RESUMEN
The objective of this study was to evaluate the safety and activity of the intratumoral administration of the immune costimulatory molecule, B7.1, encoded by a vector derived from the canarypox virus, ALVAC (ALVAC-B7.1), alone and with the intratumoral injection of ALVAC encoding the immune-stimulatory cytokine, interleukin 12 (ALVAC-IL-12). Fourteen patients with metastatic melanoma who had s.c. nodules received intratumoral injections on days 1, 4, 8, and 11. Nine patients were given escalating doses of up to 25 x 10(8) plaque-forming units of ALVAC-B7.1. Five patients were given 25 x 10(8) plaque-forming units of ALVAC-B7.1 combined with ALVAC-IL-12 50% tissue culture infective dose of 2 x 10(6). Toxicity was mild to moderate and consisted of inflammatory reactions at the injection site and fever, chills, myalgia, and fatigue. Higher levels of B7.1 mRNA were observed in ALVAC-B7.1-injected tumors compared with saline-injected control tumors. Higher levels of intratumoral vascular endothelial growth factor and IL-10, cytokines with immune suppressive activities, were also observed in ALVAC-B7.1- and ALVAC-IL-12-injected tumors compared with saline-injected controls. Serum levels of vascular endothelial growth factor increased at day 18 and returned to baseline at day 43. All patients developed antibody to ALVAC. Intratumoral IL-12 and IFN-gamma mRNA decreased. Changes in serum IL-12 and IFN-gamma levels were not observed. Tumor regressions were not observed. The intratumoral injections of ALVAC-B7.1 and ALVAC-IL-12 were well tolerated at these dose levels and at this schedule and resulted in measurable biological response. This response included the production of factors that may suppress the antitumor immunologic activity of these vectors.
Asunto(s)
Antígeno B7-1/genética , Interleucina-12/genética , Melanoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/inmunología , Virus de la Viruela de los Canarios/genética , Fatiga/etiología , Femenino , Fiebre/etiología , Expresión Génica , Terapia Genética/efectos adversos , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Humanos , Inyecciones Intralesiones , Masculino , Melanoma/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Resultado del TratamientoRESUMEN
PURPOSE: To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin) in patients with advanced malignancies when administered in cycles of once weekly for 3 of 4 weeks. EXPERIMENTAL DESIGN: Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status of < or =2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts receiving escalating doses from 800 to 4,300 mg/m(2). The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics, and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan dose and pharmacokinetic variables. RESULTS: Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m(2). Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m(2). Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be 46 +/- 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve extrapolated to infinity (AUC(0-infinity)) > 20 ng h/mL and 0 of 10 patients with an AUC(0-infinity) < or = 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma and the other with metastatic esophageal cancer. CONCLUSIONS: The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m(2). The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m(2)). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in phase 2 studies.
Asunto(s)
Antineoplásicos/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/farmacocinética , Linfoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Adulto , Anciano , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Área Bajo la Curva , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Factores de TiempoRESUMEN
PURPOSE: Antibodies targeting GD3 gangliosides highly expressed on melanomas mediate immune effector functions in vitro and inhibit animal model melanoma tumor growth in vivo. Because GD3 is expressed also on a subpopulation of human lymphocytes, we characterized the in vitro immune effects of murine R24 and a chimeric anti-GD3 antibody (KW-2871). DESIGN: Anti-GD3 complement-mediated (CMC) and antibody-dependent cellular cytotoxicity (ADCC) were tested against cell line Mel-624. Antibody-mediated lymphocyte expression of interleukin (IL)-2, IL-4, IL-10, and interferon-gamma (IFN-gamma) was quantified. The effect of antibody and antibody-treated lymphocyte supernates on effector cell ADCC and Fc receptor expression were evaluated. RESULTS: R24 and KW-2871 antibodies mediated CMC and ADCC to the Mel-624 cell line. R24 induced potent lymphocyte proliferation and enhanced lymphocyte RNA expression of IL-4 (2-4 logs), IL-10, and IFN-gamma (> 10-fold). KW-2871 induced no lymphocyte proliferation and had minimal effects on lymphokine expression (< 5-fold). Preincubation of effector cells with either antibody inhibited ADCC and reduced monocyte expression of FcgammaRI and II. Supernates of effector cells preincubated with either antibody were able to inhibit ADCC. CONCLUSIONS: R24 and KW-2871 antibody differ in their lymphocyte proliferation and lymphokine release activity but have similar inhibition of lymphocyte ADCC and FcgammaR expression in vitro.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/toxicidad , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Gangliósidos/inmunología , Linfocitos T/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , ARN Mensajero/genética , Receptores Fc/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
PURPOSE: KW-2871 (IgG1 kappa chimeric antibody) targets GD3, which is upregulated in melanomas. We conducted a phase I trial of KW-2871 in patients with metastatic melanoma. METHODS: Seventeen (17) patients were enrolled and received an initial test dose (10 mg/m2) intravenously. Two 2 weeks later, patients were stratified into 4 cohorts to receive 4 doses of KW-2871 (infused over 1 hour) at 2-week intervals (20, 40, 60, and 80 mg/m2). No premedications were administered for the test or first therapeutic doses. RESULTS: Dose-limiting toxicities were Grade 3 laryngospasm and chest tightness with the initial therapeutic infusion at doses of 80 and 60 mg/m2. The maximum tolerated dose (MTD) was established at 40 mg/m2 of KW2871. The most common side-effect was urticaria (Grades 1-3) in 16 of 16 patients during an initial therapeutic infusion without premedication. The mean terminal half-life, clearance, and area under the concentration-time curve (AUC(0-t)) at a dose of 40 mg/m2 for course 1 were 146 +/- 31 hours, 28 +/- 6 ml/hour, and 1922 +/- 491 mcg*hour/mL, respectively. Anti-human chimeric antibody was not detected. Two (2) patients in the 40 mg/m2 cohort had stable disease. CONCLUSIONS: An MTD of 40 mg/m2 without premedication was established for KW-2871, with urticaria being the most common side-effect and dose-limiting anaphylactoid infusion reactions.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Complejo CD3/inmunología , Inmunoterapia , Melanoma/inmunología , Melanoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Citocinas/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia/inmunología , Metástasis de la Neoplasia/terapiaRESUMEN
The aim of this study was to evaluate the tolerability and activity of intratumoral administered human interleukin 12 encoded by a vector derived from the canarypox virus (ALVAC-IL-12). Nine patients with surgically incurable metastatic melanoma who had subcutaneous nodules available for injection were enrolled. ALVAC-IL-12 was administered by intratumoral injection on days 1, 4, 8, and 11. Tumor nodules greater than 2 cm in diameter were injected with 2 x 10(6) median tissue culture infectious doses (TCID(50)), and smaller tumors were injected with 1 x 10(6) TCID(50). The total dose per patient per time point ranged from 1 x 10(6) to 4 x 10(6) TCID(50). Toxicity was mild to moderate and consisted of inflammatory reactions at the injection site and fever associated with chills, myalgia, and fatigue. No dose-limiting toxicities occurred. Increases in IL-12 mRNA, and also increases in interferon gamma mRNA, were observed in ALVAC-IL-12-injected tumors compared with saline-injected control tumors in four of the nine patients. ALVAC-IL-12-injected tumors were also characterized by T cell infiltration. Three patients demonstrated increases in serum IL-12 and in interferon gamma levels. All patients developed neutralizing IgG antibody to the canarypox vector. One patient manifested a complete response of injected subcutaneous metastases and uninjected in-transit metastases. The intratumoral injection of ALVAC-IL-12 at these dose levels and according to this schedule was well tolerated and resulted in measurable biologic response in patients with metastatic melanoma.
Asunto(s)
Avipoxvirus/genética , Terapia Genética , Inmunoterapia , Interleucina-12/uso terapéutico , Melanoma/terapia , Neoplasias Cutáneas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Femenino , Humanos , Inyecciones Intralesiones , Interferón gamma/metabolismo , Interleucina-12/inmunología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Linfocitos Infiltrantes de Tumor , Masculino , Melanoma/inmunología , Melanoma/patología , Persona de Mediana Edad , Plásmidos , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapéutico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: TRA-8 is a murine agonist monoclonal antibody to death receptor 5 (DR5), which is able to trigger apoptosis in DR5 positive human tumor cells without the aid of crosslinking. It has demonstrated cytotoxicity in vitro and in vivo antitumor efficacy to a wide range of solid tumors in murine xenograft models. Tigatuzumab is a humanized IgG1 monoclonal antibody derived from TRA-8. METHODS: A phase I trial of tigatuzumab in patients with relapsed/refractory carcinomas (n = 16) or lymphoma (n = 1) was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety. Three to six (3-6) patients were enrolled in successive escalating cohorts at doses ranging from 1 to 8 mg/kg weekly. RESULTS: Seventeen (17) patients enrolled, 9 in the 1-, 2-, and 4-mg/kg dose cohorts (3 in each cohort) and 8 in the 8-mg/kg dose cohort. Tigatuzumab was well tolerated with no DLTs observed, and the MTD was not reached. There were no study-drug-related grade 3 or 4, renal, hepatic, or hematologic toxicities. Plasma half-life was 6-10 days, and no anti-tigatuzumab responses were detected. Seven (7) patients had stable disease, with the duration of response ranging from 81 to 798 days. CONCLUSIONS: Tigatuzumab is well tolerated, and the MTD was not reached. The high number of patients with stable disease suggests antitumor activity.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Carcinoma/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/agonistas , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Apoptosis/efectos de los fármacos , Carcinoma/metabolismo , Carcinoma/patología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Linfoma/metabolismo , Linfoma/patología , Masculino , Persona de Mediana EdadRESUMEN
Immunization with plasmid DNA represents an attractive method for increasing cellular immune responses against cancer antigens. The safety and immunologic response of a plasmid encoding the MART-1 melanocyte differentiation antigen was evaluated in 12 patients with resected melanoma at risk for relapse. As a control, patients were also administered a plasmid encoding hepatitis B surface antigen (HBsAg). After establishing immunologic activity of the vaccines in mice, groups of three to six HLA-A2-positive patients were enrolled into one of three cohorts in which they received intramuscular injections of the MART-1 plasmid into the right deltoid and the HBsAg plasmid into the left deltoid at doses of 0.1, 0.3, or 1.0 mg on days 1, 43, 85, and 127. Injections were well tolerated. Toxicity was limited to grade 1 pain and injection site tenderness. Systemic toxicity was not observed. Although baseline MART-1-specific lymphoproliferative and ELISPOT responses were evident, no patient manifested increases after injection of the MART-1 plasmid. Furthermore, changes in MART-1-specific precursors were not evident after immunization as assessed by an in vitro stimulation assay. No patients manifested a lymphoproliferative response to HBsAg antigen, and significant antibody responses to HBsAg were also not observed. Although injections were safe, the authors could not show significant immunologic responses to plasmid encoding MART-1 or HBsAg using the dose, schedule, and route of administration applied. This study underscores species differences in the ability to respond to plasmid immunogens.