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1.
Cancer Biother Radiopharm ; 33(7): 274-281, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29989440

RESUMO

BACKGROUND: Prostate-specific membrane antigen (PSMA)-based radiopeptide/radioligand therapy represents a rapidly expanding field in the management of metastatic castrate-resistant prostate cancer (mCRPC). However, there remains concern for the development of significant toxicities in heavily pretreated patients. In this study, the authors present their local experience, with respect to efficacy and toxicity, of 22 consecutive patients treated with lutetium-177-DOTAGA-(I-y)fk(Sub-KuE) or 177Lu-PSMA I&T radioimmunotherapy for progressive mCRPC, followed up over 1 year. MATERIALS AND METHODS: All patients had progressive mCRPC, an European Cooperative Oncology Group (ECOG) ≤2 with adequate bone marrow and liver function. 177Lu-PSMA I&T therapy was administered at 8-week intervals with a mean prescribed activity of 5.5 GBq (gigabecquerel) per patient. RESULTS: Twenty patients had evaluable results, median age of 71 years, and median duration of follow-up of 17 months. Three patients (15%) experienced a G1/2 myelotoxicity and four (20%) G3/4. No incidences of myelodysplasia/acute leukemia have been identified. All toxicities were self-limiting. Baseline cytopenia was predictive of the development of subsequent G3/4 myelotoxicity (p = 0.0035). Eight patients (40%) experienced an objective PSA response, with a median time to response of 15 weeks. The median time to PSA progression was not reached. Patients receiving three cycles of therapy were statistically more likely to experience a disease response when compared to those treated with one, two, or four cycles (p < 0.0001). CONCLUSIONS: 177Lu-PSMA I&T radioimmunotherapy of progressive mCRPC is safe and effective with three cycles being the potential optimal number for determining long-term disease response.


Assuntos
Antígenos de Superfície/uso terapêutico , Glutamato Carboxipeptidase II/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Radioimunoterapia/métodos , Compostos Radiofarmacêuticos/uso terapêutico , Terapia de Salvação/métodos , Idoso , Idoso de 80 Anos ou mais , Antígenos de Superfície/química , Antígenos de Superfície/imunologia , Glutamato Carboxipeptidase II/química , Glutamato Carboxipeptidase II/imunologia , Humanos , Calicreínas/sangue , Lutécio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Próstata , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Radioimunoterapia/efeitos adversos , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/química , Estudos Retrospectivos , Terapia de Salvação/efeitos adversos , Resultado do Tratamento
2.
Mol Pharm ; 15(6): 2165-2173, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29733658

RESUMO

The overexpression of vascular endothelial growth factor (VEGF) in varying types of solid tumor renders radioimmunotherapy (RIT) with the anti-VEGF antibody bevacizumab (BV) a promising treatment. However, the slow blood clearance of BV, which may increase the occurrence risk of hematotoxicity, hinders the application of BV-RIT. Using the avidin chase is a long-known blood clearance enhancement strategy for biotinylated-mAb. To enhance RIT efficacy by increasing the radioactivity dose, we evaluated the ability of avidin to accelerate the blood clearance of yttrium-90 (90Y)-labeled biotinylated BV (90Y-Bt-BV) in a xenograft mouse model of triple-negative breast cancer (TNBC). The biodistribution study in the TNBC xenograft mice confirmed the high and specific tumor accumulation of the indium-111 (111In)-BV. The blood clearance enhancement effect of the avidin chase was demonstrated in the normal mouse studies with 111In-Bt-BV. In the subsequent biodistribution studies with the tumor-bearing mice, an optimized dose of avidin injection subsequent to 111In-Bt-BV with an appropriate biotin valency successfully accelerated the blood clearance of 111In-Bt-BV without impairing its tumor accumulation level. The avidin chase enabled an increase in the maximum tolerated dose of 90Y-Bt-BV to twice as much as that of 90Y-BV in tumor-bearing mice and thereby significantly improved the therapeutic effect of 90Y-Bt-BV compared to 90Y-BV ( p < 0.05). These results underscored the potential usefulness of 90Y-bevacizumab-RIT with the avidin chase for the treatment of VEGF-positive tumors.


Assuntos
Avidina/administração & dosagem , Bevacizumab/farmacologia , Imunoconjugados/farmacologia , Radioimunoterapia/efeitos adversos , Neoplasias de Mama Triplo Negativas/sangue , Radioisótopos de Ítrio/farmacologia , Animais , Bevacizumab/química , Biotina/química , Linhagem Celular Tumoral , Feminino , Humanos , Imunoconjugados/química , Taxa de Depuração Metabólica/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Radioimunoterapia/métodos , Distribuição Tecidual , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/radioterapia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Radioisótopos de Ítrio/química
3.
Immunotherapy ; 10(8): 699-711, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29569511

RESUMO

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy. The estimated deaths and new cases of NHL in the USA in 2018 have reached 19,910 and 74,680, respectively, with 5-year survival rate of 71%. Therapeutic interventions for NHL consist of chemotherapy, radiation therapy and immunotherapy. Radioimmunotherapy (RIT) is a potential alternative treatment for NHL that is currently used in different lines of treatment. Studies show that nuclear medicine physicians and radiation oncologists are not yet certain about the proper line for administration of RIT. Herein, we have reviewed the efficiency and toxicity of RIT as the first line of treatment, and discussed potential novel indications, and strategies such as modifying induction therapy and using rituximab maintenance to optimize the efficiency of RIT as the first line of treatment. Our review indicates that it is more logical to postpone conventional therapies to the second or third lines of treatment instead of RIT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia de Consolidação , Linfoma não Hodgkin/radioterapia , Radioimunoterapia , Anticorpos Monoclonais/uso terapêutico , Humanos , Quimioterapia de Indução , Quimioterapia de Manutenção , Radioimunoterapia/efeitos adversos , Rituximab/uso terapêutico , Resultado do Tratamento
4.
J Pediatr Hematol Oncol ; 40(6): e394-e396, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28816801

RESUMO

The antivascular endothelial growth factor antibody, bevacizumab, is effective against several malignancies in adults but unproven in pediatric oncology. In early phase pediatric studies toxicities were similar to those in adults. Bowel perforation in adults is a rare but serious toxicity, but has not been hitherto reported in children. A 5-year-old boy with chemoresistant neuroblastoma treated with bevacizumab plus radioimmunotherapy developed acute abdominal pain. Computed tomography scan showed free abdominal air and pneumatosis coli. Emergency laparotomy and bowel diversion were performed leading to complete recovery and timely continuation of antineuroblastoma therapy. Early recognition and rapid intervention can prevent a catastrophic outcome in bevacizumab-related bowel perforation.


Assuntos
Bevacizumab/efeitos adversos , Perfuração Intestinal , Neuroblastoma , Radioimunoterapia/efeitos adversos , Tomografia Computadorizada por Raios X , Bevacizumab/administração & dosagem , Pré-Escolar , Humanos , Perfuração Intestinal/induzido quimicamente , Perfuração Intestinal/diagnóstico por imagem , Masculino , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/terapia
5.
J Nucl Med ; 58(11): 1735-1742, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28705917

RESUMO

Radioimmunotherapy of solid tumors using antibody-targeted radionuclides has been limited by low therapeutic indices (TIs). We recently reported a novel 3-step pretargeted radioimmunotherapy (PRIT) strategy based on a glycoprotein A33 (GPA33)-targeting bispecific antibody and a small-molecule radioactive hapten, a complex of 177Lu and S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (177Lu-DOTA-Bn), that leads to high TIs for radiosensitive tissues such as blood (TI = 73) and kidney (TI = 12). We tested our hypothesis that a fractionated anti-GPA33 DOTA-PRIT regimen calibrated to deliver a radiation absorbed dose to tumor of more than 100 Gy would lead to a high probability of tumor cure while being well tolerated by nude mice bearing subcutaneous GPA33-positive SW1222 xenografts. Methods: We treated groups of nude mice bearing 7-d-old SW1222 xenografts with a fractionated 3-cycle anti-GPA33 DOTA-PRIT regimen (total administered 177Lu-DOTA-Bn activity, 167 MBq/mouse; estimated radiation absorbed dose to tumor, 110 Gy). In randomly selected mice undergoing treatment, serial SPECT/CT imaging was used to monitor treatment response and calculate radiation absorbed doses to tumor. Necropsy was done on surviving animals 100-200 d after treatment to determine frequency of cure and assess select normal tissues for treatment-related histopathologies. Results: Rapid exponential tumor progression was observed in control treatment groups (i.e., no treatment or 177Lu-DOTA-Bn only), leading to euthanasia due to excessive tumor burden, whereas 10 of 10 complete responses were observed for the DOTA-PRIT-treated animals within 30 d. Treatment was well tolerated, and 100% histologic cure was achieved in 9 of 9 assessable animals without detectable radiation damage to critical organs, including bone marrow and kidney. Radiation absorbed doses to tumor derived from SPECT/CT (102 Gy) and from biodistribution (110 Gy) agreed to within 6.9%. Of the total dose of approximately 100 Gy, the first dose contributes 30%, the second dose 60%, and the third dose 10%. Conclusion: In a GPA33-positive human colorectal cancer xenograft mouse model, we validated a SPECT/CT-based theranostic PRIT regimen that led to 100% complete responses and 100% cures without any treatment-related toxicities, based on high TIs for radiosensitive tissues. These studies support the view that anti-GPA33 DOTA-PRIT will be a potent radioimmunotherapy regimen for GPA33-positive colorectal cancer tumors in humans.


Assuntos
Anticorpos Biespecíficos , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/terapia , Radioimunoterapia/métodos , Nanomedicina Teranóstica/métodos , Animais , Relação Dose-Resposta à Radiação , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos Nus , Octreotida/efeitos adversos , Octreotida/análogos & derivados , Octreotida/uso terapêutico , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/uso terapêutico , Radioimunoterapia/efeitos adversos , Radiometria , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/uso terapêutico , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Br J Haematol ; 178(3): 427-433, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28466487

RESUMO

Histological transformation (HT) of follicular lymphoma (FL) to an aggressive lymphoma after chemotherapy remains a key issue. The incidence of HT after radioimmunotherapy (RIT) is unknown. This single institution study analysed the risk of HT in FL after treatment with yttrium-90 ibritumomab tiuxetan in 115 consecutive patients treated during 1987-2012. RIT was administered for progressive FL in 111 (97%) patients and as first-line therapy in the remaining 4. 28% (n = 32) had HT, occurring at a median of 60 months from diagnosis and 20 months after RIT. 48% (12/25) of patients who received fludarabine developed HT. The estimated 10-year risk of HT in the fludarabine and non-fludarabine groups was 67% and 26% respectively (P = 0·015). Only prior fludarabine was significantly associated with predicting the risk of HT after RIT. 8% (9/115) of patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (tMDS/AML) at a median of 41·4 months (range, 5-89). The estimated 10-year risk of tMDS/AML in non-fludarabine treated patients (n = 90) versus fludarabine treated (n = 25) was 13% and 29%, respectively. The estimated overall risk of FL undergoing HT at 10 years without fludarabine exposure appears similar to patients reported in the literature that have not received RIT. Patients with prior purine-analogue therapy are at significantly higher risk of HT.


Assuntos
Leucemia Mieloide Aguda/etiologia , Linfoma Folicular/terapia , Síndromes Mielodisplásicas/etiologia , Segunda Neoplasia Primária/etiologia , Radioimunoterapia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Quimioterapia Adjuvante/efeitos adversos , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/etiologia , Radioimunoterapia/métodos , Fatores de Risco , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto Jovem , Radioisótopos de Ítrio/efeitos adversos , Radioisótopos de Ítrio/uso terapêutico
7.
Adv Exp Med Biol ; 995: 53-71, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28321812

RESUMO

Several factors must be considered to successfully integrate immunotherapy with radiation into clinical practice. One such factor is that concepts arising from preclinical work must be tested in combination with radiation in preclinical models to better understand how combination therapy will work in patients; examples include checkpoint inhibitors, tumor growth factor-beta (TGF-ß) inhibitors, and natural killer (NK) cell therapy. Also, many radiation fields and fractionation schedules typically used in radiation therapy had been standardized before the introduction of advanced techniques for radiation planning and delivery that account for changes in tumor size, location, and motion during treatment, as well as uncertainties introduced by variations in patient setup between treatment fractions. As a result, radiation therapy may involve the use of large treatment volumes, often encompassing nodal regions that may not be irradiated with more conformal techniques. Traditional forms of radiation in particular pose challenges for combination trials with immunotherapy. This chapter explores these issues in more detail and provides insights as to how radiation therapy can be optimized to combine with immunotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Neoplasias/terapia , Doses de Radiação , Radioimunoterapia/métodos , Animais , Antineoplásicos/efeitos adversos , Humanos , Fatores Imunológicos/efeitos adversos , Terapia de Alvo Molecular , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Radioimunoterapia/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Microambiente Tumoral
8.
J Immunother ; 40(2): 71-76, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28125513

RESUMO

Dendritic cells (DC) are highly efficient antigen-presenting cells. DC may be used to create DC vaccines against cancer, but the optimal strategies remain to be elucidated. This study aimed to examine the benefits and adverse effects of using esophageal cancer cell antigens to stimulate DC to trigger the specific immune response in patients with esophageal cancer undergoing radiotherapy. This was an observational cohort study performed at Lianshui County People's Hospital between September 2010 and June 2012. Forty patients with esophageal cancer planned to receive radiotherapy were selected, and 28 received the DC vaccine. DC were isolated, loaded with antigens, and intradermally injected after being cultured for 1 week. One week after injection, the patients underwent a delayed-type hypersensitivity test. Serum Th1 cytokines [interleukin (IL)-2, IL-12, and interferon (IFN)-γ] and antigen-specific IFN-γCD8 T cells were tested before and after vaccination. Patients were followed up for 2 years. Adverse events were monitored. Patients in the vaccine group tolerated the DC vaccine. Levels of serum IL-2 (+92.4%), IL-12 (+70.9%), and IFN-γ (+214.3%) as well as the proportion of IFN-γCD8 T cells (3.0-16.4-fold) were significantly increased compared with baseline and the control group (all P<0.05). The 1- (82.1% vs. 50.0%, P=0.04) and 2-year survival (67.8% vs. 33.3%, P=0.04) was improved by vaccination. Only 2 patients showed mild fever. In conclusion, the DC vaccine triggered the specific immune response and induced the secretion of Th1 cytokines. The vaccine may lead to better survival, but this have to be confirmed. Adverse events were rare and mild.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Carcinoma de Células Escamosas/imunologia , Células Dendríticas/imunologia , Neoplasias Esofágicas/imunologia , Radioimunoterapia/métodos , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Células Cultivadas , Estudos de Coortes , Citocinas/sangue , Células Dendríticas/transplante , Neoplasias Esofágicas/mortalidade , Feminino , Febre/etiologia , Seguimentos , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Radioimunoterapia/efeitos adversos , Análise de Sobrevida , Células Th1/imunologia
9.
Adv Drug Deliv Rev ; 109: 102-118, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-26705852

RESUMO

Radioimmunotherapy (RIT) aims to selectively deliver radionuclides emitting α-particles, ß-particles or Auger electrons to tumors by conjugation to monoclonal antibodies (mAbs) that recognize tumor-associated antigens/receptors. The approach has been most successful for treatment of non-Hodgkin's B-cell lymphoma but challenges have been encountered in extending these promising results to the treatment of solid malignancies. These challenges include the low potency of ß-particle emitters such as 131I, 177Lu or 90Y which have been commonly conjugated to the mAbs, due to their low linear energy transfer (LET=0.1-1.0keV/µm). Furthermore, since the ß-particles have a 2-10mm range, there has been dose-limiting non-specific toxicity to hematopoietic stem cells in the bone marrow (BM) due to the cross-fire effect. Conjugation of mAbs to α-particle-emitters (e.g. 225Ac, 213Bi, 212Pb or 211At) or Auger electron-emitters (e.g. 111In, 67Ga, 123I or 125I) would increase the potency of RIT due to their high LET (50-230keV/µm and 4 to 26keV/µm, respectively). In addition, α-particles have a range in tissues of 28-100µm and Auger electrons are nanometer in range which greatly reduces or eliminates the cross-fire effect compared to ß-particles, potentially reducing their non-specific toxicity to the BM. In this review, we describe the results of preclinical and clinical studies of RIT of cancer using radioimmunoconjugates emitting α-particles or Auger electrons, and discuss the potential of these high LET forms of radiation to improve the outcome of cancer patients.


Assuntos
Partículas alfa , Elétrons , Imunoconjugados/uso terapêutico , Transferência Linear de Energia , Neoplasias/radioterapia , Radioimunoterapia , Radioisótopos/uso terapêutico , Partículas alfa/uso terapêutico , Animais , Elétrons/uso terapêutico , Humanos , Imunoconjugados/efeitos adversos , Radioimunoterapia/efeitos adversos , Radioisótopos/efeitos adversos
10.
Oncotarget ; 8(6): 9155-9173, 2017 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-27893434

RESUMO

BACKGROUND: Cancer patients often report behavioral and cognitive changes following cancer treatment. These effects can be seen in patients who have not yet received treatment or have received only peripheral (non-brain) irradiation. Novel treatments combining radiotherapy (RT) and immunotherapy (IT) demonstrate remarkable efficacy with respect to tumor outcomes by enhancing the proinflammatory environment in the tumor. However, a proinflammatory environment in the brain mediates cognitive impairments in other neurological disorders and may affect brain function in cancer patients receiving these novel treatments. Currently, gaps exist as to whether these treatments impact the brain in individuals with or without tumors and with regard to the underlying mechanisms. RESULTS: Combined treatment with precision RT and checkpoint inhibitor IT achieved control of tumor growth. However, BALB/c mice receiving combined treatment demonstrated changes in measures of anxiety levels, regardless of tumor status. C57BL/6J mice with tumors demonstrated increased anxiety, except following combined treatment. Object recognition memory was impaired in C57BL/6J mice without tumors following combined treatment. All mice with tumors showed impaired object recognition, except those treated with RT alone. Mice with tumors demonstrated impaired amygdala-dependent cued fear memory, while maintaining hippocampus-dependent context fear memory. These behavioral alterations and cognitive impairments were accompanied by increased microglial activation in mice receiving immunotherapy alone or combined with RT. Finally, based on tumor status, there were significant changes in proinflammatory cytokines (IFN-γ, IL-6, IL-5, IL-2, IL-10) and a growth factor (FGF-basic). MATERIALS AND METHODS: Here we test the hypothesis that IT combined with peripheral RT have detrimental behavioral and cognitive effects as a result of an enhanced proinflammatory environment in the brain. BALB/c mice with or without injected hind flank CT26 colorectal carcinoma or C57BL/6J mice with or without Lewis Lung carcinoma were used for all experiments. Checkpoint inhibitor IT, using an anti-CTLA-4 antibody, and precision CT-guided peripheral RT alone and combined were used to closely model clinical treatment. We assessed behavioral and cognitive performance and investigated the immune environment using immunohistochemistry and multiplex assays to analyze proinflammatory mediators. CONCLUSIONS: Although combined treatment achieved tumor growth control, it affected the brain and induced changes in measures of anxiety, cognitive impairments, and neuroinflammation.


Assuntos
Antineoplásicos Imunológicos/toxicidade , Comportamento Animal , Encéfalo , Carcinoma Pulmonar de Lewis/terapia , Transtornos Cognitivos/etiologia , Cognição , Neoplasias Colorretais/terapia , Encefalite/etiologia , Lesões por Radiação/etiologia , Radioimunoterapia/efeitos adversos , Animais , Ansiedade/etiologia , Ansiedade/psicologia , Aprendizagem por Associação , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/efeitos da radiação , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Encéfalo/efeitos da radiação , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Cognição/efeitos dos fármacos , Cognição/efeitos da radiação , Transtornos Cognitivos/imunologia , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Citocinas/imunologia , Citocinas/metabolismo , Depressão/etiologia , Depressão/psicologia , Encefalite/imunologia , Encefalite/fisiopatologia , Encefalite/psicologia , Comportamento Exploratório , Feminino , Memória , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Atividade Motora , Comportamento de Nidação , Lesões por Radiação/imunologia , Lesões por Radiação/fisiopatologia , Lesões por Radiação/psicologia , Dosagem Radioterapêutica , Fatores de Tempo
11.
Eur J Nucl Med Mol Imaging ; 44(3): 517-532, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27844106

RESUMO

Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Ensaios Clínicos como Assunto , Linfoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/efeitos adversos , Animais , Anticorpos Monoclonais/uso terapêutico , Humanos , Linfoma/radioterapia , Radioimunoterapia/efeitos adversos , Radioimunoterapia/métodos , Compostos Radiofarmacêuticos/uso terapêutico
12.
Cancer ; 123(4): 638-649, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-27763687

RESUMO

BACKGROUND: In previous work, a single administration of anticarcinoembryonic antigen (anti-CEA) 131 I-labetuzumab radioimmunotherapy (RIT) after complete resection of colorectal liver metastases was well tolerated and significantly improved survival compared with controls. In the current phase 2 trial, the authors studied repeated RIT in the same setting, examining safety, feasibility, and efficacy. METHODS: Sixty-three patients (median age, 64.5 years) received RIT at 40 to 50 millicuries/m2 per dose. Before the receipt of RIT, restaging was performed with computed tomography/magnetic resonance imaging and 18 F-fluorodeoxyglucose-positron emission to confirm that patients were "truly adjuvant." Patients who had elevated serum CEA levels or radiographically inconclusive new lesions were classified as "possibly nonadjuvant," but they also received RIT. Time to progression (TTP), overall survival (OS), and cause-specific survival (CSS) were calculated. The median follow-up was 54 months. RESULTS: After the first course of RIT, 14 of 63 patients experienced National Cancer Institute Common Toxicity Criteria grade 4 hematotoxicity; 19 patients did not receive the second course of RIT because of impaired performance status (N = 5) or relapse (N = 14). After the second course of RIT, 9 of 44 patients experienced National Cancer Institute Common Toxicity Criteria grade 4 hematotoxicity. Five patients developed myelodysplastic syndrome (MDS) from 22 to 55 months after their last RIT. The median TTP, OS, and CSS for all patients were 16, 55, and 60 months, respectively. The "truly adjuvant" patients (N = 39) had an improved median TTP (not reached vs 6.1 months; hazard ratio, 0.12; P < .001), OS (75.6 vs 33.4 months; hazard ratio, 0.44; P = .014), and CSS (not reached vs 41.4 months; hazard ratio,0.42; P = .014) compared with "possibly nonadjuvant" patients (N = 24). CONCLUSIONS: Repeated RIT with 131 I-labetuzumab is feasible but is associated with hematotoxicity. Survival is very encouraging, especially for "truly adjuvant" patients. However, the maximum safe dose of 131 I-labetuzumab is a single administration of 50 millicuries/m2 . Cancer 2017;123:638-649. © 2016 American Cancer Society.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno Carcinoembrionário/imunologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Radioimunoterapia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígeno Carcinoembrionário/uso terapêutico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/radioterapia , Neoplasias Colorretais/cirurgia , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Radioisótopos do Iodo/efeitos adversos , Radioisótopos do Iodo/uso terapêutico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
13.
Curr Clin Pharmacol ; 12(1): 4-10, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27908252

RESUMO

Lung cancer is the main reason of cancer death worldwide. About 30% of non-small-cell lung cancer (NSCLC) cases are diagnosed with locally advanced disease (stage III). This is a mixed population including patients who have far more extensive and bulky disease than others. Management of these patients continue to be a challenge; frequently, patients have both local recurrence and distant metastases in this stage and the prognosis is very poor with a 5-year overall survival estimated between 3% and 7% for inoperable disease. The standard treatment for these patients is concurrent chemo-radiotherapy (CRT) improving survival when compared to sequential combination as shown in several metanalysis. Recently, immune-therapies, including checkpoint inhibitor, such as monoclonal antibodies against programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), have shown to enhance survival compared to chemotherapy in patients with advanced NSCLC. The integration of radiotherapy with immunotherapy is a conceptually promising strategy and several preclinical experiments have further developed the rationale for combining them. Radiotherapy has the capacity to overcome a lot of tumor immune escape mechanisms through the liberation of immunogenic private antigens showing a better local control and augmenting the immune response of systemic agents. This manuscript discusses the potential clinical interest for the combination of radiation and immunotherapy in locally advanced NSCLC.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Doses de Radiação , Radioimunoterapia/métodos , Animais , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Radioimunoterapia/efeitos adversos , Radioimunoterapia/mortalidade , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos
14.
Cancer Lett ; 381(2): 296-304, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-27524505

RESUMO

Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy ß-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerated by NOD Rag1(null) IL2rγ(null) (NRG) mice and did not reveal signs of organ long-term toxicity 80 days post injection. Combination therapy of the diabody RIC with unconjugated anti-CD20 Rituximab demonstrated therapeutic efficacy in established disseminated mantle cell lymphoma xenograft models. When compared with the combination of the IgG formatted (177)Lu anti-CD22 antibody and Rituximab, dual targeted therapy with the diabody RIC achieved an improved reduction of disease burden in the first nine days following treatment. The data indicate that the PEGylated anti-CD22 diabody may have potential for extending the repertoire of radiopharmaceuticals for the treatment of patients with B-NHL.


Assuntos
Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Linfoma de Burkitt/radioterapia , Imunoconjugados/farmacologia , Lutécio/farmacologia , Linfoma de Célula do Manto/radioterapia , Radioimunoterapia/métodos , Radioisótopos/farmacologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacocinética , Anticorpos Biespecíficos/toxicidade , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/toxicidade , Linfoma de Burkitt/imunologia , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Feminino , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/toxicidade , Imunoglobulinas Intravenosas/farmacologia , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/genética , Lutécio/farmacocinética , Lutécio/toxicidade , Linfoma de Célula do Manto/imunologia , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos Nus , Radioimunoterapia/efeitos adversos , Radioisótopos/farmacocinética , Radioisótopos/toxicidade , Rituximab/farmacologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J BUON ; 21(2): 326-32, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27273941

RESUMO

PURPOSE: To evaluate the differences in the outcomes of patients with stage II and IIIa non-small cell lung cancer (NSCLC) treated with either 131I-labeled mouse/human chimeric monoclonal antibody against intracellular DNA exposed in necrotic and degenerating regions of tumors (131I-chTNT-mediated radioimmunotherapy) combined with percutaneous microwave coagulation therapy (PMCT) guided by computed tomography (CT) or with postoperative adjuvant chemoradiation. METHODS: Ninety-six patients with stage II and IIIa NSCLC were randomized into two groups. Group A included 49 patients who were treated with chemotherapy with docetaxel and cisplatin and three-dimensional conformal radiotherapy 3-4 weeks after surgery. Group B included 47 patients treated with 131I-chTNT and PMCT sequentially, with follow-up chemotherapy. RESULTS: The survival rates of patients in group A for the first and second years were 79.59% and 48.98%, respectively. The median survival was 23.0 months. Survival rates at 1 and 2 years for group B were 82.98% and 53.19%, respectively and the median survival was 29.1 months. The survival rate of group B patients for the first and second years was better compared with group A, and the difference in median survival between the groups was statistically significant (p<0.05). However, median survival and the incidence of adverse events were not significantly different between the two groups. CONCLUSIONS: 131I-chTNT radioimmunotherapy with PMCT has a complementary effect in NSCLC, which can effectively improve therapeutic ratio and survival of patients effectively and has the same effect as that of post-operative adjuvant chemoradiation.


Assuntos
Técnicas de Ablação , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia Adjuvante , Neoplasias Pulmonares/terapia , Micro-Ondas/uso terapêutico , Radioimunoterapia , Radioterapia Conformacional , Técnicas de Ablação/efeitos adversos , Técnicas de Ablação/mortalidade , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimiorradioterapia Adjuvante/efeitos adversos , Quimiorradioterapia Adjuvante/mortalidade , China , Cisplatino , Docetaxel , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Micro-Ondas/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioimunoterapia/efeitos adversos , Radioimunoterapia/mortalidade , Dosagem Radioterapêutica , Radioterapia Conformacional/efeitos adversos , Radioterapia Conformacional/mortalidade , Análise de Sobrevida , Taxoides/administração & dosagem , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
17.
Eur J Haematol ; 97(6): 576-582, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27157440

RESUMO

BACKGROUND: Non-Hodgkin lymphoma patients have a 25% increased risk of secondary primary neoplasms (SPNs). Regarding the controversy about the increased risk of SPN in patients exposed to radioimmunotherapy (RIT), we have analyzed this issue in a cohort of follicular lymphoma (FL) patients treated with/without RIT. PATIENTS AND METHODS: A retrospective study including all consecutive FL patients diagnosed since 2001 was performed. Demographic, clinical data including the incidence of any kind of neoplasm (excluding basocellular skin carcinoma) were recorded. RESULTS: A total of 242 patients were registered, male/female: 103/139, mean age: 59.9 yr (15-86), stage IV (57.8%), and Follicular Lymphoma Prognostic Index (FLIPI) low-risk (62.15%) predominance. Ninety-six patients (39.7%) were treated with 90Y-IT. The median follow-up for patients treated or not with 90Y-IT was 61 (8-273) and 38 (1-171) months. With respect to SPN incidence, 38 (15.6%) patients have at least two cancers, in 17 (44.7%), FL was the SPN; for the rest (226), the global incidence of SPNs was 9.3% (21), but there were no differences related to the exposition or not to 90Y-IT (P = 0.26). In seven patients, more than two (2-6) different therapies were registered; four were exposed to fludarabine-based therapy, three to radiotherapy and two to autologous stem-cell transplantation, and in the RIT cohort, two patients developed myelodysplastic syndrome. CONCLUSION: This is one of the largest single institution reports assessing the risk of SPN in FL patients treated (96) or not (146) with 90Y-IT. It seems that 90Y-IT does not increase significantly the risk of SPN but avoiding its use after fludarabine and other intense cytotoxic schemes is recommended.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfoma Folicular/epidemiologia , Linfoma Folicular/radioterapia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Feminino , Seguimentos , Humanos , Incidência , Linfoma Folicular/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioimunoterapia/efeitos adversos , Estudos Retrospectivos , Medição de Risco , Adulto Jovem
18.
Nucl Med Biol ; 43(4): 227-31, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27067042

RESUMO

INTRODUCTION: Radioimmunotherapy (RIT) is a unique therapeutic modality that combines biologic and radiolytic mechanisms to induce tumor kill. RIT is underutilized in the community outpatient setting. METHODS: This is an institutional review of patients treated with RIT at St. John Hospital and Medical Center (SJH&MC) 2003-2011. RIT agents were dosed according to recommended guidelines. Response was assessed using the Revised Response Criteria for Malignant Lymphoma and toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events. The primary aim was to assess overall response rate (ORR) and overall survival (OS). The secondary aim was to assess the impact of variable host and disease factors on the ORR to RIT and OS. RESULTS: Forty-eight patients were treated with RIT within the specified period at SJH&MC; of which 52% with follicular lymphoma (FL) and 46% with diffuse large B cell lymphoma (DLBCL). The majority of patients had relapsed or refractory disease (98%). Median duration of follow-up was 17 months. The ORR was 73% with 44% complete remission (CR) rate and OS of 48 months. The ORR was 79% with 58% CR rate and OS of 82 months among FL patients. Among DLBCL patients, the ORR was 65% with 30% CR rate and OS of 39 months. Response to last therapy before RIT was the only significant predictor of response to RIT and a significant predictor of OS in multivariate analyses. Prior exposure to EBRT did not predict response or survival in multivariate analyses. Toxicity was manageable and predominantly hematologic. CONCLUSIONS: RIT is effective and feasible for use in the community outpatient setting. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Patients with B-cell NHL can safely receive RIT close to home. With some coordination of effort, it is not difficult for community-based cancer centers to implement this treatment modality.


Assuntos
Linfoma não Hodgkin/radioterapia , Radioimunoterapia/efeitos adversos , Radioimunoterapia/métodos , Características de Residência , Segurança , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
19.
Oncotarget ; 7(22): 33306-15, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27119227

RESUMO

The standard treatment for ductal carcinoma in situ (DCIS) of the breast is surgical resection, followed by radiation. Here, we tested localized therapy of DCIS in mice using the immunoconjugate 225Ac linked-trastuzumab delivered through the intraductal (i.duc) route. Trastuzumab targets HER-2/neu, while the alpha-emitter 225Ac (half-life, 10 days) delivers highly cytotoxic, focused doses of radiation to tumors. Systemic 225Ac, however, elicits hematologic toxicity and at high doses free 213Bi, generated by its decay, causes renal toxicity. I.duc delivery of the radioimmunoconjugate could bypass its systemic toxicity. Bioluminescent imaging showed that the therapeutic efficacy of intraductal 225Ac-trastuzumab (10-40 nCi per mammary gland; 30-120 nCi per mouse) in a DCIS model of human SUM225 cancer cells in NSG mice was significantly higher (p<0.0003) than intravenous (120 nCi per mouse) administration, with no kidney toxicity or loss of body weight. Our findings suggest that i.duc radioimmunotherapy using 225Ac-trastuzumab deserves greater attention for future clinical development as a treatment modality for early breast cancer.


Assuntos
Actínio/administração & dosagem , Partículas alfa , Neoplasias da Mama/radioterapia , Carcinoma Intraductal não Infiltrante/radioterapia , Imunoconjugados/administração & dosagem , Radioimunoterapia/métodos , Radioisótopos/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Receptor ErbB-2/metabolismo , Trastuzumab/administração & dosagem , Actínio/farmacocinética , Actínio/toxicidade , Partículas alfa/efeitos adversos , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/imunologia , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Humanos , Imunoconjugados/farmacocinética , Células MCF-7 , Camundongos Endogâmicos NOD , Radioimunoterapia/efeitos adversos , Radioisótopos/farmacocinética , Radioisótopos/toxicidade , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/toxicidade , Receptor ErbB-2/imunologia , Distribuição Tecidual , Trastuzumab/farmacocinética , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Br J Haematol ; 174(4): 571-81, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27101934

RESUMO

This phase 2 study evaluated the efficacy and safety of inotuzumab ozogamicin (InO) in patients with indolent B-cell non-Hodgkin lymphoma (NHL) refractory to rituximab alone, rituximab plus chemotherapy or anti-CD20 radioimmunotherapy. Patients received InO 1·8 mg/m(2) intravenously on a 28-d cycle for a planned 4-8 cycles. The initial InO dose and schedule could be adjusted for tolerability and patients were allowed to receive 2 additional cycles (up to 8 total) after achieving a complete response (CR). The primary endpoint was overall response. Eighty-one patients were enrolled, among whom 48 (59%) received ≥3 InO cycles and 13 (16%) completed the treatment phase. The overall response rate was 67% (CR, 31%). Median (95% confidence interval) progression-free survival was 12·7 (8·9-26·9) months; median overall survival was not reached. Haematological adverse events (AEs) were common, particularly thrombocytopenia (74%) and neutropenia (56%). These were also the most common AEs leading to treatment discontinuation (37% and 11%, respectively); 58% of patients reported AEs leading to treatment discontinuation. InO demonstrated robust activity in these heavily pretreated patients, although treatment duration was limited by haematological toxicities. Additional studies may determine dosing regimens that allow for reduced toxicity.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Linfoma de Células B/tratamento farmacológico , Terapia de Salvação/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Células B/complicações , Linfoma de Células B/mortalidade , Linfoma de Células B/radioterapia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/etiologia , Radioimunoterapia/efeitos adversos , Indução de Remissão , Terapia de Salvação/efeitos adversos , Taxa de Sobrevida , Trombocitopenia/induzido quimicamente , Trombocitopenia/etiologia , Resultado do Tratamento
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