RESUMO
An antimouse immune response is invariable following administration of murine monoclonal antibody (mAb), precluding effective multidose therapy. In advanced colorectal cancer patients, we carried out a pilot study with multiple doses of 131I-labeled CC49 administered with deoxyspergualin (DSG), an immunomodulator, to determine its effect on immune response. Cumulative toxicity and efficacy were also evaluated. Six patients with tumor-associated glycoprotein 72-expressing colorectal cancer were treated i.v. with 15 mCi/m2 131I-labeled to 20 mg mAb CC49 biweekly, along with concurrent DSG 200 mg/m2 daily for 5 days, for a maximum of four courses. None had received prior murine mAbs. All patients had targeting of radioactivity to known tumor sites following initial infusion. Four of six patients received all four courses of therapy, three without any acute side effects. In these patients, there was no change in serum clearance with variable tumor targeting following repeat infusions. Two patients had = grade II anaphylactoid reactions, which were treated without sequelae. One of these had faster serum clearance of radioactivity following repeat infusions of 131I-labeled CC49. Human antimouse antibody titers in all patients were significantly less compared to concurrent times in patients receiving CC49 without DSG (P < 0.05). There was no correlation between the human antimouse antibody titer and serum clearance or tumor targeting of 131I-labeled CC49. There were no clinical responses. We concluded that multiple doses of murine antibody 131I-labeled CC49 can be safely administered with no change in serum or whole-body kinetics in 50% of patients treated biweekly. DSG may reduce the human immune response to the murine mAb.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/radioterapia , Neoplasias Hepáticas/radioterapia , Radioimunoterapia/métodos , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Antineoplásicos/administração & dosagem , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Feminino , Guanidinas/administração & dosagem , Humanos , Imunossupressores/administração & dosagem , Radioisótopos do Iodo/administração & dosagem , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Projetos Piloto , CintilografiaRESUMO
This Phase I/II radioimmunotherapy study was carried out to determine the maximum tolerated dose (MTD) and therapeutic potential of 131I-G250. Thirty-three patients with measurable metastatic renal cell carcinoma were treated. Groups of at least three patients received escalating amounts of 1311I (30, 45, 60, 75, and 90 mCi/m2) labeled to 10 mg of mouse monoclonal antibody G250, administered as a single i.v. infusion. Fifteen patients were studied at the MTD of activity. No patient had received prior significant radiotherapy; one had received prior G250. Whole-body scintigrams and single-photon emission computed tomography images were obtained in all patients. There was targeting of radioactivity to all known tumor sites that were > or =2 cm. Reversible liver function test abnormalities were observed in the majority of patients (27 of 33 patients). There was no correlation between the amount of 131I administered or hepatic absorbed radiation dose (median, 0.073 Gy/mCi) and the extent or nature of hepatic toxicity. Two of the first six patients at 90 mCi/m2 had grade > or =3 thrombocytopenia; the MTD was determined to be 90 mCi/m2 131I. Hematological toxicity was correlated with whole-body absorbed radiation dose. All patients developed human antimouse antibodies within 4 weeks posttherapy; retreatment was, therefore, not possible. Seventeen of 33 evaluable patients had stable disease. There were no major responses. On the basis of external imaging, 131I-labeled mouse monoclonal antibody G250 showed excellent localization to all tumors that were > or =2 cm. Seventeen of 33 patients had stable disease, with tumor shrinkage observed in two patients. Antibody immunogenicity restricted therapy to a single infusion. Studies with a nonimmunogenic G250 antibody are warranted.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células Renais/radioterapia , Imunoconjugados/uso terapêutico , Radioisótopos do Iodo/uso terapêutico , Neoplasias Renais/radioterapia , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Contagem de Células Sanguíneas/efeitos da radiação , Carcinoma de Células Renais/diagnóstico por imagem , Feminino , Humanos , Imunoconjugados/efeitos adversos , Radioisótopos do Iodo/efeitos adversos , Radioisótopos do Iodo/farmacocinética , Neoplasias Renais/diagnóstico por imagem , Fígado/efeitos dos fármacos , Fígado/efeitos da radiação , Masculino , Pessoa de Meia-Idade , Radioimunoterapia , Radiometria , Cintilografia , Irradiação Corporal TotalRESUMO
UNLABELLED: CC49 is a murine monoclonal antibody (MAb) that reacts against the TAG-72 antigen. We carried out a Phase I study with escalating doses of 131I-CC49 in patients with advanced colorectal cancer expressing the TAG-72 antigen to determine the dose-limiting toxicity and therapeutic efficacy, if any, of the radioimmunoconjugate. METHODS: Twenty-four patients with TAG-72- expressing colorectal cancer were treated with escalating doses of 131I-CC49 starting at 15 mCi/m2 and going up to 90 mCi/m2 of 131I labeled to 20 mg MAb CC49. Patients were selected if TAG-72 was expressed in > or = 50% of cells in previously resected tumor and at least one metastasis was demonstratable on standard imaging such as CT. All patients had failed conventional chemotherapy and had not received prior radiotherapy or murine MAb. Patients were under radiation isolation precautions until whole-body radioactivity decreased to < or = 5 mR/hr at 1 m. Whole-body scintigrams were obtained prior to discharge and 1 and 2 wk after infusion in all patients. SPECT imaging was carried out at least once in all patients. RESULTS: All patients had excellent targeting of radioactivity to known tumor sites. There was no nonhematologic toxicity. Hematologic toxicity was more pronounced in those patients who had received extensive prior chemotherapy. There were no major responses. All patients developed an immune response (HAMA) within 4 wk of therapy. CONCLUSION: Radioimmunotherapy with 131I-CC49 is safe and there is significant therapeutic efficacy in this Phase I trial at the doses studied. There is excellent targeting of radioactivity to antigen-positive tumors. Dose-limiting toxicity is hematopoietic, with the maximum tolerated dose in this group of heavily pretreated patients being 75 mCi/m2.
Assuntos
Adenocarcinoma/radioterapia , Neoplasias Colorretais/radioterapia , Radioisótopos do Iodo/uso terapêutico , Radioimunoterapia , Neoplasias Abdominais/radioterapia , Neoplasias Abdominais/secundário , Adenocarcinoma/imunologia , Adenocarcinoma/secundário , Adulto , Idoso , Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Relação Dose-Resposta à Radiação , Feminino , Glicoproteínas/análise , Humanos , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-IdadeRESUMO
UNLABELLED: A model that describes the pharmacokinetic distribution of 131I-labeled G250 antibody is developed. METHODS: Previously collected pharmacokinetic data from a Phase I-II study of 131I-G250 murine antibody against renal cell carcinoma were used to develop a mathematical model describing antibody clearance from serum and the whole body. Survey meter measurements, obtained while the patient was under radiation precautions, and imaging data, obtained at later times, were combined to evaluate whole-body clearance kinetics over an extended period. RESULTS: A linear two-compartment model was found to provide good fits to the data. The antibody was injected into Compartment 1, the initial distribution volume (Vd) of the antibody, which included serum. The antibody exchanged with the rest of the body, Compartment 2, and was eventually excreted. Data from 13 of the 16 patients fit the model with unique parameters; the maximum, median and minimum values for model-derived Vd were 6.3, 3.7 and 2.11, respectively. The maximum, median and minimum values for the excretion rate were 8 x 10(-2), 2.4 x 10(-2) and 1.3 x 10(-2) hr(-1), respectively. Parameter sensitivity analysis showed that a change in the transfer rate constant from serum to the rest of the body had the greatest effect on serum cumulative activity and that the rate constant for excretion had the greatest effect on whole-body cumulative activity. CONCLUSION: A linear two-compartment model was adequate in describing the serum and whole-body kinetics of G250 antibody distribution. The median initial distribution volume predicted by the model was consistent with the nominal value of 3.81. A wide variability in fitted parameters was observed among patients, reflecting the differences in individual patient clearance and exchange kinetics of G250 antibody. By selecting median parameter values, such a model may be used to evaluate and design prolonged multiple administration radioimmunotherapy protocols.