RESUMO
Harnessing the patient's own immune system against an established cancer has proven to be a successful strategy. Within the last years, several antibodies blocking critical "checkpoints" that control the activation of T cells, the immune cells able to kill cancer cells, have been approved for the use in patients with different tumours. Unfortunately, these cases remain a minority. Over the last years, radiotherapy has been reported as a means to turn a patient's own tumour into an in situ vaccine and generate anti-tumour T cells in patients who lack sufficient anti-tumour immunity. Indeed, review data show that the strategy of blocking multiple selected immune inhibitory targets in combination with radiotherapy has the potential to unleash powerful anti-tumour responses and improve the outcome of metastatic solid tumours. Here, we review the principal tumours where research in this field has led to new knowledge and where radioimmunotherapy becomes a reality.
Assuntos
Neoplasias/terapia , Radioimunoterapia/métodos , Humanos , Neoplasias/imunologia , Neoplasias/patologia , PrognósticoRESUMO
INTRODUCTION The availability of monoclonal antibodies in Cuba has facilitated development and application of innovative techniques (immunoscintigraphy and radioimmunotherapy) for cancer diagnosis and treatment. Objective Review immunoscintigraphy and radioimmunotherapy techniques and analyze their use in Cuba, based on the published literature. In this context, we describe the experience of Havana's Clinical Research Center with labeled monoclonal antibodies for cancer diagnosis and treatment during the period 1993-2013. EVIDENCE ACQUISITION Basic concepts concerning cancer and monoclonal antibodies were reviewed, as well as relevant international and Cuban data. Forty-nine documents were reviewed, among them 2 textbooks, 34 articles by Cuban authors and 13 by international authors. All works published by the Clinical Research Center from 1993 through 2013 were included. Bibliography was obtained from the library of the Clinical Research Center and Infomed, Cuba's national health telematics network, using the following keywords: monoclonal antibodies, immunoscintigraphy and radioimmunotherapy. RESULTS Labeling the antibodies (ior t3, ior t1, ior cea 1, ior egf/r3, ior c5, h-R3, 14F7 and rituximab) with radioactive isotopes was a basic line of research in Cuba and has fostered their use as diagnostic and therapeutic tools. The studies conducted demonstrated the good sensitivity and diagnostic precision of immunoscintigraphy for detecting various types of tumors (head and neck, ovarian, colon, breast, lymphoma, brain). Obtaining different radioimmune conjugates with radioactive isotopes such as 99mTc and 188Re made it possible to administer radioimmunotherapy to patients with several types of cancer (brain, lymphoma, breast). The objective of 60% of the clinical trials was to determine pharmacokinetics, internal dosimetry and adverse effects of monoclonal antibodies, as well as tumor response; there were few adverse effects, no damage to vital organs, and a positive tumor response in a substantial percentage of patients. CONCLUSIONS Cuba has experience with production and radiolabeling of monoclonal antibodies, which facilitates use of these agents. Studies in Cuba conducted by the Clinical Research Center over the past 20 years have yielded satisfactory results. Evidence obtained suggests promising potential of monoclonal antibodies and nuclear medicine, with immunoscintigraphy and radioimmunotherapy techniques providing alternatives for cancer diagnosis and treatment in Cuba.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias/diagnóstico , Radioimunodetecção/métodos , Radioimunoterapia/métodos , Cuba , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapiaRESUMO
Center for Genetic Engineering and Biotechnology (CIGB)-M3 is a trivalent recombinant single-chain Fv antibody fragment specific for carcinoembryonic antigen (CEA). Preclinical studies with radiolabeled CIGB-M3 have showed that the antibody fragment accumulates in human colon tumor xenografts growing in nude mice. A Phase I clinical trial was carried out to determine safety, biodistribution, and pharmacokinetics of the radiolabeled CIGB-M3 in two groups of patients with CEA+ colorectal cancers. Group I (10 patients) received a single intravenous injection of 0.3 mg of (131)I-CIGB-M3 (16.7-23.3 mCi/mg). Group II (7 patients) received 1 mg (5-7 mCi/mg). No adverse events related to the injected product were recorded, and no immunology response was detected up to 6 months after the injection. Tumors were detected in 15 of the 17 studied cases. The pharmacokinetic profile showed beta half-times of 14.1 and 6.3 hours for Groups I and II, respectively. Seventy-two (72) hours after the administration of the product, 85% of the total injected activity was excreted in urine in the form of free (131)I. The kidneys were identified as the organs that can limit the maximum tolerated dose. The (131)I-CIGB-M3 was safe in patients with colorectal cancer. The biodistribution and pharmacokinetic data suggest that the product can be further tested for molecular radiotherapy of CEA+tumors.
Assuntos
Anticorpos/química , Antígeno Carcinoembrionário/metabolismo , Radioisótopos do Iodo/farmacologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Fragmentos de Imunoglobulinas/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Radioimunoterapia/métodos , Radiometria , Anticorpos de Cadeia Única/química , Fatores de TempoRESUMO
Radioimmunotherapy (RIT) may improve the management of malignant gliomas. A Phase I clinical trial was performed to evaluate, for the first time, the toxicity and clinical effect of an intracavitary administration of a single dose of Nimotuzumab (h-R3) labeled wit (188)Re. Nimotuzumab is a humanized monoclonal antibody directed against epidermal growth factor receptors. Three patients with anaplastic astrocytoma (AA) and 8 with glioblastoma multiforme (GBM) were intended to be treated with 3 mg of mAb labelled with 10 or 15 mCi of (188)Re. In patients treated with 10 mCi (n=6) transitory worsening of pre-existing neurological symptoms were observed. Two patients treated with 15 mCi (n=4) developed early severe neurological symptoms and one also developed late severe toxicity (radionecrosis). In the group treated with 10 mCi, 1 GBM patient died in progression 6 months after the treatment, 2 patients (1 GBM and 1 AA) developed stable disease during 3 months. One GBM patient had partial response for more than 1 year and 2 patients (1 GBM and 1 AA) were asymptomatic and in complete response after 3 years of treatment. Maximal tolerated dose of the radioimmunoconjugate (188)Re-Nimotuzumab was 3 mg of the h-R3 labelled with 10 mCi of (188)Re. The radioimmunoconjugate showed a high retention in the surgical created resection cavity and the brain adjacent tissues with a mean value of 85.5 % of the injected dose one hour post-administration. This radioimmunoconjugate may be relatively safe and a promising therapeutic approach for treating high grade gliomas.
Assuntos
Anticorpos Monoclonais/toxicidade , Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Radioimunoterapia/métodos , Rênio/efeitos adversos , Adulto , Idoso , Anticorpos Monoclonais/farmacocinética , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Radioimunoterapia/efeitos adversos , Radioisótopos/efeitos adversos , Radioisótopos/uso terapêutico , Rênio/uso terapêuticoRESUMO
AIM: To evaluate the biodistribution, internal radiation dosimetry and toxicity of the humanized MAb h-R3 labelled with Tc in humans. METHODS: Twenty-five patients with suspected epithelial-derived tumours were included in this study and divided into two groups: group I consisted of 10 patients who received 3 mg/1110 MBq (3 mg/30 mCi); and group II consisted of 15 patients who received 6 mg/2220 MBq (6 mg/60 mCi). Single photon emission computed tomography (SPECT) and planar images, and multiple blood and urine samples were collected up to 24 h after injection. Haematological parameters and adverse effects were classified according to the WHO criteria. Biodistribution, human anti-mouse antibody (HAMA) response and absorbed doses were estimated and reported. RESULTS: Liver, spleen, kidneys and heart were identified as source organs. Their higher uptakes were 53.3+/-6.4%ID, 2.0+/-1.4%ID, 9.8+/-4.3%ID and 2.8+/-0.9%ID, respectively. The urinary bladder and large intestine also had a significant uptake. The mean urinary excretion was around 22%ID. The liver received the highest absorbed doses followed by the kidneys and the urinary bladder wall. There were no haematological or biochemical abnormalities with clinical significance related to the product. No patient developed HAMA response. Preliminary analysis of clinical results showed a sensitivity of 76.5% and a specificity of 100%. CONCLUSIONS: The results of this study suggest that Tc-h-R3 could be used in patients in a safe and effective way, for the diagnosis of epithelial-derived tumours at the two evaluated dose levels.
Assuntos
Anticorpos Monoclonais/química , Receptores ErbB/química , Neoplasias Epiteliais e Glandulares/terapia , Radioimunodetecção/métodos , Radioimunoterapia/métodos , Tecnécio/farmacologia , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Autoanticorpos/química , Receptores ErbB/imunologia , Feminino , Humanos , Imunoconjugados/química , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Compostos de Organotecnécio , Radiometria , Compostos Radiofarmacêuticos/farmacologia , Sensibilidade e Especificidade , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Contagem Corporal TotalRESUMO
BACKGROUND: Therapies using Y-anti-CD20 or I-anti-CD20 have demonstrated their efficacy in patients with B-cell non-Hodgkin's lymphoma. Re is a radionuclide useful for radioimmunotherapy. AIM: To develop a procedure for efficient labelling of anti-CD20 with Re from lyophilized formulations to achieve high radiochemical yield, high specific activity and preservation of the molecular recognition after a simple kit reconstitution without further purification. METHODS: Re-anti-CD20 was prepared by a direct labelling method using sodium tartrate as a weak competing ligand. Different lyophilized formulations were prepared to optimize tartrate and stannous chloride concentration, pH and reaction time. To evaluate the biological recognition a comparative study of the in-vitro binding of Re-anti-CD20, I-anti-CD20 (positive control) and Re-anti-CEA (negative control) to normal B lymphocytes was performed. Biodistribution studies in normal mice were accomplished to assess the in-vivo Re-anti-CD20 complex stability. RESULTS: Re labelled anti-CD20 was obtained with high radiochemical purities (>97%) and high specific activity (0.5-0.7 GBq . mg) 1-1.5 h after addition of sodium perrhenate solution to a kit containing 4.4 muM anti-CD20, 4 mM anhydrous stannous chloride, and 140 mM dihydrate sodium tartrate at pH 4. The binding of Re-anti-CD20 to cells was in the same range as I-anti-CD20 (>80%) and was significantly different to cell binding of Re-anti-CEA (<10%). No evidence of free Re release was found at 2, 4 and 24 h after Re-anti-CD20 administration in mice. Lyophilized kits showed high stability during the storage at 4 degrees C for 6 months. CONCLUSIONS: Optimal reaction conditions were defined enabling high radiochemical purities of Re-anti-CD20 to be obtained routinely and therefore potentially useful in the treatment of non-Hodgkin's lymphoma.
Assuntos
Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Linfoma não Hodgkin/radioterapia , Radioimunoterapia/métodos , Animais , Antígenos CD20 , Avaliação Pré-Clínica de Medicamentos , Marcação por Isótopo/métodos , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Especificidade de Órgãos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição TecidualRESUMO
188Re is one of the radioisotopes expected to emerge as useful for therapy. Development of new radiopharmaceuticals based on 188Re depends on the radiolabeling methods used, which would give stable complexes having predefined radiochemical properties and in vitro and in vivo stability. This paper has attempted to provide a perspective of 188Re-labeled monoclonal antibodies, their radiolabeling characteristics, methods for quality control of radioimmunoconjugates and in vitro stability for radioimmunotherapy of solid tumors. The direct method of 188Re radiolabeling of antibodies by reductive attachment of 188Re in which free sulfhydryl groups have been generated by reduction of the intramolecular S-S disulfide bonds has been shown to be a promising approach in particular. Moreover, excellent methods have been developed to test the radionuclide, radiochemical purity and stability of 188Re-radioimmunoconjugates using high performance liquid chromatography (HPLC) and paper chromatography.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias/terapia , Radioimunoterapia/métodos , Radioisótopos/uso terapêutico , Rênio/uso terapêutico , Animais , Anticorpos Monoclonais/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Cromatografia em Papel , Estabilidade de Medicamentos , Humanos , Imunoconjugados/isolamento & purificação , Técnicas In Vitro , Camundongos , Controle de Qualidade , Radioimunoterapia/normas , Radioisótopos/isolamento & purificação , Radioisótopos/normas , Rênio/isolamento & purificação , Rênio/normasRESUMO
The increased interest in the availability of radionuclides for therapy has resulted from the recent success and potential importance of radiolabeled antibodies for both diagnosis and therapy. There is a widespread interest in the availability of 188Re for various therapeutic applications, particularly for attachment to tumor-specific monoclonal antibodies for radioimmunotherapy. This review provides a perspective of 188Re-direct labeled MAbs for radioimmunotherapy of solid tumors, normal organ biodistribution, absorbed radiation doses to normal organs and tumors, and the toxicity to bone marrow and normal tissues. Methods for calculation of mean absorbed radiation doses to the whole body, various normal organs, and tumors have been developed using source-organ residence times and the methods developed by the Medical Internal Radiation Dose (MIRD) committee. The toxicity for 188Re-labeled antibodies is predominantly hematopoietic, with platelets and white blood cells being most sensitive to the effects of radiation. Rhenium-188 would be the isotope of choice for radioimmunotherapeutic applications because of cost, availability, and favorable radiation characteristics. Rhenium-188 has a half-life of 16.9 h and maximum beta energy of 2.118 MeV. This isotope is particularly attractive because it can be supplied conveniently from 188W/188Re-radionuclide generator system.
Assuntos
Anticorpos Monoclonais/farmacocinética , Neoplasias/terapia , Radioimunoterapia/métodos , Rênio , Animais , Anticorpos Monoclonais/efeitos adversos , Humanos , Marcação por Isótopo , Radioisótopos , Radiometria , Distribuição TecidualRESUMO
The age of monoclonal antibodies arose with the papers by Köhler and Milstein in 1975. By means of a fusion between a neoplastic cell with one which produced a specific antibody they obtained a hybrid or clonal cell. Five years later, Nadler et al issued the first report of a patient with lymphoma treated with monoclonal antibodies. After the first announcement, diverse research centers have reported the clinical results obtained in various neoplasias treated with radioactive monoclonal antibodies directed against antigens associated with neoplasias, as well as non-specific tumoral antigens, including lymphomas, melanomas and cancers of the colon, ovary and breast.