51, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24029126

RESUMO

Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , Humanos
16.
Sci Transl Med ; 5(184): 184ra59, 2013 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-23658244

RESUMO

High-grade gliomas are extremely difficult to treat because they are invasive and therefore not curable by surgical resection; the toxicity of current chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles to target enzyme/prodrug therapy selectively to tumors. We used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, and are genetically and functionally stable. In vivo biodistribution studies demonstrated NSC retention of tumor tropism, even in mice pretreated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor-bearing and orthotopic glioma-bearing immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was about one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, nontoxic, and effective in mice. These data have led to approval of a first-in-human study of an allogeneic NSC-mediated enzyme/prodrug-targeted cancer therapy in patients with recurrent high-grade glioma.


Assuntos
Glioma/tratamento farmacológico , Glioma/terapia , Células-Tronco Neurais/citologia , Pró-Fármacos/uso terapêutico , Animais , Linhagem Celular , Citosina Desaminase/metabolismo , Feminino , Citometria de Fluxo , Flucitosina/metabolismo , Flucitosina/uso terapêutico , Fluoruracila/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Células-Tronco Neurais/metabolismo , Pró-Fármacos/metabolismo
17.
Eur J Cancer ; 49(7): 1634-40, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23380277

RESUMO

PURPOSE: The primary objective of this study was to use intracerebral microdialysis (ICMD) to determine the neuropharmacokinetics of bafetinib, a dual BCR-Abl/Lyn tyrosine kinase inhibitor that may have activity against gliomas. METHODS: A microdialysis catheter was placed into either peritumoural or enhancing brain tissue of seven patients at the time of tumour resection or biopsy. Twenty-four hours later, bafetinib was administered, 240 or 360 mg po, repeating the same dose 12 h later. Dialysate samples were continuously collected for 24h, with plasma samples obtained in parallel. One to two weeks after finishing ICMD, patients were allowed to resume taking bafetinib continuously while being observed for toxicity and tumour response. RESULTS: Twenty-six dialysate samples per patient were collected (n=6) and analysed for bafetinib by tandem mass spectrometry. Bafetinib concentrations in the brain were below the lower limit of detection of the assay (0.1 ng/ml) in all samples except one from a single subject that was 0.52 ng/ml. The mean plasma bafetinib maximum concentrations after dose 1 and 2 were 143±99 and 247±73 ng/ml, respectively. Only one patient remained on treatment past two cycles, and no radiographic responses were seen. CONCLUSIONS: Bafetinib does not sufficiently cross intact or disrupted blood-brain barrier, and therefore, systemic administration of bafetinib is not recommended when investigating this drug as a treatment for brain tumours. ICMD can be a valuable research tool in early drug development. Lead-in ICMD studies can be performed relatively quickly, requiring only a small number of patients, and without significantly disrupting standard cancer care.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Adulto , Idoso , Área Sob a Curva , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Cromatografia Líquida de Alta Pressão , Soluções para Diálise/análise , Relação Dose-Resposta a Droga , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Avaliação de Estado de Karnofsky , Masculino , Espectrometria de Massas , Meningites Bacterianas/induzido quimicamente , Taxa de Depuração Metabólica , Microdiálise/métodos , Projetos Piloto , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Resultado do Tratamento , Quinases da Família src/antagonistas & inibidores
19.
Expert Opin Drug Metab Toxicol ; 6(12): 1477-91, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20969450

RESUMO

IMPORTANCE OF THE FIELD: many promising targeted agents and combination therapies are being investigated for brain cancer. However, the results from recent clinical trials have been disappointing. A better understanding of the disposition of drug in the brain early in drug development would facilitate appropriate channeling of new drugs into brain cancer clinical trials. AREAS COVERED IN THIS REVIEW: barriers to successful drug activity against brain cancer and issues affecting intratumoral drug concentrations are reviewed. The use of the microdialysis technique for extracellular fluid (ECF) sampling and its application to drug distribution studies in brain are reviewed using published literature from 1995 to the present. The benefits and limitations of microdialysis for performing neuorpharmacokinetic (nPK) and neuropharmacodynamic (nPD) studies are discussed. WHAT THE READER WILL GAIN: the reader will gain an appreciation of the challenges involved in identifying agents likely to have efficacy in brain cancer, an understanding of the general principles of microdialysis, and the power and limitations of using this technique in early drug development for brain cancer therapies. TAKE HOME MESSAGE: a major factor preventing efficacy of anti-brain cancer drugs is limited access to tumor. Intracerebral microdialysis allows sampling of drug in the brain ECF. The resulting nPK/nPD data can aid in the rational selection of drugs for investigation in brain tumor clinical trials.


Assuntos
Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Microdiálise/métodos , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/patologia , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Desenho de Drogas , Líquido Extracelular/metabolismo , Humanos , Distribuição Tecidual
20.
Clin Cancer Res ; 15(22): 7092-8, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19861433

RESUMO

PURPOSE: Intracerebral microdialysis (ICMD) is an accepted method for monitoring changes in neurochemistry from acute brain injury. The goal of this pilot study was to determine the feasibility of using ICMD to examine the neuropharmacokinetics of temozolomide in brain interstitium following oral administration. EXPERIMENTAL DESIGN: Patients with primary or metastatic brain tumors had a microdialysis catheter placed in peritumoral brain tissue at the time of surgical debulking. Computerized tomography scan confirmed the catheter location. Patients received a single oral dose of temozolomide (150 mg/m2) on the first postoperative day, serial plasma and ICMD samples were collected over 24 hours, and temozolomide concentrations were determined by tandem mass spectrometry. RESULTS: Nine patients were enrolled. Dialysate and plasma samples were successfully collected from seven of the nine patients. The mean temozolomide areas under the concentration-time curve (AUC) in plasma and brain interstitium were 17.1 and 2.7 microg/mL x hour, with an average brain interstitium/plasma AUC ratio of 17.8%. The mean peak temozolomide concentration in the brain was 0.6 +/- 0.3 microg/mL, and the mean time to reach peak level in brain was 2.0 +/- 0.8 hours. CONCLUSIONS: The use of ICMD to measure the neuropharmacokinetics of systemically administered chemotherapy is safe and feasible. Concentrations of temozolomide in brain interstitium obtained by ICMD are consistent with published data obtained in a preclinical ICMD model, as well as from clinical studies of cerebrospinal fluid. However, the delayed time required to achieve maximum temozolomide concentrations in brain suggests that current chemoradiation regimens may be improved by administering temozolomide 2 to 3 hours before radiation.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Radioterapia/métodos , Administração Oral , Idoso , Antineoplásicos Alquilantes/farmacocinética , Área Sob a Curva , Neoplasias Encefálicas/cirurgia , Terapia Combinada/métodos , Dacarbazina/farmacocinética , Estudos de Viabilidade , Feminino , Humanos , Masculino , Microdiálise , Pessoa de Meia-Idade , Projetos Piloto , Espectrometria de Massas em Tandem/métodos , Temozolomida
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