RESUMEN
Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) are widely used in non-small cell lung cancer patients harboring activating EGFR mutations. However, resistance mechanisms, particularly the T790âM mutation, hamper longer-term therapeutic success of first and second generation EGFR-TKIs. To address this unmet medical need, EGFR-TKIs of the third generation are under clinical development. Relevant clinical efficacy with mainly mild to moderate class-specific side effects has been shown for third-generation EGFR-TKIs. Molecular testing is of major importance in deciding for treatment with third generation EGFR-TKIs. This article elucidates the developmental state of third generation EGFR-TKIs with its focus on Osimertinib, the first and currently the only compound in this class which is approved in Germany. Additionally, the medical importance of molecular diagnosis using tumor tissue and circulating tumor DNA is discussed.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos , Alemania , Humanos , Neoplasias Pulmonares/patología , Terapia Molecular Dirigida , MutaciónRESUMEN
Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25). Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration: ClinicialTrials.gov identifier: CNCT02193633.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Benzamidas/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/patología , Morfolinas/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/patología , Esquema de Medicación , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Dosis Máxima Tolerada , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 2 de la Rapamicina/antagonistas & inhibidores , Persona de Mediana Edad , Morfolinas/efectos adversos , Morfolinas/farmacocinética , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Criterios de Evaluación de Respuesta en Tumores Sólidos , Proteínas Quinasas S6 Ribosómicas/metabolismoRESUMEN
PURPOSE: The controlled phase III trial SATURN demonstrated that maintenance therapy with erlotinib after the first-line platinum-based chemotherapy prolonged progression-free survival (PFS) and overall survival (OS) of non-small cell lung cancer (NSCLC) patients with advanced, non-progressive disease. We conducted the non-interventional study SATURN NIS to investigate the effectiveness and tolerability of erlotinib maintenance in daily clinical practice. METHODS: This single-arm NIS screened 290 patients with locally advanced or metastatic NSCLC (stage IIIB or IV) and stable disease after standard platinum-based first-line chemotherapy in 95 institutions across Germany. Erlotinib was dosed and administered corresponding to the terms of the marketing authorization at the time of recruitment. The main effectiveness endpoint was subjects' OS at 1 year. Subgroup analyses of survival estimates of OS and PFS were performed. RESULTS: 272 patients were eligible for analysis (median age 66 years, 37.1% females, 99.6% Caucasian, median ECOG performance status 1, 61.8% adenocarcinoma, 96.3% of patients with stable disease). Maintenance therapy with erlotinib resulted in median OS comparable to that of the SATURN phase III trial 10.4 months [95% CI: (8.8; 12.5) vs. 11.9 months]. The 1-year survival rate was 45.6% [95% CI: (37.5%; 53.6%)]. No new safety signals were observed. As expected, patients with epidermal growth factor receptor (EGFR) mutations derived a greater benefit concerning OS and PFS than EGFR-wild-type patients. Moreover, a significant association of OS and PFS and the smoking status was observed. CONCLUSIONS: The results of this non-interventional study support the current clinical practice of erlotinib switch maintenance in EGFR-mutation-positive patients.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Clorhidrato de Erlotinib/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Receptores ErbB/genética , Clorhidrato de Erlotinib/efectos adversos , Femenino , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Quimioterapia de Mantención/métodos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Tasa de Supervivencia , Resultado del TratamientoAsunto(s)
Antineoplásicos/uso terapéutico , Bortezomib/uso terapéutico , Quimioterapia de Consolidación , Mieloma Múltiple/terapia , Trasplante de Células Madre , Adulto , Anciano , Antineoplásicos/efectos adversos , Bortezomib/efectos adversos , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Trasplante AutólogoRESUMEN
Background: The aim of this study was to evaluate patient preference and satisfaction for the subcutaneous (s.c.) versus intravenous (i.v.) formulation of rituximab given with chemotherapy in previously untreated patients with CD20+ diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients and methods: Patients received eight cycles of rituximab according to 2 schedules: Arm A received 1 cycle rituximab i.v. (375 mg/m2) and 3 cycles rituximab s.c. (1400 mg) then 4 cycles rituximab i.v.; Arm B received 4 cycles rituximab i.v. (375 mg/m2) then 4 cycles rituximab s.c. (1400 mg). Alongside rituximab, both arms received 6-8 cycles of chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), cyclophosphamide, vincristine, prednisone (CVP), or bendamustine as per standard local practice). Preference for s.c. or i.v. administration was evaluated using the Patient Preference Questionnaire (PPQ) at cycles 6 and 8. Patient satisfaction and convenience were assessed using the Cancer Therapy Satisfaction Questionnaire (CTSQ), and Rituximab Administration Satisfaction Questionnaire (RASQ) at cycles 4 and 8. Results: At the primary data cut-off (19 January 2015), the intent-to-treat population comprised 743 patients. The majority had DLBCL (63%) and baseline characteristics were balanced between arms. At cycle 8, 81% of patients completing the PPQ preferred rituximab s.c. Preference was not impacted by treatment sequence or disease type. Patient satisfaction as measured by RASQ was higher for s.c. versus i.v. CTSQ scores were similar between arms. Adverse events were generally balanced between administration routes and no new safety signals were detected. Conclusion: Most previously untreated patients with CD20+ DLBCL or FL preferred s.c. to i.v. rituximab administration. Patient satisfaction with rituximab treatment was generally greater with s.c. administration. Registered clinical trial number: NCT01724021 (ClinicalTrials.gov).
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Antineoplásicos/administración & dosificación , Linfoma Folicular/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Prioridad del Paciente , Rituximab/administración & dosificación , Adulto , Anciano , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Cruzados , Femenino , Humanos , Infusiones Intravenosas , Infusiones Subcutáneas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Rituximab/efectos adversosRESUMEN
Lung cancer is a leading cause of cancer related death worldwide. Non-small cell lung cancer (NSCLC) represents 85â% of all lung cancer cases and approximately 40â% of all patients impress with a metastatic disease at the time of diagnosis. Stage IV NSCLC has a poor prognosis and is incurable. The recommended standard therapy in this case is a palliative supportive systemic chemotherapy. However, a distinctive subgroup of patients with stage IV NSCLC appear clinically with an oligometastatic disease and may qualify for surgical therapy. There is evidence that patients with synchronous or metachronus solitary satellite nodules, either located intrapulmonary or extrapulmonary, benefit from surgical resection.
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Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/cirugía , Humanos , Neoplasias Pulmonares/diagnóstico , Selección de PacienteRESUMEN
Preliminary evidence suggests that the multikinase inhibitor sorafenib has clinical activity in FLT3-ITD-positive (FLT3-ITD) acute myeloid leukemia (AML). However, the quality and sustainability of achievable remissions and clinical variables that influence the outcome of sorafenib monotherapy are largely undefined. To address these questions, we evaluated sorafenib monotherapy in 65 FLT3-ITD AML patients treated at 23 centers. All but two patients had relapsed or were chemotherapy-refractory after a median of three prior chemotherapy cycles. Twenty-nine patients (45%) had undergone prior allogeneic stem cell transplantation (allo-SCT). The documented best responses were: hematological remission in 24 patients (37%), bone marrow remission in 5 patients (8%), complete remission (with and without normalization of peripheral blood counts) in 15 patients (23%) and molecular remission with undetectable FLT3-ITD mRNA in 10 patients (15%), respectively. Seventeen of the patients without prior allo-SCT (47%) developed sorafenib resistance after a median treatment duration of 136 days (range, 56-270 days). In contrast, allo-SCT patients developed sorafenib resistance less frequently (38%) and significantly later (197 days, range 38-225 days; P=0.03). Sustained remissions were seen exclusively in the allo-SCT cohort. Thus, sorafenib monotherapy has significant activity in FLT3-ITD AML and may synergize with allogeneic immune effects to induce durable remissions.
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Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Piridinas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/metabolismo , Anciano , Femenino , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Estudios Retrospectivos , SorafenibRESUMEN
BACKGROUND: In the placebo-controlled phase III SATURN study, maintenance erlotinib after first-line chemotherapy demonstrated significantly prolonged progression-free survival (PFS) and overall survival (OS) in the overall study population of patients with advanced non-small-cell lung cancer (NSCLC). METHODS: After four cycles of platinum-based doublet chemotherapy, patients without progressive disease (PD) were randomised to erlotinib (150 mg/day) or placebo until PD or unacceptable toxicity. In this pre-planned analysis, data are assessed according to response to first-line chemotherapy (complete/partial response [CR/PR] or stable disease [SD]). RESULTS: Following first-line chemotherapy, 889 non-PD patients were included in the intention-to-treat population (55% SD; 44% CR/PR; <1% unknown response). Erlotinib maintenance therapy significantly prolonged PFS in both the SD (hazard ratio [HR] = 0.68; P < 0.0001) and CR/PR (HR = 0.74; P = 0.0059) groups, while OS was significantly prolonged in the SD group only (HR = 0.72; P = 0.0019). The erlotinib-related OS benefit in the SD group remained significant across subgroups, irrespective of tumour histology and/or EGFR mutation status. The incidence of adverse events was similar in the SD group and the overall population, and erlotinib treatment did not negatively impact quality of life. CONCLUSIONS: Patients with advanced NSCLC and SD following first-line platinum-based doublet chemotherapy derive a significant OS benefit from maintenance erlotinib therapy.
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Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Compuestos de Platino/administración & dosificación , Quinazolinas/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Clorhidrato de Erlotinib , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: An increasing proportion of patients are exposed to anthracyclines and/or taxanes in the adjuvant or neoadjuvant setting. Re-exposure in the metastatic stage is limited by drug resistance, thus evaluation of non-cross-resistant regimens is mandatory. METHODS: Anthracycline-pretreated patients were randomly assigned to three gemcitabine-based regimens. Chemotherapy consisted of gemcitabine 1.000 mg m(-2) plus vinorelbin 25 mg m(-2) on days 1+8 (GemVin), or plus cisplatin 30 mg m(-2) on days 1+8 (GemCis), or plus capecitabine 650 mg m(-2) b.i.d. orally days 1-14 (GemCap), q3w. The primary end point was response rate. RESULTS: A total of 141 patients were recruited on the trial. The overall response rates were 39.0% (GemVin), 47.7% (GemCis) and 34.7% (GemCap). Median progression-free survival was estimated with 5.7, 6.9 and 8.3 months, respectively. Corresponding median survival times were 17.5 (GemVin), 13.0 (GemCis) and 19.4 months (GemCap). Neutropenia ≥grade 3 occurred in 16.7% (Gem/Vin), 4.4% (GemCis) and 0% (Gem/Cap), whereas non-haematological toxicities were rarely severe except grade 3 hand-foot syndrome in 2.0% of the GemCap patients (per patient analysis). CONCLUSIONS: This randomised phase II trial has revealed comparable results for three gemcitabine-based regimens regarding treatment efficacy and toxicity. Gemcitabine-based chemotherapy appears to be a worthwhile treatment option for pretreated patients with metastatic breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Capecitabina , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , Vinorelbina , GemcitabinaRESUMEN
Shortening duration of chemotherapy-induced neutropenia may reduce risk of infection and aid subsequent chemotherapy delivery. Cycle 1 neutrophil recovery was evaluated in 59 elderly women with breast cancer receiving adjuvant FEC100 (5-fluorouracil 500 mg/m(2), epirubicin 100mg/m(2) and cyclophosphamide 500 mg/m(2)) and randomized to pegfilgrastim primary prophylaxis (PP) from cycle 1, or secondary prophylaxis (SP, i.e., subsequent to a neutropenic event [no G-CSF in cycle 1]). In cycle 1, grade 4 neutropenia occurred in 77% (PP; N=30) and 72% (SP; N=29). Duration of grade 3-4 neutropenia was shorter with pegfilgrastim than without. Mean absolute neutrophil count (ANC) recovered above 1.0 x 10(9)/L by day 9 (pegfilgrastim) versus days 16-18 (without). At last observation (> or =day 14+/-2), no PP patient had ANC <1.0 x 10(9)/L versus approximately 25% of those receiving no pegfilgrastim. In conclusion, cycle 1 pegfilgrastim improved recovery from severe neutropenia in elderly breast cancer patients receiving adjuvant FEC100.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neutropenia/tratamiento farmacológico , Anciano , Antineoplásicos/efectos adversos , Femenino , Filgrastim , Humanos , Polietilenglicoles , Proteínas RecombinantesRESUMEN
This randomized phase 2 study explored the feasibility of delivering four to six cycles of the dose-intensified regimen FEC-100 (5-fluorouracil, epirubicin, and cyclophosphamide) to elderly patients with stage II-III breast cancer, using pegfilgrastim for neutrophil support. Sixty patients aged 65-77 years received single 6mg doses of pegfilgrastim on day 2 of FEC-100, either as primary prophylaxis (all cycles: PP), or as secondary prophylaxis (all cycles following a neutropenic event: SP). Neutropenic events (a composite endpoint that included grade 3 neutropenia+fever, grade 4 neutropenia, infectious complication requiring systemic anti-infectives and chemotherapy dose delay/reduction) occurred in 24/30 (80%) of the PP and 21/29 (72%) of the SP group in the first cycle. Most patients received all chemotherapy cycles at full dose on schedule (26/30 [87%] PP; 20/29 [69%] SP). These data indicate that delivery of FEC-100 is feasible with pegfilgrastim support in elderly breast cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Neutropenia/prevención & control , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Neoplasias de la Mama/complicaciones , Ciclofosfamida/administración & dosificación , Ciclofosfamida/toxicidad , Epirrubicina/administración & dosificación , Epirrubicina/toxicidad , Femenino , Filgrastim , Fluorouracilo/administración & dosificación , Fluorouracilo/toxicidad , Factor Estimulante de Colonias de Granulocitos/toxicidad , Humanos , Neutropenia/inducido químicamente , Infecciones Oportunistas/inducido químicamente , Polietilenglicoles , Premedicación , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
BACKGROUND: Patients with follicular (FL) or mantle cell lymphoma (MCL) are incurable with conventional therapy. We investigated the safety and efficacy of rituximab consolidation after autologous stem cell transplantation (ASCT) in order to prevent relapse by clearance of minimal residual disease (MRD). METHODS: Rituximab was given approximately 8 weeks after CD34+ cell enriched ASCT at 375 mg/m2, weekly for 4 weeks. Monitoring of MRD was performed by repetitive PCR analyses. RESULTS: Thirty-one patients were included; one died early after ASCT before rituximab administration. Thirty patients (20 FL, 10 MCL) were evaluable after rituximab consolidation, and 27 of these were assessable for MRD detection. Rituximab consolidation post-ASCT was safe, the most common toxicity being infection. At a median follow-up of 42 months (range 13-96) after ASCT, 25 patients were censored with an actuarial event-free survival (EFS) of 81% at 4 and 5 years. Four patients (two FL, two MCL) relapsed, and one additional MCL patient died unexpectedly in complete remission. PCR-negativity was observed in 22% of the patients before ASCT, 53% post-ASCT (P=0.0547), 72% after rituximab (P=0.0018) and 100% at 6 months post-transplant (P < 0.001). CONCLUSIONS: One single course of rituximab consolidation given after ASCT is safe, may help to eliminate MRD and may translate into improved EFS in both FL and MCL patients.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales de Origen Murino , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infecciones/inducido químicamente , Leucopenia/inducido químicamente , Linfoma Folicular/terapia , Linfoma de Células del Manto/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Trasplante de Células Madre de Sangre Periférica , Cuidados Posoperatorios , Rituximab , Análisis de Supervivencia , Trasplante Autólogo , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of three different dose levels of pegylated granulocyte colony-stimulating factor (Ro 25-8315) on progenitor cell mobilization and hematologic recovery in cancer patients. PATIENTS AND METHODS: Breast cancer patients (n = 36) were randomly assigned to receive before (part I) and after (part II) chemotherapy either a single-dose injection of Ro 25-8315 (20 microg/kg, n = 9; 60 microg/kg, n = 9; 100 microg/kg, n = 10) or a standard daily dose of filgrastim (part I, 10 microg/kg/d; part II, 5 microg/kg/d) (control group, n = 8). RESULTS: Overall, Ro 25-8315 was well tolerated. In part I, more progenitor cell mobilization was observed with Ro 25-8315 100 microg/kg. The peak of circulating CD34(+) cells was obtained at day +5 in the four groups, and the absolute neutrophil count (ANC) returned to less than 20 x 10(9)/L by day +15. In part II, high levels of circulating CD34(+) cells (> 20 cells/microL) were obtained in all four groups. The chemotherapy-induced neutropenia (< 1 x 10(9)/L) was similar in the four groups. Ro 25-8315 100 microg/kg was more effective than filgrastim in reducing the number of patients with an ANC less than 0.5 x 10(9)/L on day +12 after chemotherapy. CONCLUSION: A single injection of Ro 25-8315 100 microg/kg might be the optimal dose for steady-state peripheral-blood progenitor cell mobilization. A single injection of 20, 60, or 100 microg/kg could be as efficient as daily administration of filgrastim to correct chemotherapy-induced cytopenia. The optimal dose of Ro 25-8315 should be determined according to the planned chemotherapy regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Movilización de Célula Madre Hematopoyética/métodos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neutropenia/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Adulto , Antígenos CD34/efectos de los fármacos , Seguridad de Productos para el Consumidor , Relación Dosis-Respuesta a Droga , Femenino , Factor Estimulante de Colonias de Granulocitos/farmacocinética , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Neutropenia/inducido químicamente , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Polietilenglicoles/farmacocinética , Proteínas RecombinantesRESUMEN
Dendritic cells (DC) are recognized as the most potent antigen-presenting cells with the ability to stimulate naive resting T cells and to initiate primary immune responses. Encouraging results in vaccination studies in animal models and the development of protocols to generate sufficient numbers of human DC for clinical application have led to attempts to verify the feasibility and efficacy of this approach in patients in the context of Phase I/II vaccination trials. This review aims to present a concise overview of the current knowledge in DC development and biology and describes the recent data of the first published DC-based vaccination studies. These preliminary trials indicate that immunotherapies utilizing DC-presenting tumor-associated antigens can safely be administered to patients with cancer and induce significant immunologic and clinical responses.
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Adyuvantes Inmunológicos , Presentación de Antígeno , Vacunas contra el Cáncer , Células Dendríticas/trasplante , Inmunoterapia Activa , Neoplasias/terapia , Animales , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Células Cultivadas , Quimiocinas/metabolismo , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Estudios de Factibilidad , Femenino , Humanos , Melanoma/inmunología , Melanoma/terapia , Neoplasias/inmunología , Neoplasias/prevención & control , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/prevención & control , Neoplasias Experimentales/terapia , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/terapia , Linfocitos T Citotóxicos/inmunología , VacunaciónRESUMEN
The epithelial mucin MUC1 is overexpressed on the cell surface of many epithelial malignancies as well as on some B-cell lymphomas and multiple myelomas. Recently, we identified two HLA-A2-restricted T-cell epitopes derived from the MUC1 protein. To further extend the potential application of these peptides, we analyzed the expression of MUC1 on blast cells from patients with acute myelogenous leukemia (AML; n = 43) and several other hematological malignancies including acute lymphoblastic leukemia (n = 24), chronic lymphocytic leukemia (n = 36), hairy cell leukemia (n = 9), follicular lymphoma (n = 7), and multiple myeloma (n = 12). Using reverse transcription-PCR and MUC1-specific monoclonal antibodies, MUC1 expression was found in 67% of AML samples and 92% of myeloma samples. To analyze the presentation of MUC1 peptides by primary AML blasts, we induced MUC1-specific CTLs in vitro using peptide-pulsed dendritic cells from HLA-A2+ healthy donors as antigen-presenting cells. These CTLs efficiently lysed in an antigen-specific and HLA-A2-restricted manner not only target cells pulsed with the antigenic peptide but also tumor cell lines including multiple myeloma cells and primary AML blasts that constitutively expressed both MUC1 and HLA-A2. The specificity of the CTLs was confirmed in a cold target inhibition assay. Our data demonstrate that MUC1-derived peptides are tumor antigens in AML and several other hematological malignancies that could potentially be used for immunotherapeutic approaches.
Asunto(s)
Neoplasias Hematológicas/inmunología , Mucina-1/inmunología , Linfocitos T Citotóxicos/inmunología , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos , Presentación de Antígeno/inmunología , Células Dendríticas/inmunología , Epítopos de Linfocito T/inmunología , Antígeno HLA-A2/inmunología , Humanos , Leucemia Mieloide Aguda/inmunología , Activación de Linfocitos/inmunología , Mucina-1/biosíntesis , Mieloma Múltiple/inmunologíaRESUMEN
The epithelial mucin MUC1 is overexpressed on many epithelial malignancies as well as on some B-cell lymphomas and multiple myelomas. In the present study, we described MUC1 expression also on primary AML blasts. To analyze the presentation of MUC1-derived HLA-A2 restricted peptides by primary AML blasts, we induced MUC1-specific cytotoxic T-lymphocytes (CTLs) in vitro using peptide pulsed dendritic cells from HLA-A2+ healthy donors as antigen-presenting cells. These CTLs efficiently lysed primary AML blasts that constitutively expressed both MUC1 and HLA-A2. The specificity of the CTLs was confirmed in a cold target inhibition assay. Our data demonstrate that MUC1-derived peptides are tumor antigens in AML which could potentially be used for immunotherapeutic approaches.
Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Células Dendríticas/inmunología , Antígeno HLA-A2/inmunología , Neoplasias Hematológicas/terapia , Inmunoterapia Activa , Leucemia Mieloide/inmunología , Mucina-1/inmunología , Proteínas de Neoplasias/inmunología , Fragmentos de Péptidos/inmunología , Linfocitos T Citotóxicos/inmunología , Enfermedad Aguda , Presentación de Antígeno , Antígenos de Neoplasias/biosíntesis , Antígenos de Neoplasias/química , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/terapia , Carcinoma/inmunología , Carcinoma/terapia , Citotoxicidad Inmunológica , Epítopos/inmunología , Femenino , Antígeno HLA-A2/biosíntesis , Neoplasias Hematológicas/inmunología , Humanos , Inmunización , Leucemia Mieloide/patología , Masculino , Repeticiones de Minisatélite , Mucina-1/biosíntesis , Mucina-1/química , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/química , Neoplasia Residual/terapia , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/terapia , Señales de Clasificación de Proteína , VacunaciónAsunto(s)
Antivirales/uso terapéutico , Infecciones por Citomegalovirus/epidemiología , Citomegalovirus/aislamiento & purificación , Foscarnet/uso terapéutico , Ganciclovir/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Reacción en Cadena de la Polimerasa , Trasplante Homólogo/efectos adversos , Adulto , Trasplante de Médula Ósea/efectos adversos , Citomegalovirus/genética , Citomegalovirus/crecimiento & desarrollo , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/transmisión , Femenino , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Humanos , Huésped Inmunocomprometido , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Riesgo , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Autólogo/efectos adversos , Activación ViralRESUMEN
Signal-regulatory proteins (SIRPs) represent a new family of inhibitory/activating receptor pairs. They consist of 3 highly homologous immunoglobulin (Ig)-like domains in their extracellular regions, but differ in their cytoplasmic regions by the presence (SIRPalpha) or absence (SIRPbeta) of immunoreceptor tyrosine-based inhibitory motifs (ITIMs). To analyze the differential expression on hematopoietic cells, function and ligand binding capacity of SIRPalpha and SIRPbeta molecules, soluble fusion proteins consisting of the extracellular domains of SIRPalpha1, SIRPalpha2, and SIRPbeta1, as well as SIRPalpha/beta-specific and SIRPbeta-specific monoclonal antibodies (MoAbs) were generated. In contrast to SIRPalpha1 and SIRPalpha2, no adhesion of SIRPbeta1 to CD47 could be detected by cell attachment assays and flow cytometry. Using deletion constructs of SIRPalpha1, the epitope responsible for SIRPalpha1 binding to CD47 could be confined to the N-terminal Ig-like loop. Flow cytometry analysis with SIRPalpha/beta- and SIRPbeta-specific MoAbs revealed that SIRPalpha but not SIRPbeta is expressed on CD34(+)CD38(-) hematopoietic cells. In addition, a strong SIRPalpha expression was also observed on primary myeloid dendritic cells (DCs) from peripheral blood as well as on in vitro generated DCs. Analysis of the T-cell stimulatory capacity of in vitro generated DCs in the presence of soluble SIRPalpha1 fusion proteins as well as SIRPalpha/beta-specific and CD47-specific MoAbs revealed a significant reduction of T-cell proliferation in mixed lymphocyte reaction and inhibition of induction of primary T-cell responses under these conditions. In contrast, soluble SIRPalpha or SIRPbeta-specific antibodies had no effect. The data suggest that the interaction of SIRPalpha with CD47 plays an important role during T-cell activation and induction of antigen-specific cytotoxic T-lymphocyte responses by DCs.