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1.
Future Oncol ; : 1-14, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38652041

RESUMEN

CD39 is the rate-limiting enzyme for the molecular signal cascade leading to the generation of ADP and adenosine monophosphate (AMP). In conjunction with CD73, CD39 converts adenosine triphosphate (ATP) to ADP and AMP, which leads to the accumulation of immunosuppressive adenosine in the tumor microenvironment. This review focuses on the role of CD39 and CD73 in immune response and malignant progression, including the expression of CD39 within the tumor microenvironment and its relationship to immune effector cells, and its role in antigen presentation. The role of CD39- and CD73-targeting therapeutics and cancer-directed clinical trials investigating CD39 modulation are also explored.


[Box: see text].

2.
Int J Mol Sci ; 25(6)2024 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-38542143

RESUMEN

The emergence of targeted therapeutics in ovarian cancer, particularly poly (ADP-ribose) polymerase inhibitors (PARPi's), has created additional opportunities for patients seeking frontline and recurrent disease management options. In particular, PARPi's have shown clinical benefits in BRCA mutant and/or homologous recombination deficient (HRD) ovarian cancer. Until recently, response was thought to be limited in BRCA wild-type, homologous recombination proficient (HRP) cancers. Therefore, attempts have been made at combination therapy involving PARPi to improve patient outcomes. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated underwhelming results involving ovarian cancer. Many are searching for reliable biomarkers of immune response to increase efficacy of ICI therapy involving ovarian cancer. In this review, we examine the evidence supporting the combination of PARPi and ICIs in ovarian cancer, which is still lacking.


Asunto(s)
Neoplasias Ováricas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Femenino , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Recombinación Homóloga , Biomarcadores
3.
BMC Cancer ; 21(1): 1154, 2021 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-34711195

RESUMEN

Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2 results in homologous recombination deficiency (HRD) and can be a target for therapeutic strategies including poly (ADP-ribose) polymerase inhibitors (PARPi). However, response is limited in patients who are not HRD, highlighting the need for reliable and robust HRD testing. This manuscript will review BRCA1/2 function and homologous recombination proficiency in respect to breast and ovarian cancer. The current standard testing methods for HRD will be discussed as well as trials leading to approval of PARPi's. Finally, standard of care treatment and synthetic lethality will be reviewed.


Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1/fisiología , Genes BRCA2/fisiología , Recombinación Homóloga/fisiología , Neoplasias Ováricas/genética , Reparación del ADN por Recombinación/fisiología , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Variación Genética , Humanos , Mutación , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/fisiología
4.
Gynecol Oncol ; 163(3): 459-464, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34702567

RESUMEN

OBJECTIVE: Previously, Vigil demonstrated clinical benefit to prolong relapse free and overall survival in the BRCA wild-type (BRCA-wt), homologous recombination proficient (HRP) patient population. Here we provide long term follow up of 3 years in the HRP patient population enrolled in the Phase 2b VITAL study. METHODS: HRP patients treated with Vigil (n = 25) or placebo (n = 20) who were enrolled in the Phase 2b, double-blind, placebo-controlled (VITAL study, NCT02346747) were followed for safety, OS and RFS. OS and RFS from time of randomization (immediately prior to maintenance therapy) and from debulking tissue procurement time points were analyzed by Kaplan-Meier (KM) and restricted mean survival time (RMST) analysis. RESULTS: OS for Vigil treated patients at 3 years has not yet reached median OS time point (95% CI 41.6 months to not achieved) compared to 26.9 (95% CI 17.4 months to not achieved) in placebo treated patients (HR 0.417 p = 0.020). Three year RFS also showed benefit to Vigil (stratified HR 0.405, p = 0.011) and no long term toxicity to Vigil was observed. Three year OS for Vigil of 70% vs. 40% for placebo from time of randomization was observed (p = 0.019). RMST analysis was also significant for OS (45.7 vs. 32.8 months, p = 0.008) and RFS (p = 0.025). CONCLUSION: In conclusion, results suggest durable activity of Vigil on RFS and OS and support further evaluation of Vigil in HRP ovarian cancer.


Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Neoplasias Ováricas/terapia , Anciano , Ensayos Clínicos Fase II como Asunto , Femenino , Recombinación Homóloga , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de Supervivencia
5.
Gynecol Oncol ; 161(3): 676-680, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33715892

RESUMEN

OBJECTIVE: Recently, Vigil showed significant clinical benefit with improvement in relapse free (RFS) and overall survival (OS) in pre-planned subgroup analysis in stage III/IV newly diagnosed ovarian cancer patients with BRCA wild type (BRCA-wt) molecular profile. Here we analyze homologous recombination (HR) status of patients enrolled in the Phase 2b VITAL study and determine clinical benefit of Vigil in HR proficient (P) patients. METHODS: Patients were previously enrolled in a Phase 2b, double-blind, placebo-controlled trial. All were in complete response with Stage III/IV high grade serious, endometroid or clear cell ovarian cancer. HR status was determined using MyChoice®CDx score (<42 = HRP) (Myriad Genetics, Inc., UT). Post-hoc analyses were carried out using Kaplan Meier and restricted mean survival time (RMST) analysis to evaluate RFS and OS based on HR deficiency (D) status. RESULTS: RFS was improved with Vigil (n = 25) in HRP patients compared to placebo (n = 20) (HR = 0.386; 90% CI 0.199-0.750; p = 0.007), results were verified by RMST (p = 0.017). Similarly, OS benefit was observed in Vigil group compared to placebo (HR = 0.342; 90% CI 0.141-0.832; p = 0.019). Results with OS were also verified with RMST (p = 0.008). CONCLUSION: Vigil exhibited clinical benefit in HRP molecular profile patients.


Asunto(s)
Carcinoma Epitelial de Ovario/tratamiento farmacológico , Modafinilo/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Recombinación Homóloga , Humanos , Inmunoterapia , Persona de Mediana Edad , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Tasa de Supervivencia , Estados Unidos
6.
Future Oncol ; 17(21): 2817-2830, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34058833

RESUMEN

Patients who have mutations of the genes BRCA1 or BRCA2 are at an increased risk for developing breast and ovarian cancer. BRCA1/2 function as tumor suppressor genes, responsible for regulating DNA repair, and play an essential role in homologous recombination. Mutation of BRCA1/2 results in homologous recombination deficiency and genomic instability which drives oncogenesis and cancer proliferation. Recently, BRCA1/2 gene expression has been implicated in regulating immune response. Here we discuss the signaling pathway of BRCA1/2 in relation to breast and ovarian cancer, with emphasis on how dysregulation facilitates the path to malignancy and current treatment options.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias de la Mama/genética , Neoplasias Ováricas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinogénesis/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Inestabilidad Genómica , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Mutación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Pronóstico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , Reparación del ADN por Recombinación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
7.
Future Oncol ; 17(13): 1683-1694, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33726502

RESUMEN

Radiation therapy (RT) in some cases results in a systemic anticancer response known as the abscopal effect. Multiple hypotheses support the role of immune activation initiated by RT-induced DNA damage. Optimal radiation dose is necessary to promote the cGAS-STING pathway in response to radiation and initiate an IFN-1 signaling cascade that promotes the maturation and migration of dendritic cells to facilitate antigen presentation and stimulation of cytotoxic T cells. T cells then exert a targeted response throughout the body at areas not subjected to RT. These effects are further augmented through the use of immunotherapeutic drugs resulting in increased T-cell activity. Tumor-infiltrating lymphocyte presence and TREX1, KPNA2 and p53 signal expression are being explored as prognostic biomarkers.


Asunto(s)
Quimioradioterapia/métodos , Células Dendríticas/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/radioterapia , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Movimiento Celular/efectos de la radiación , Ensayos Clínicos como Asunto , Daño del ADN/inmunología , Daño del ADN/efectos de la radiación , Células Dendríticas/efectos de la radiación , Exodesoxirribonucleasas/análisis , Exodesoxirribonucleasas/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/efectos de la radiación , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/mortalidad , Fosfoproteínas/análisis , Fosfoproteínas/metabolismo , Pronóstico , Supervivencia sin Progresión , Dosificación Radioterapéutica , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/efectos de la radiación , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de la radiación , Proteína p53 Supresora de Tumor/análisis , Proteína p53 Supresora de Tumor/metabolismo , alfa Carioferinas/análisis , alfa Carioferinas/metabolismo
8.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-34207103

RESUMEN

Ovarian cancer response to immunotherapy is limited; however, the evaluation of sensitive/resistant target treatment subpopulations based on stratification by tumor biomarkers may improve the predictiveness of response to immunotherapy. These markers include tumor mutation burden, PD-L1, tumor-infiltrating lymphocytes, homologous recombination deficiency, and neoantigen intratumoral heterogeneity. Future directions in the treatment of ovarian cancer include the utilization of these biomarkers to select ideal candidates. This paper reviews the role of immunotherapy in ovarian cancer as well as novel therapeutics and study designs involving tumor biomarkers that increase the likelihood of success with immunotherapy in ovarian cancer.


Asunto(s)
Inmunoterapia , Neoplasias Ováricas/terapia , Medicina de Precisión , Antígenos de Neoplasias/inmunología , Biomarcadores de Tumor , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Terapia Molecular Dirigida , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/etiología , Neoplasias Ováricas/mortalidad , Medicina de Precisión/efectos adversos , Medicina de Precisión/métodos , Resultado del Tratamiento
9.
Lancet Oncol ; 21(12): 1661-1672, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33271095

RESUMEN

BACKGROUND: Gemogenovatucel-T is an autologous tumour cell vaccine manufactured from harvested tumour tissue, which specifically reduces expression of furin and downstream TGF-ß1 and TGF-ß2. The aim of this study was to determine the safety and efficacy of gemogenovatucel-T in front-line ovarian cancer maintenance. METHODS: This randomised, double-blind, placebo-controlled, phase 2b trial involved 25 hospitals in the USA. Women aged 18 years and older with stage III/IV high-grade serous, endometrioid, or clear cell ovarian cancer in clinical complete response after a combination of surgery and five to eight cycles of chemotherapy involving carboplatin and paclitaxel, and an Eastern Cooperative Oncology Group status of 0 or 1 were eligible for inclusion in the study. Patients were randomly assigned (1:1) to gemogenovatucel-T or placebo by an independent third party interactive response system after successful screening using randomly permuted block sizes of two and four and stratified by extent of surgical cytoreduction and neoadjuvant versus adjuvant chemotherapy. Gemogenovatucel-T (1 × 107 cells per injection) or placebo was administered intradermally (one per month) for a minimum of four and up to 12 doses. Patients, investigators, and clinical staff were masked to patient allocation until after statistical analysis. The primary endpoint was recurrence-free survival, analysed in the per-protocol population. All patients who received at least one dose of gemogenovatucel-T were included in the safety analysis. The study is registered with ClinicalTrials.gov, NCT02346747. FINDINGS: Between Feb 11, 2015, and March 2, 2017, 310 patients consented to the study at 22 sites. 217 were excluded. 91 patients received gemogenovatucel-T (n=47) or placebo (n=44) and were analysed for safety and efficacy. The median follow-up from first dose of gemogenovatucel-T was 40·0 months (IQR 35·0-44·8) and from first dose of placebo was 39·8 months (35·5-44·6). Recurrence-free survival was 11·5 months (95% CI 7·5-not reached) for patients assigned to gemogenovatucel-T versus 8·4 months (7·9-15·5) for patients assigned to placebo (HR 0·69, 90% CI 0·44-1·07; one-sided p=0·078). Gemogenovatucel-T resulted in no grade 3 or 4 toxic effects. Two patients in the placebo group had five grade 3 toxic events, including arthralgia, bone pain, generalised muscle weakness, syncope, and dyspnea. Seven patients (four in the placebo group and three in the gemogenovatucel-T group) had 11 serious adverse events. No treatment-related deaths were reported in either of the groups. INTERPRETATION: Front-line use of gemogenovatucel-T immunotherapy as maintenance was well tolerated but the primary endpoint was not met. Further investigation of gemogenovatucel-T in patients stratified by BRCA mutation status is warranted. FUNDING: Gradalis.


Asunto(s)
Vacunas contra el Cáncer/administración & dosificación , Carcinoma Endometrioide/terapia , Neoplasias Ováricas/terapia , Anciano , Vacunas contra el Cáncer/efectos adversos , Carcinoma Endometrioide/inmunología , Carcinoma Endometrioide/patología , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos
10.
Oncologist ; 25(11): e1604-e1613, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32356383

RESUMEN

LESSONS LEARNED: Although this study of idelalisib in patients with PDAC was limited in size and duration because of early termination, idelalisib exposure resulted in an overall safety profile consistent with studies in hematological malignancies, except that the incidences of diarrhea and colitis were reduced in patients with PDAC. Preclinical studies of the PI3K pathway in PDAC and positive clinical results of PI3K inhibition in other cancers support the continued development of PI3K inhibitors in PDAC. BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal solid tumors and is often refractory to treatment. Phosphatidylinositol-3 kinase (PI3K) δ inhibition influences regulatory immune cell function and improves survival in preclinical PDAC models. Here, idelalisib, an inhibitor of PI3Kδ, was investigated as treatment for metastatic PDAC. METHODS: This was an open-label, multicenter, phase Ib, nonrandomized, dose-escalation study. Study aims were to investigate the maximum tolerated dose, safety, pharmacokinetics/pharmacodynamics, and efficacy of idelalisib alone and in combination with chemotherapeutics-nab-paclitaxel and modified (m)FOLFOX6. RESULTS: Because of early termination, only 16 patients were enrolled in the single-agent idelalisib arm, 12 of whom received at least one dose of idelalisib. The most common treatment-emergent adverse events (≥25%) related to idelalisib (n = 12) were increased aspartate aminotransferase, pyrexia, and maculopapular rash. One patient presented with diarrhea; no cases of colitis were reported. One patient discontinued treatment because of pyrexia and maculopapular rash; two patients died because of disease progression. CONCLUSION: This study was terminated because factors contributing to safety concerns in phase III studies of idelalisib for hematological malignancies were not fully understood. In this small sample of patients with metastatic PDAC, exposure to idelalisib resulted in safety findings consistent with previous studies, with reduced diarrhea/colitis.


Asunto(s)
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Purinas , Quinazolinonas , Adenocarcinoma/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas , Purinas/efectos adversos , Purinas/uso terapéutico , Quinazolinonas/efectos adversos , Quinazolinonas/uso terapéutico
11.
Future Oncol ; 16(9): 483-495, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32100561

RESUMEN

Given recent advances in cancer immune therapy, specifically use of checkpoint inhibitors, understanding the link between autoimmunity and cancer is essential. Rheumatoid arthritis (RA) affects about 1% of the population, and early diagnosis is key to prevent joint damage. Management consists of disease-modifying antirheumatic drugs that alter normal immunologic pathways, which could affect malignancy growth and survival. Prolonged immune dysregulation and the resulting inflammatory response associated with development of RA may also lead to increased cancer development risk. RA has long been associated with increased risk of non-Hodgkin's lymphoma [1] and further evidence supports relationship to lung cancer [2]. This review will address the mechanisms behind cancer development and progression in RA patients, biomarkers and assess cancer risk and early detection.


Asunto(s)
Artritis Reumatoide/etiología , Neoplasias/patología , Neoplasias/terapia , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Progresión de la Enfermedad , Humanos , Inmunoterapia/efectos adversos , Inflamación , Neoplasias/inmunología , Riesgo
12.
Future Oncol ; 16(1): 4251-4264, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31755321

RESUMEN

Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in KIT and PDGFRA. Ripretinib has emerged as a promising investigational agent for the treatment of gastrointestinal stromal tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Naftiridinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proyectos de Investigación , Urea/análogos & derivados , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/patología , Humanos , Mesilato de Imatinib/administración & dosificación , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Sunitinib/administración & dosificación , Tasa de Supervivencia , Urea/uso terapéutico , Adulto Joven
13.
Oncology ; 97(2): 59-74, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31261152

RESUMEN

Chimeric antigen receptor (CAR) modified T-cell therapy, a unique platform technology highlighting precision medicine through utilization of molecular biology and cell-based therapeutics has shown unprecedented rates in patients with hematological malignancies such as acute lymphocyte leukemia, non-Hodgkin's lymphoma and multiple myeloma (MM). With the approval of CD19-targeted CAR T-cells by the Food and Drug Administration in acute lymphoblastic leukemia (ALL) and NHL, this technology is positioned for aggressive expansion to combination therapeutic opportunities and proof of principle towards utility in other malignant disorders. However, despite the impressive results seen with hematological malignancies, CAR T-cells have shown limited efficacy in solid tumors with several unsuccessful preclinical studies. Regardless, these attempts have provided us with a better understanding of the imminent challenges specific to solid tumors even if they have not so far led to expanded clinical treatment opportunities outside ALL/NHL/MM. This review summarizes our current understanding of CAR T-cell mechanism of action, while presenting the major limitations of CAR T-cell derived treatments in solid tumors. We further discuss recent findings and present new potential strategies to overcome the challenges facing solid tumor targeting by CAR T-cell platforms.


Asunto(s)
Inmunoterapia Adoptiva , Linfoma no Hodgkin/terapia , Mieloma Múltiple/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores Quiméricos de Antígenos/inmunología , Antígenos CD19/inmunología , Humanos , Prueba de Estudio Conceptual
14.
Br J Clin Pharmacol ; 85(7): 1464-1473, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30845347

RESUMEN

AIMS: This phase I study evaluated the effects of the moderate cytochrome P450 (CYP) 3A inhibitor fluconazole and the strong CYP3A/P-glycoprotein (P-gp) inhibitor itraconazole on the pharmacokinetics of the investigational neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme inhibitor pevonedistat in patients with advanced solid tumours. METHODS: Patients received single doses of intravenous pevonedistat 8 mg m-2 , alone and with fluconazole (loading: 400 mg; maintenance: 200 mg once daily), or pevonedistat 8, 15 or 20 mg m-2 , alone and with itraconazole 200 mg once daily. Serial blood samples for pevonedistat pharmacokinetics were obtained pre- and post-infusion on days 1 (alone) and 8 (with fluconazole/itraconazole). After completing the pharmacokinetic portion, patients remaining on study received pevonedistat with docetaxel or carboplatin and paclitaxel. RESULTS: The ratios of geometric mean area under the concentration-time curves (n; 90% confidence interval) of pevonedistat in the presence vs. absence of fluconazole or itraconazole were 1.11 (12; 1.03-1.19) and 1.14 (33; 1.07-1.23), respectively. Fifty patients (98%) experienced at least one adverse event (AE), with maximum severity of grade 1-2 in 28 patients (55%) and of grade ≥3 in 22 patients (43%). The most common drug-related AEs were vomiting (12%), diarrhoea (10%) and nausea (8%). No new safety findings were observed for pevonedistat. CONCLUSIONS: Fluconazole or itraconazole had insignificant effects on pevonedistat pharmacokinetics, indicating minor contributions of CYP3A/P-gp to pevonedistat clearance. The safety profile of single doses of pevonedistat plus steady-state fluconazole or itraconazole was consistent with prior clinical experience, with no new safety signals observed.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclopentanos/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacología , Neoplasias/tratamiento farmacológico , Pirimidinas/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Carboplatino/administración & dosificación , Ciclopentanos/administración & dosificación , Ciclopentanos/efectos adversos , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/efectos adversos , Docetaxel/administración & dosificación , Interacciones Farmacológicas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Fluconazol/administración & dosificación , Fluconazol/efectos adversos , Fluconazol/farmacología , Humanos , Itraconazol/administración & dosificación , Itraconazol/efectos adversos , Itraconazol/farmacología , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos
15.
Future Oncol ; 15(33): 3861-3876, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31668087

RESUMEN

Selective delivery of therapeutic agents into solid tumors has been a major challenge impeding the achievement of long-term disease remission and cure. The need to develop alternative drug delivery routes to achieve higher drug concentration in tumor tissue, reduce unwanted off-target side effects and thus achieve greater therapeutic efficacy, has resulted in an explosive body of research. Bifidobacterium spp. are anaerobic, nonpathogenic, Gram-positive bacteria, commensal to the human gut that are a possible anticancer drug-delivery vehicle. In this review, we describe Bifidobacterium's microbiology, current clinical applications, overview of the preclinical work investigating Bifidobacterium's potential to deliver anticancer therapy, and review the different strategies used up to date. Finally, we discuss both current challenges and future prospects.


Asunto(s)
Bifidobacterium/fisiología , Sistemas de Liberación de Medicamentos/métodos , Inmunoterapia/métodos , Oncología Médica/métodos , Neoplasias/terapia , Medicina de Precisión/métodos , Animales , Antineoplásicos/administración & dosificación , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Genes Reporteros/genética , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Humanos , Oncología Médica/tendencias , Neoplasias/genética , Neoplasias/inmunología , Plásmidos/genética , Medicina de Precisión/tendencias , Probióticos/administración & dosificación , Resultado del Tratamiento
16.
Future Oncol ; 15(26): 3053-3069, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31411057

RESUMEN

Natural killer (NK) cells lead immune surveillance against cancer and early elimination of small tumors. Owing to their ability to engage tumor targets without the need of specific antigen, the therapeutic potential of NK cells has been extensively explored in hematological malignancies. In solid tumors, however, their role in the clinical arena remains poorly exploited despite a broad accumulation of preclinical data. In this article, we review our current knowledge of NK cells' biology, and highlight the challenges facing NK cell antitumor strategies in solid tumors. We further summarize the abundant preclinical attempts at overcoming these challenges, present past and ongoing clinical trial data and finally discuss the potential impact of novel insights on the development of NK cell-based therapies.


Asunto(s)
Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Animales , Humanos , Vigilancia Inmunológica , Inmunoterapia Adoptiva , Neoplasias/etiología , Neoplasias/metabolismo , Neoplasias/terapia , Células Madre Neoplásicas/metabolismo , Receptores KIR/metabolismo , Transducción de Señal , Escape del Tumor/genética , Escape del Tumor/inmunología
17.
Invest New Drugs ; 36(2): 248-258, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28852909

RESUMEN

Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC0-inf) and maximum concentrations (Cmax) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.


Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Azepinas/farmacocinética , Drogas en Investigación/farmacocinética , Esomeprazol/uso terapéutico , Itraconazol/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/farmacocinética , Rifampin/uso terapéutico , Área Bajo la Curva , Azepinas/sangre , Azepinas/farmacología , Azepinas/uso terapéutico , Relación Dosis-Respuesta a Droga , Drogas en Investigación/farmacología , Drogas en Investigación/uso terapéutico , Esomeprazol/farmacología , Femenino , Humanos , Itraconazol/farmacología , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/sangre , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Rifampin/farmacología
18.
Invest New Drugs ; 36(2): 240-247, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28819760

RESUMEN

Aims A primary objective of this study was to investigate the effect of single and multiple doses of alisertib, an investigational Aurora A kinase inhibitor, on the QTc interval in patients with advanced malignancies. The dose regimen used was the maximum tolerated dose which was also the recommended phase 3 dose (50 mg twice daily [BID] for 7 days in 21-day cycles). Methods Patients received a single dose of alisertib (50 mg) on Day 1, and multiple doses of alisertib (50 mg BID) on Days 4 through to the morning of Day 10 of the first cycle of treatment. Triplicate ECGs were collected at intervals over 10 to 24 h via Holter recorders on Days -1 (baseline), 1 and 10. Changes from time-matched baseline values were calculated for various ECG parameters including QTc, heart rate, PR and QRS intervals. Alisertib pharmacokinetics were also assessed during the study, and an exposure-QTc analysis was conducted. Results Fifty patients were included in the QTc analysis. The upper bounds of the 95% confidence intervals for changes from time-matched baseline QTcF and QTcI values were <5 ms across all study days, time points and correction methods. Alisertib did not produce clinically relevant effects on heart rate, PR or QRS intervals. There was no evidence of a concentration-QTc effect relationship. Conclusions Alisertib does not cause QTc prolongation and can be concluded to not have any clinically relevant effects on cardiac repolarization or ECG parameters at the single agent maximum tolerated dose of 50 mg BID.


Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Azepinas/uso terapéutico , Drogas en Investigación/uso terapéutico , Electrocardiografía , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Aurora Quinasa A/metabolismo , Azepinas/sangre , Azepinas/farmacocinética , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Metaboloma , Neoplasias/patología , Pirimidinas/sangre , Pirimidinas/farmacocinética
20.
J Pediatr Hematol Oncol ; 39(4): e183-e186, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28338569

RESUMEN

Ewing sarcoma is a highly resistant disease with a <10% chance of survival at 5 years after failure of frontline chemotherapy. This is a case report of an Ewing sarcoma patient with metastatic disease recurrence <2 years after standard chemotherapy/radiation who achieved a durable and sustained complete response after 2 series of treatments with Vigil (GMCSF/bi-shRNA furin DNA autologous tumor immunotherapy) serially manufactured from first and second recurrences with ELISPOT assay correlation. Results support justification of further testing of Vigil with ELISPOT assay as a biomarker to assess level of immune response and correlation with disease control.


Asunto(s)
Compuestos de Bencidrilo/administración & dosificación , Vacunas contra el Cáncer/administración & dosificación , Inmunoterapia/métodos , Sarcoma de Ewing/terapia , Adolescente , Compuestos de Bencidrilo/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Ensayo de Immunospot Ligado a Enzimas , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Humanos , Modafinilo , ARN Interferente Pequeño/uso terapéutico , Terapia Recuperativa/métodos , Sarcoma de Ewing/diagnóstico , Resultado del Tratamiento
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