RESUMEN
Lymphoseek is a receptor-binding radiopharmaceutical specifically designed for sentinel lymph node (SLN) mapping. We conducted a clinical trial which measured the injection site clearance and sentinel lymph node accumulation after a single intradermal injection of Lymphoseek or unfiltered [(99m)Tc]sulfur colloid (TcSC) using a "2-day" protocol for SLN mapping of breast cancer. Eleven patients with breast cancer participated in this study. Five patients received an intradermal administration of 1.0 nmol of (99m)Tc-labeled Lymphoseek; SLN mapping was performed on four subjects within 19 to 27 h. Six subjects received an intradermal administration of TcSC; SLN mapping was performed on five subjects within 18 to 26 h. Lymphoseek exhibited a significantly (P<.001) faster injection site clearance than TcSC. The mean Lymphoseek clearance half-time was 2.18+/-1.09 h compared to 57.4+/-92.8 h for TcSC. The mean sentinel lymph node uptake of Lymphoseek (1.5+/-1.7%) and TcSC (3.5+/-3.1%) was statistically equivalent (P=.213). When an intradermal injection is employed, Lymphoseek demonstrated faster injection site clearance than unfiltered [(99m)Tc]sulfur colloid and persistent SLN accumulation for at least 24 h.
Asunto(s)
Dextranos/farmacocinética , Ganglios Linfáticos/metabolismo , Mananos/farmacocinética , Compuestos de Organotecnecio/farmacocinética , Ácido Pentético/farmacocinética , Radiofármacos/farmacocinética , Azufre Coloidal Tecnecio Tc 99m/farmacocinética , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Dextranos/administración & dosificación , Femenino , Humanos , Inyecciones Intradérmicas , Mananos/administración & dosificación , Persona de Mediana Edad , Compuestos de Organotecnecio/administración & dosificación , Ácido Pentético/administración & dosificación , Radiactividad , Radiofármacos/administración & dosificación , Biopsia del Ganglio Linfático Centinela , Pentetato de Tecnecio Tc 99m/análogos & derivados , Azufre Coloidal Tecnecio Tc 99m/administración & dosificación , Factores de TiempoRESUMEN
Lymphoseek is a molecular imaging agent specifically designed for sentinel lymph node (SLN) mapping. We conducted a Phase I trial which measured the injection site clearance and SLN accumulation after a single intra dermal injection of Lymphoseek or [99mTc]sulfur colloid protocol. Ten patients with breast cancer participated in this study. Five patients received an intradermal administration of 1.0 nmol of 99mTc-labeled Lymphoseek and five patients received an intradermal administration of filtered [99mTc]sulfur colloid (fTcSC). Lymphoseek exhibited a significantly (P<.001) faster injection site clearance than fTcSC. The mean Lymphoseek clearance half-time was 2.61+/-0.72 h compared to 24.1+/-17.7 h for fTcSC. The mean SLN uptake of Lymphoseek (1.1+/-.5%) and fTcSC (2.5+/-4.9%) was statistically equivalent (P=.28). When an intra dermal injection was employed, Lymphoseek demonstrated faster injection site clearance than fTcSC.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/metabolismo , Dextranos/farmacocinética , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/metabolismo , Mananos/farmacocinética , Compuestos de Organotecnecio/farmacocinética , Ácido Pentético/farmacocinética , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Dextranos/administración & dosificación , Femenino , Humanos , Inyecciones Intradérmicas , Ganglios Linfáticos/patología , Metástasis Linfática , Mananos/administración & dosificación , Tasa de Depuración Metabólica , Persona de Mediana Edad , Compuestos de Organotecnecio/administración & dosificación , Ácido Pentético/administración & dosificación , Cintigrafía , Radiofármacos/administración & dosificación , Radiofármacos/farmacocinética , Biopsia del Ganglio Linfático Centinela/métodos , Pentetato de Tecnecio Tc 99m/análogos & derivados , Distribución TisularRESUMEN
BACKGROUND: Lymphoseek is a molecular imaging agent specifically designed for sentinel lymph node mapping. We conducted a phase I clinical trial in which Lymphoseek was compared with filtered [(99m)Tc]sulfur colloid (fTcSC) for melanoma sentinel lymph node detection. METHODS: Twenty-four patients (33-81 years) with melanoma participated in this study. Four groups of six patients received an intradermal administration (.5 mCi) of 1.0, 5.0, or 10.0 nmol of (99m)Tc-labeled Lymphoseek or filtered [(99m)Tc]sulfur colloid. The injection site clearance was monitored by nuclear imaging for 3 hours. Lymph nodes obtained by gamma-guided biopsy (4.0-8.7 hours after injection) were assayed for radioactivity. Clinical chemistry values were monitored (before injection, before surgery, and 4 and 24 hours), and whole-body scans were acquired at 1 and 12 hours after injection. RESULTS: Lymphoseek exhibited a significantly (P < .001) faster injection site clearance at all dose levels. The mean Lymphoseek clearance half-time was 2.17 +/- .96 hours (n = 18) compared with 14.7 +/- 6.3 hours for fTcSC (n = 6). The mean sentinel lymph node uptakes of Lymphoseek (.73% +/- .94%) and fTcSC (.85% +/- 1.19%) were statistically equivalent (P = .68). Lymphoseek exhibited a lower mean number of sentinel lymph nodes per basin (1.6) than fTcSC (1.9). No adverse events were observed, nor were any clinically significant alterations in laboratory parameters. Radiation absorbed doses were lower than filtered [(99m)Tc]sulfur colloid. CONCLUSIONS: The molecular imaging agent Lymphoseek demonstrated faster injection site clearance and equivalent primary sentinel node uptake when compared with filtered [(99m)Tc]sulfur colloid.
Asunto(s)
Ganglios Linfáticos/diagnóstico por imagen , Melanoma/diagnóstico por imagen , Radiofármacos , Biopsia del Ganglio Linfático Centinela/métodos , Neoplasias Cutáneas/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Cintigrafía , Neoplasias Cutáneas/patología , Pentetato de Tecnecio Tc 99m/análogos & derivados , Azufre Coloidal Tecnecio Tc 99mRESUMEN
PURPOSE: The purpose of this research was to determine the toxicity and immunological activity of large multivalent immunogen (LMI), a preparation of tumor cell membranes affixed to amorphous silica microbeads, in patients with melanoma. EXPERIMENTAL DESIGN: Nineteen patients with metastatic (stage IV) melanoma were entered into the study, of whom 15 received the full 3 months of treatment with LMI. LMI was administered without adjuvant, one-half intradermally (i.d.) and the other half s.c. Because we expected little toxicity, we first treated 2 patients at each dose level, 10-, 30-, or 100-million tumor cell equivalents on weeks 0, 4, and 8, and subsequently randomized the remaining 13 patients to receive treatment with one of those dosage schedules, for a total of 19 patients. Two patients who were registered were found to be ineligible because of brain metastases, and 2 others did not complete the course of treatment for reasons other than toxicity. Thus, 15 patients were fully evaluable. Patients with evidence of a clinical response (at least stable disease at the 12-week checkpoint) had the option of continuing treatment at 4-week intervals. Frequencies of cytolytic T cell precursors against HLA-A2 matched melanoma cells, and delayed-type hypersensitivity to a melanoma cell membrane preparation from a component melanoma cell line were performed to measure immunological efficacy, and serum chemistries and complete blood counts were performed every 2 weeks throughout the study to measure possible toxicity. Computed tomography scans were performed pretreatment and at week 12 to measure possible beneficial effects on known lesions. RESULTS: Eight of the 15 evaluable patients had an increase in cytolytic T-cell precursors during the course of therapy, usually by day 42. No patient had demonstrable delayed-type hypersensitivity to a melanoma membrane preparation before or after treatment. No toxicity of any kind was observed. A degree of clinical effectiveness of LMI was suggested by the elicitation of stable disease in 5 patients at 12 weeks. One patient had >50% regression of a lung nodule but progression of disease to the brain, whereas a second patient had a bona fide partial remission of a 3-cm diameter solitary lung nodule. CONCLUSIONS: LMI was nontoxic, improved immunological reactivity to melanoma cells, and showed evidence of clinical effectiveness (shrinkage of tumor) in 1 patient. Additional studies with LMI with added adjuvant materials, in melanoma and other cancers, appear warranted.
Asunto(s)
Antígenos de Neoplasias/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Membrana Celular/inmunología , Melanoma/terapia , Linfocitos T Citotóxicos/inmunología , Adyuvantes Inmunológicos , Adulto , Anciano , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Citotoxicidad Inmunológica , Femenino , Antígeno HLA-A2/metabolismo , Humanos , Hipersensibilidad Tardía , Masculino , Melanoma/inmunología , Melanoma/secundario , Persona de Mediana Edad , Inducción de Remisión , Dióxido de Silicio/químicaRESUMEN
[(99m)Tc]DTPA-mannosyl-dextran is a receptor-binding radiopharmaceutical specifically designed for sentinel lymph node mapping. The purpose of this study was to test the biodistribution and safety of [(99m)Tc]DTPA-mannosyl-Dextran at different molar doses. Twenty-four female breast cancer patients participated in this study. Four groups of 6 patients received an injection of 0.2, 1.0, or 5.0 nmol of [(99m)Tc]DTPA-mannosyl-Dextran or filtered [(99m)Tc]sulfur colloid. The injection site clearance was monitored by dynamic imaging for three hours. Whole body scans were acquired at 2.5 and 12, and lymph nodes were assayed for radioactivity after gamma-guided sentinel lymph node biopsy. Injection site clearance of [(99m)Tc]DTPA-mannosyl-Dextran was not statistically different in a dose-dependent manner. Dose-dependent sentinel node uptake was observed (p = 0.03). There were no clinically significant alterations in laboratory parameters among all dose levels at 4 h or 24 h post injection compared to preoperative levels. Radiation absorbed doses did not differ among the three dose levels, but were lower than filtered [(99m)Tc]sulfur colloid.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/metabolismo , Dextranos/farmacocinética , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/metabolismo , Mananos/farmacocinética , Compuestos de Organotecnecio/farmacocinética , Ácido Pentético/farmacocinética , Biopsia del Ganglio Linfático Centinela/métodos , Adulto , Anciano , Dextranos/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inyecciones Intralesiones , Metástasis Linfática , Mananos/administración & dosificación , Tasa de Depuración Metabólica , Persona de Mediana Edad , Especificidad de Órganos , Compuestos de Organotecnecio/administración & dosificación , Ácido Pentético/administración & dosificación , Cintigrafía , Radiofármacos/administración & dosificación , Radiofármacos/farmacocinética , Pentetato de Tecnecio Tc 99m/análogos & derivados , Distribución TisularRESUMEN
BACKGROUND: Lymphoseek is a new radiopharmaceutical that accumulates in lymphatic tissue by binding to a receptor that resides on the surface of macrophage cells. We conducted a phase I clinical trial in which Lymphoseek was compared with filtered [(99m)Tc]sulfur colloid (fTcSC) for sentinel node detection in patients with breast cancer. METHODS: Twelve women (42-71 years) with breast cancer were randomly assigned to a 3-hour imaging protocol with peritumoral/subdermal injections (.5 mCi) of either Lymphoseek (1 nmol; molecular weight, 28 kDa; diameter,.007 micro m) or.2 micro m of fTcSC. Serial images were acquired for 180 minutes. Sentinel nodes, excised within 4.2 to 7.3 hours of administration, were assayed in a dose calibrator. RESULTS: The receptor-binding agent, Lymphoseek, exhibited a significantly (P =.0025) faster injection site clearance (rate,.255 +/-.147/hour; fTcSC rate,.014 +/-.018/hour); the mean Lymphoseek clearance half-time was 2.72 +/- 1.57 hours compared with 49.5 +/- 38.5 hours for fTcSC. The primary sentinel node uptake of Lymphoseek (range,.02%-1.12%; mean,.55% +/-.43%) and fTcSC (range,.00%-1.93%; mean,.65% +/-.63%) did not differ (P =.75). Lymphoseek exhibited a lower mean number of sentinel nodes per study (n = 1.3) than fTcSC (n = 1.7) and a higher concordance with Lymphazurin. CONCLUSIONS: The molecular receptor-binding agent Lymphoseek demonstrated faster injection site clearance and equivalent primary sentinel node uptake when compared with fTcSC.
Asunto(s)
Neoplasias de la Mama/patología , Dextranos , Metástasis Linfática/diagnóstico , Mananos , Compuestos de Organotecnecio , Ácido Pentético , Radiofármacos , Biopsia del Ganglio Linfático Centinela/métodos , Azufre Coloidal Tecnecio Tc 99m , Adulto , Anciano , Femenino , Humanos , Inyecciones Subcutáneas , Macrófagos , Persona de Mediana Edad , Pentetato de Tecnecio Tc 99m/análogos & derivadosRESUMEN
PURPOSE: A therapeutic lyophilized melanoma vaccine consisting of two mechanically disrupted allogeneic melanoma cell lines and the immunological adjuvant Detox-PC (Melacine) has demonstrated encouraging activity in metastatic malignant melanoma, often in regimens containing pretreatment with low-dose cyclophosphamide. In addition, IFN-alpha2b (INTRON A; Schering-Plough Corporation, Kenilworth, NJ) has shown efficacy in melanoma refractory to Melacine. In this Phase II trial, the combination of cyclophosphamide, Melacine, and IFNalpha was tested in metastatic malignant melanoma. EXPERIMENTAL DESIGN: Eligibility criteria included measurable disease, no prior systemic therapy for a minimum of 4 weeks, and adequate marrow, renal, and hepatic function. Cyclophosphamide was administered once at a dose of 300 mg/m(2) i.v. on day -3 before the first dose of Melacine. Melacine was administered at a dose of 2 x 10(7) tumor cell equivalents per dose admixed with 0.25 ml of Detox-PC s.c. once a week on weeks 1-4 and week 6. Melacine maintenance was then given monthly from the 8th week, until progression or intolerable toxicity. IFN was started in the evening after the fourth dose of Melacine at a dose of 5,000,000 units/m(2) 3 times a week, and continued until progression. RESULTS: Forty-seven patients were enrolled, of whom 39 completed the full course and were considered evaluable. The toxicity of the regimen was minimal and consisted mainly of pain at injection sites and granulomas caused by Detox-PC, and constitutional symptoms attributable to IFN. In 39 evaluable patients, the overall objective response rate was 10.2%, but 64% of patients had stabilization of their disease for at least 16 weeks. The median time to disease progression in evaluable patients was 8 months [95% confidence interval (CI), 6-13 months]. Median survival time for all of the 47 patients enrolled was 12.5 months (95% CI, 8-15 months) with a median time to disease progression of 4 months (95% CI, 3-7 months). CONCLUSION: Despite a low objective response rate, this combination holds great promise because of its tolerability and the high proportion of prolonged durations of remission or disease stabilization that it elicited.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoterapia Activa , Neoplasias Pulmonares/terapia , Melanoma/terapia , Neoplasias Cutáneas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Vacunas contra el Cáncer/administración & dosificación , Ciclofosfamida/administración & dosificación , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Metástasis Linfática , Linfocinas , Masculino , Melanoma/inmunología , Melanoma/secundario , Persona de Mediana Edad , Proteínas Recombinantes , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/secundario , Tasa de Supervivencia , Resultado del TratamientoAsunto(s)
Antineoplásicos/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Interferón-alfa/uso terapéutico , Lípido A/análogos & derivados , Melanoma/terapia , Neoplasias Cutáneas/terapia , Células Tumorales Cultivadas , Antineoplásicos/farmacología , Ensayos Clínicos como Asunto , Proteínas del Citoesqueleto/administración & dosificación , Combinación de Medicamentos , Humanos , Interferón-alfa/farmacología , Lípido A/administración & dosificación , Melanoma/patología , Estudios Multicéntricos como Asunto , Metástasis de la Neoplasia , Neoplasias Cutáneas/patología , Análisis de SupervivenciaRESUMEN
PURPOSE: To study distribution and toxicity of cytolytic T lymphocytes (CTLs) against a single melanoma epitope. PATIENTS AND METHODS: CD8(+) T cells obtained by leukapheresis from 10 patients with disseminated HLA-A2.1(+), tyrosinase-positive melanomas were immunized in vitro against tyrosinase(369-377) (YMNGTMSQV). Drosophila cells transduced with HLA-A2.1, CD80, and CD54 (intracellular adhesion molecule-1) were used for priming, followed by two rounds of immunization with mononuclear cells as antigen-presenting cells. 1 x 10(8) CTL were infused intravenously (IV) on day 1. CTL frequency was measured by limiting dilutions in five patients. (111)In labeling and scintigraphy measured distribution of CTL in next five. Five days later, 1 x 10(8) CTLs were infused on 4 successive days to both groups. Immunohistology of response was judged by biopsies. RESULTS: Infusions were nontoxic. CTLs were undetectable in the blood, going to lungs within 5 minutes. At 4, 24, and 72 hours, they were found in liver and spleen. Lesions were visualized by scintiscans in one responding patient where two subcutaneous nodules were noted at 4 and 24 hours. A second patient had a partial response and remains alive with disease 2 years later. CD8(+) T cells were found in lesions of responders, associated with the presence of HLA-A2 molecules and tyrosinase. Two nonresponders without tyrosinase and HLA-A2 molecules had a paucity of CD8(+) T cells in their lesions. Whether the CD8(+) T cells in lesions of responders were those we had reinfused is uncertain. CONCLUSION: CTLs immunized against a single melanoma epitope were nontoxic but did not specifically localize to tumor sites. Nevertheless, two patients had disease regression. Additional therapeutic studies with specifically immunized CTL seem justified.