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1.
Cancer Immunol Immunother ; 60(10): 1447-60, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21647691

RESUMO

Prior to the advent of VEGF-targeted therapies, renal cell carcinoma (RCC) was among the few solid tumors shown to respond to cytokine-based therapies such as interleukin-2 (IL-2) and interferon alpha. Previous work has shown that aminobisphosphonates, including zoledronic acid (ZA), are capable of activating human Vγ9 Vδ2 T cells in vitro, and these cells can be further expanded with IL-2. Moreover, these Vγ9 Vδ2 T cells have cytolytic activity in vitro to multiple human tumor cell lines. In the current report, we have conducted a pilot trial in patients with metastatic RCC, evaluating different doses of ZA in combination with low-dose IL-2 to determine whether combining these agents can promote in vivo proliferation of Vγ9 Vδ2 T cells and elicit an antitumor response. In 12 patients evaluated, no objective clinical responses were observed by RECIST criteria; however, two patients experienced prolonged stable disease. A modest increase in Vγ9 Vδ2 T-cell frequency could be detected by Day 8 of therapy in four of the nine patients who received at least one cycle of therapy, but not to the magnitude anticipated from preclinical models. Repeated administration of IL-2 and ZA resulted in both a diminished in vivo percentage of Vγ9 Vδ2 T cells as well as impaired expansion in vitro after the first cycle of therapy. These results suggest that repeated administration of IL-2 and ZA, at the doses and schedules used in this trial, may actually inhibit the proliferative capacity of Vγ9 Vδ2 T cell in patients with metastatic RCC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/terapia , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Interleucina-2/uso terapêutico , Neoplasias Renais/terapia , Linfócitos T/transplante , Adulto , Idoso , Separação Celular , Feminino , Citometria de Fluxo , Humanos , Imunoterapia/métodos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Ácido Zoledrônico
2.
J Clin Oncol ; 27(25): 4047-54, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19636017

RESUMO

PURPOSE: Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer. PATIENTS AND METHODS: Twenty-two patients were treated in a dose-escalation trial with 100 microg, 500 microg, or 1,500 microg plasmid DNA, coadministered intradermally with 200 microg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment. RESULTS: No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFN gamma-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054). CONCLUSION: The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.


Assuntos
Adenocarcinoma/terapia , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Neoplasias da Próstata/terapia , Proteínas Tirosina Fosfatases/imunologia , Fosfatase Ácida , Adenocarcinoma/enzimologia , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adjuvantes Imunológicos/administração & dosagem , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Injeções Intradérmicas , Interferon gama/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Proteínas Recombinantes , Fatores de Tempo , Resultado do Tratamento , Vacinas de DNA/administração & dosagem
3.
Clin Cancer Res ; 11(18): 6625-33, 2005 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16166441

RESUMO

PURPOSE: To determine whether the preclinical antitumor and antiangiogenic activity of 2-methoxyestradiol can be translated to the clinic. EXPERIMENTAL DESIGN: Men with hormone-refractory prostate cancer were enrolled into this phase II randomized, double-blind trial of two doses of oral 2-methoxyestradiol capsules (400 and 1,200 mg/d) given in 4-week cycles. Pharmacokinetic sampling was done on day 1 of cycles 1 and 2 and trough samples were obtained weekly. RESULTS: Thirty-three men were accrued between February and September 2001. The notable toxicity related to therapy was one grade 2 and two grade 3 episodes of liver transaminase elevation, which resolved with continued treatment in two patients. There were two cases of deep venous thromboses. The drug had nonlinear pharmacokinetic, rapid conversion to 2-methoxyestrone and approximately 85% conjugation. Trough plasma levels of unconjugated 2-methoxyestradiol and 2-methoxyestrone were approximately 4 and 40 ng/mL, respectively. Prostate-specific antigen declines between 21% and 40% were seen in seven patients in the 1,200 mg group and in one patient in the 400 mg group. The higher-dose group showed significantly decreased prostate-specific antigen velocity (P = 0.037) and compared with the 400 mg dose had a longer median time to prostate-specific antigen progression (109 versus 67 days; P = 0.094) and time on study (126 versus 61 days; P = 0.024). There was a 2.5- and 4-fold increase in sex hormone-binding globulin for the 400 and 1,200 mg dose levels, respectively, at days 28 and 56. CONCLUSION: 2-Methoxyestradiol is well tolerated and, despite suboptimal plasma levels and limited oral bioavailability with this capsule formulation, still showed some anticancer activity at 1,200 mg/d.


Assuntos
Estradiol/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , 2-Metoxiestradiol , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Área Sob a Curva , Cápsulas , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Resistencia a Medicamentos Antineoplásicos , Estradiol/farmacocinética , Estradiol/uso terapêutico , Feminino , Fator 2 de Crescimento de Fibroblastos/urina , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/metabolismo , Fatores de Tempo , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/urina
4.
Invest New Drugs ; 21(3): 367-72, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-14578686

RESUMO

OBJECTIVE: We conducted a phase II multicenter trial of perillyl alcohol in patients with advanced hormone refractory prostate cancer (HRPC). The primary endpoint was to evaluate the 6-month progression-free survival given the potential cytostatic nature of the drug. Secondary objectives included assessing acute and chronic toxicities, as well as measuring objective response rates. METHODS: Patients with metastatic androgen-independent prostate cancer that failed at least one prior chemotherapeutic or experimental regimen were eligible. Perillyl alcohol was administered orally at 1200 mg/m2/dose four times daily and continued until disease progression or development of unacceptable toxicity. RESULTS: Fifteen patients were eligible. Six patients received less than one cycle (4 weeks) of drug, four of which stopped because of drug intolerance. Only six patients received more than two cycles of therapy and were considered evaluable for response. Main toxicity included grade 1-2 gastrointestinal intolerance (nausea/vomiting in 60% of the patients) and fatigue (47%). One patient developed a grade 4 hypokalemia that was felt likely attributable to the drug. No objective responses were seen. All patients either progressed or withdrew from the study secondary to drug intolerance before the 6-month time period. CONCLUSION: Perillyl alcohol administered at this dose and formulation did not have any objective clinical activity in this patient population.


Assuntos
Antineoplásicos/uso terapêutico , Monoterpenos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Androgênios/metabolismo , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Esquema de Medicação , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Monoterpenos/efeitos adversos , Monoterpenos/farmacocinética , Neoplasias da Próstata/patologia , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta1 , Resultado do Tratamento
5.
Clin Cancer Res ; 8(9): 2820-7, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12231522

RESUMO

This Phase I study of 1alpha-hydroxyvitamin D(2), an p.o. administered vitamin D analogue, in patients with advanced hormone-refractory prostate cancer was designed to assess the toxicity, pharmacokinetic and biological markers of drug activity, and lastly tumor response data to recommend a dose for Phase II studies. 1alpha-Hydroxyvitamin D(2) was administered daily at doses ranging from 5 to 15 microg/day. Patients were monitored for toxicity and tumor response, and blood and urine samples were collected for pharmacokinetics (1alpha,25-dihydroxyvitamin D(2) levels) and other parameters of biological activity (bone markers, parathyroid hormone, urine calcium, and serum phosphorus levels). Twenty-five patients were enrolled. Main toxicities were hypercalcemia with associated renal insufficiency. No other significant toxicity was seen. Pharmacokinetics showed an increase in the active metabolite 1alpha,25-dihydroxyvitamin D(2) that reached a plateau by week 4 despite continuous drug dosing. Elevation in daily urinary calcium excretion and serum phosphorus levels was seen, whereas a decrease in serum parathyroid hormone was evident. Two patients showed evidence of a partial response, whereas 5 others achieved disease stabilization for > or =6 months. 1alpha-Hydroxyvitamin D(2) was well tolerated with main toxicities being hypercalcemia and renal insufficiency. All of the toxicity was reversible with drug discontinuation. Evidence for drug activity was seen in surrogate markers, and pharmacokinetic analysis showed substantial increases in vitamin D metabolite levels among the various cohorts. Whereas the defined maximum tolerated dose was not reached, the recommended Phase II dose was 12.5 microg/day given continuously.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Ergocalciferóis/uso terapêutico , Pró-Fármacos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Terapia de Salvação , Adenocarcinoma/sangue , Adenocarcinoma/urina , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/sangue , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/urina , Biomarcadores Tumorais/sangue , Cálcio/urina , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Ergocalciferóis/efeitos adversos , Ergocalciferóis/sangue , Ergocalciferóis/farmacocinética , Ergocalciferóis/urina , Humanos , Hipercalcemia/induzido quimicamente , Falência Renal Crônica/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Osteocalcina/sangue , Hormônio Paratireóideo/sangue , Fósforo/sangue , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/urina , Resultado do Tratamento
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