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1.
Ann Hematol ; 99(5): 1073-1079, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32125469

RESUMO

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) and for relapse in 45 (50%) patients. Most patients received 90Y-IT as consolidation after chemoimmunotherapy in first line (98%) and in relapse (53%). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%. and 1 pt. (2%) PD, and for 4 pts. (9%), no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95% CI, 1.03-2.32) years, and median OS was 4.05 (95% CI, 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib.


Assuntos
Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/radioterapia , Radioimunoterapia , Sistema de Registros , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
2.
Cancer Radiother ; 24(2): 153-158, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32089502

RESUMO

The radiobiological concepts described for conventional doses per fraction (1.8 to 2Gy) seem difficult to translate to high doses per fraction radiobiology. In fact, specific mechanisms are involved during high dose per fraction irradiation, involving vascular microenvironment damage and anti tumor immune response. The "5R's" of "classical" radiobiology (factors influencing the response of healthy or cancer cells to irradiation) seem to play a less important role in case of high doses per fraction. In addition, applicability of the linear quadratic model in this context is debated. It is therefore difficult to obtain reliable equivalent doses, hence the importance of including our patients in clinical trials, especially in case of concomitant systemic treatments. In addition to stereotactic radiotherapy, flash irradiations defined by a dose rate approximately 2000 times faster than "conventional" irradiation can also deliver high doses per fraction, with a much better tolerance for normal tissue without loss of anti tumor efficacy. Finally, availability of robust prospective data is a prerequisite to answer the question of short and long-term risk/benefit ratio of these different irradiation techniques.


Assuntos
Fracionamento da Dose de Radiação , Neoplasias/radioterapia , Radiobiologia , Radiocirurgia , Vasos Sanguíneos/efeitos da radiação , Ciclo Celular/efeitos da radiação , Morte Celular , Proliferação de Células , Sobrevivência Celular , Humanos , Imunidade Celular/efeitos da radiação , Modelos Teóricos , Consumo de Oxigênio , Tolerância a Radiação , Radiobiologia/legislação & jurisprudência , Radioimunoterapia/métodos , Radiocirurgia/legislação & jurisprudência , Medição de Risco
3.
Br J Radiol ; 93(1109): 20190147, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31971824

RESUMO

Concerns have been raised about potential toxic interactions when colony-stimulating factors (CSFs) and chemoradiation are concurrently performed. In 2006, the ASCO guidelines advised against their concomitant use. Nevertheless, with the development of modern radiotherapy techniques and supportive care, the therapeutic index of combined chemotherapy, radiotherapy, and CSFs is worth reassessing. Recent clinical trials testing chemoradiation in lung cancer let investigators free to decide the use of concomitant CSFs or not. No abnormal infield event was reported after the use of modern radiotherapy techniques and concomitant chemotherapy regimens. These elements call for further investigation to set new recommendations in favour of the association of chemoradiation and CSFs. Moreover, radiotherapy could induce anticancer systemic effects mediated by the immune system in vitro and in vivo. With combined CSFs, this effect was reinforced in preclinical and clinical trials introducing innovative radioimmunotherapy models. So far, the association of radiation with CSFs has not been combined with immunotherapy. However, it might play a major role in triggering an immune response against cancer cells, leading to abscopal effects. The present article reassesses the therapeutic index of the combination CSFs-chemoradiation through an updated review on its safety and efficacy. It also provides a special focus on radioimmunotherapy.


Assuntos
Quimiorradioterapia/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Animais , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/terapia , Camundongos , Radioimunoterapia/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma de Pequenas Células do Pulmão/terapia
4.
Br J Radiol ; 93(1107): 20190224, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31317768

RESUMO

The combination of radiotherapy and immunotherapy is one of the most promising strategies for cancer treatment. Recent clinical results support the pre-clinical experiments pointing to a benefit for the combined treatment in metastatic patients. Charged particle therapy (using protons or heavier ions) is considered one of the most advanced radiotherapy techniques, but its cost remains higher than conventional X-ray therapy. The most important question to be addressed to justify a more widespread use of particle therapy is whether they can be more effective than X-rays in combination with immunotherapy. Protons and heavy ions have physical advantages compared to X-rays that lead to a reduced damage to the immune cells, that are required for an effective immune response. Moreover, densely ionizing radiation may have biological advantages, due to different cell death pathways and release of cytokine mediators of inflammation. We will discuss results in esophageal cancer patients showing that charged particles can reduce the damage to blood lymphocytes compared to X-rays, and preliminary in vitro studies pointing to an increased release of immune-stimulating cytokines after heavy ion exposure. Pre-clinical and clinical studies are ongoing to test these hypotheses.


Assuntos
Neoplasias Esofágicas/radioterapia , Radioterapia com Íons Pesados/métodos , Terapia com Prótons/métodos , Radioimunoterapia/métodos , Morte Celular , Citocinas/metabolismo , DNA/efeitos da radiação , Dano ao DNA , Neoplasias Esofágicas/imunologia , Humanos , Imunoterapia/economia , Mediadores da Inflamação/metabolismo , Linfócitos/efeitos da radiação , Linfopenia/etiologia , Raios X/efeitos adversos
5.
Crit Rev Oncol Hematol ; 144: 102830, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31733443

RESUMO

Radiotherapy (RT) represents a mainstay in the treatment of brain metastases (BMs) from solid tumors. Immunotherapy (IT) has improved survival of metastatic cancer patients across many tumor types. The combination of RT and IT for the treatment of BMs has a strong rationale, but data on efficacy and safety of this combination is still limited. A systematic search of PubMed, the Cochrane Central Register of Controlled Trials, and EMBASE was conducted. 33 studies were included for a total of 1520 patients, most of them with melanoma (87%). Median pooled OS was 15.9 months (95%CI 13.9-18.1). One- and 2-year OS rates were 55.2% (95% CI 49.3-60.9) and 35.7% (95% CI 30.4-41.3), respectively. Addition of IT to RT was associated with improved OS (HR = 0.54, 95%CI 0.44-0.67; P < 0.001). For patients with BMs from solid tumors, addition of concurrent IT to brain RT is able to increase survival and provide long term control.


Assuntos
Neoplasias Encefálicas/radioterapia , Radioimunoterapia , Humanos , Imunoterapia , Melanoma , Segunda Neoplasia Primária
6.
Chem Commun (Camb) ; 55(96): 14506-14509, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31735949

RESUMO

Polymers are an attractive anchoring platform for the synthesis of radioimmunoconjugates. They enable independent control over the amount of radioisotope loading and antibody attachment, which is pivotal in developing tailorable formulations for personalised medicine. Herein, we report the synthesis of p(HEMA-ran-GMA) for the conjugation of lutetium ions and rituximab as a functional platform for radioimmunotherapy. We demonstrate the suitability of this platform using non-Hodgkin's lymphoma cells.


Assuntos
Imunoconjugados/química , Linfoma não Hodgkin/radioterapia , Radioimunoterapia , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Química Click , Compostos de Epóxi/química , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Lutécio/química , Metacrilatos/química , Polímeros/química , Rituximab/química , Rituximab/farmacologia , Rituximab/uso terapêutico
7.
Am Surg ; 85(10): 1118-1124, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31657306

RESUMO

Prospective randomized studies have demonstrated a survival benefit of immunotherapy in stage IV cutaneous melanoma. Some retrospective studies have hypothesized a synergistic effect of radiation and immunotherapy. Our objective was to identify whether there is a survival benefit for patients treated with radiation and immunotherapy in stage IV cutaneous melanoma of the head and neck (CMHN). The National Cancer Database was used to identify patients with stage IV CMHN between 2012 and 2014. These patients were stratified based on receipt of radiation and immunotherapy. Adjusted Cox regression was used to analyze overall survival. A total of 542 patients were identified with stage IV CMHN, of whom 153 (28%) patients received immunotherapy. Receipt of immunotherapy (hazard ratio [HR] 0.69, P = 0.02) and negative LNs (HR 0.50, P = 0.002) were independently associated with improved survival, whereas radiation conferred no survival benefit (HR 1.17, P = 0.26). Patients who received immunotherapy without radiation were associated with significantly improved survival compared with those who received immunotherapy with radiation (P < 0.0001). However, of patients who received radiation, the addition of immunotherapy did not seem to improve survival (P = 0.979). In stage IV CMHN, immunotherapy confers a 32 per cent survival benefit. The use of immunotherapy in patients who require radiation, however, is not associated with improved survival.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/mortalidade , Ipilimumab/uso terapêutico , Melanoma/terapia , Neoplasias Cutâneas/terapia , Adulto , Idoso , Análise de Variância , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Imunoterapia/métodos , Linfonodos/patologia , Masculino , Melanoma/mortalidade , Melanoma/patologia , Melanoma/radioterapia , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Radioimunoterapia/métodos , Radioimunoterapia/mortalidade , Radioterapia/mortalidade , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/radioterapia , Análise de Sobrevida , Fatores de Tempo
8.
Int J Radiat Oncol Biol Phys ; 105(2): 410-422, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255687

RESUMO

PURPOSE: Fibroblast growth factor receptor 2 (FGFR2) has been previously reported to be overexpressed in several types of cancer, whereas the expression in normal tissue is considered to be moderate to low. Thus, FGFR2 is regarded as an attractive tumor antigen for targeted alpha therapy. This study reports the evaluation of an FGFR2-targeted thorium-227 conjugate (FGFR2-TTC, BAY 2304058) comprising an anti-FGFR2 antibody, a chelator moiety covalently conjugated to the antibody, and the alpha particle-emitting radionuclide thorium-227. FGFR2-TTC was assessed as a monotherapy and in combination with the DNA damage response inhibitor ATRi BAY 1895344. METHODS AND MATERIALS: The in vitro cytotoxicity and mechanism of action were evaluated by determining cell viability, the DNA damage response marker γH2A.X, and cell cycle analyses. The in vivo efficacy was determined using human tumor xenograft models in nude mice. RESULTS: In vitro mechanistic assays demonstrated upregulation of γH2A.X and induction of cell cycle arrest in several FGFR2-expressing cancer cell lines after treatment with FGFR2-TTC. In vivo, FGFR2-TTC significantly inhibited tumor growth at a dose of 500 kBq/kg in the xenograft models NCI-H716, SNU-16, and MFM-223. By combining FGFR2-TTC with the ATR inhibitor BAY 1895344, an increased potency was observed in vitro, as were elevated levels of γH2A.X and inhibition of FGFR2-TTC-mediated cell cycle arrest. In the MFM-223 tumor xenograft model, combination of the ATRi BAY 1895344 with FGFR2-TTC resulted in significant tumor growth inhibition at doses at which the single agents had no effect. CONCLUSIONS: The data provide a mechanism-based rationale for combining the FGFR2-TTC with the ATRi BAY 1895344 as a new therapeutic approach for treatment of FGFR2-positive tumors from different cancer indications.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Neoplasias da Mama/radioterapia , Inibidores de Proteínas Quinases/uso terapêutico , Radioimunoterapia/métodos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/uso terapêutico , Tório/uso terapêutico , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quelantes/uso terapêutico , Dano ao DNA , Combinação de Medicamentos , Sinergismo Farmacológico , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Histonas/metabolismo , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Camundongos , Camundongos Nus , Terapia de Alvo Molecular/métodos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Tório/farmacocinética , Compostos de Tório/uso terapêutico , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
9.
BMC Cancer ; 19(1): 325, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953466

RESUMO

BACKGROUND: For progressive metastatic medullary thyroid carcinoma (MTC), the available treatment options with tyrosine kinase inhibitors result in grade 3-4 adverse events in a large number of patients. Peptide Receptor Radionuclide Therapy (PRRT), which has also been suggested to be a useful treatment for MTC, is usually well tolerated, but evidence on its effectivity is very limited. METHODS: Retrospective evaluation of treatment effects of PRRT in a highly selected group of MTC patients, with progressive disease or refractory symptoms. In addition, a retrospective evaluation of uptake on historical 111In-DTPA-octreotide scans was performed in patients with detectable tumor size > 1 cm. RESULTS: Over the last 17 years, 10 MTC patients were treated with PRRT. Four out of 10 patients showed stable disease at first follow-up (8 months after start of therapy) whereas the other 6 were progressive. Patients with stable disease were characterized by a combination of both a high uptake on 111In-DTPA-octreotide scan (uptake grade ≥ 3) and a positive somatostatin receptor type 2a (SSTR2a) expression of the tumor by immunohistochemistry. Retrospective evaluation of historical 111In-DTPA-octreotide scans of 35 non-treated MTC patients revealed low uptake (uptake grade 1) in the vast majority of patients 31/35 (89%) with intermediate uptake (uptake grade 2) in the remaining 4/35 (11%). CONCLUSIONS: PRRT using 177Lu-octreotate could be considered as a treatment in those patients with high uptake on 111In-DTPA-octreotide scan (uptake grade 3) and positive SSTR2a expression in tumor histology. Since this high uptake was present in a very limited number of patients, this treatment is only suitable in a selected group of MTC patients.


Assuntos
Carcinoma Neuroendócrino/radioterapia , Octreotida/análogos & derivados , Radioimunoterapia/métodos , Receptores de Somatostatina/metabolismo , Neoplasias da Glândula Tireoide/radioterapia , Adulto , Idoso , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/administração & dosagem , Octreotida/uso terapêutico , Seleção de Pacientes , Ácido Pentético/administração & dosagem , Ácido Pentético/análogos & derivados , Intervalo Livre de Progressão , Cintilografia/métodos , Estudos Retrospectivos , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Adulto Jovem
10.
Int Rev Immunol ; 38(2): 79-91, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931651

RESUMO

Radioimmunotherapy (RIT) is a novel strategy for treating non-Hodgkin lymphoma (NHL). Several studies have shown the promising results of using RIT in NHL, which have led to FDA approval for two RIT agents in treating low grade NHL. In spite of these favorable results in low-grade NHL, most of the aggressive or relapsed/refractory NHL subjects experience relapses following RIT. Although more aggressive treatments such as myeloablative doses of RIT followed by stem cell transplantation appear to be able to provide a longer survival for some patients these approaches are associated with significant treatment-related adverse events and challenging to deliver in most centers. Therefore, it seems reasonable to develop treatment approaches that enhance the efficiency of RIT, while reducing its toxicity. In this paper, novel methods that improve the efficiency of RIT and reduce its toxicity through various mechanisms are reviewed. Further clinical development of these methods could expand the NHL patient groups eligible for receiving RIT, and even extend the use of RIT to new indications and disease groups in future.


Assuntos
Linfoma não Hodgkin/terapia , Radioimunoterapia , Animais , Quelantes/química , Quelantes/farmacologia , Gerenciamento Clínico , Composição de Medicamentos , Sinergismo Farmacológico , Humanos , Marcação por Isótopo , Ligantes , Linfoma não Hodgkin/etiologia , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/farmacologia , Polietilenoglicóis/química , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Radioimunoterapia/métodos , Resultado do Tratamento
11.
J Neurooncol ; 143(1): 101-106, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30879172

RESUMO

PURPOSE: We explored the use of intraventricular 131I-Omburtamab targeting B7-H3 in patients with ETMR. METHODS: Patients were enrolled in an IRB approved, phase 1, 3 + 3 dose escalation trial. Patients with CNS disease expressing the antibody target antigen B7-H3 were eligible. We report on a cohort of three patients with ETMR who were enrolled on the study. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR. Patients received 2 mCi 131I-Omburtamab as a tracer followed by one or two therapeutic 131I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after 131I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted. RESULTS: Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received 131I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to 131I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then 131I-Omburtamab (36 mCi). 131I-Omburtamab was well-tolerated. Mean dose delivered by 131I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.8 years and 2.3 years after diagnosis, respectively; patient 3 died of progressive disease 7 months after therapy (2 years after diagnosis). CONCLUSIONS: 131I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, 131I-Omburtamab may have therapeutic benefit for patients with ETMR.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neoplasias do Sistema Nervoso Central/radioterapia , Radioisótopos do Iodo/uso terapêutico , Neoplasias Embrionárias de Células Germinativas/radioterapia , Anticorpos Monoclonais/líquido cefalorraquidiano , Anticorpos Monoclonais Murinos/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Pré-Escolar , Evolução Fatal , Feminino , Humanos , Lactente , Injeções Intraventriculares , Radioisótopos do Iodo/líquido cefalorraquidiano , Masculino , Neoplasias Embrionárias de Células Germinativas/líquido cefalorraquidiano , Neoplasias Embrionárias de Células Germinativas/diagnóstico por imagem , Radioimunoterapia , Radiometria , Medula Espinal/diagnóstico por imagem
12.
Eur Radiol ; 29(7): 3935-3944, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30899979

RESUMO

PURPOSE: To determine the earliest optimal timing for assessment of early response following radioimmunotherapy in non-Hodgkin lymphoma patients using FDG-PET/CT. METHODS: FDG-PET/CT was performed prior to treatment (PET1), at 2 (PET2) weeks, and at 6 (PET3) weeks after 90Y-ibritumomab radioimmunotherapy in 55 patients. Response was evaluated based on the Deauville 5-point scale and Lugano criteria as well as semiquantitative analysis and compared with progression-free survival (PFS). RESULTS: PET 2 showed complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD) in 33, 13, 6, and 3 patients, respectively, while PET 3 in 41, 8, 3, and 3 patients, respectively. Mean SUVmax of 168 target lesions decreased over time (PET1, 2, 3; 5.58 ± 2.58, 1.87 ± 1.78, 1.75 ± 2.25, respectively). Progression or recurrence after a median of 12.6 months (range 2.6-72.0 months) was seen in 44 patients. Patients with CMR or metabolic response (CMR + PMR) on PET2 showed significantly longer PFS as compared to those who did not (p = 0.00028 and p = 0.029, respectively). A similar significant difference was observed based on PET3 (p = 0.00013 and p = 0.017, respectively). The same trend was observed when analyzing only the subgroup of patients with follicular lymphoma (N = 43/55) (p < 0.0001). CONCLUSION: Use of FDG-PET/CT findings with Lugano criteria for assessing early response to radioimmunotherapy after 6 weeks allowed for accurate evaluation and prognostic stratification, though scanning after 2 weeks was too soon to precisely evaluate response. KEY POINTS: • The optimal timing of FDG-PET/CT to obtain a suitable tool for assessment of response after 90 Y-ibritumomab radioimmunotherapy of lymphoma has not yet been defined. • Assessment after 6 weeks by FDG-PET/CT using the Lugano criteria accurately evaluates treatment response and prognosis. • FDG-PET/CT performed 2 weeks after radioimmunotherapy is too early as it significantly misses objective responses.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Radioimunoterapia/métodos , Cintilografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B , Progressão da Doença , Feminino , Fluordesoxiglucose F18/administração & dosagem , Humanos , Linfoma de Células B/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Prospectivos
13.
Int Immunopharmacol ; 70: 498-503, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30875561

RESUMO

Chimeric antigen receptor T (CAR-T) cell therapy provides possibility for the treatment of malignancies since clinical trials have shown that CAR-T therapy has a significant anti-tumor effect. Although many efforts have been made to improve the efficacy and reduce the side effects of CAR-T therapy, there are still many problems to solve. With the rapid development of this field, combination immunotherapy has been proved to improve the efficacy of CAR-T therapy. Studies have shown that radiotherapy, chemotherapy, oncolytic virotherapy, BTK inhibitors and immune checkpoint blockade-based therapy may further enhance the efficacy of CAR-T therapy while CRISPR/Cas9 technology and IL-1 blockade may improve the safety. In this review, we summarized the advantages and the mechanisms of the combination immunotherapy based on CAR-T cell therapy.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/genética , Linfócitos T/fisiologia , Animais , Anticorpos Monoclonais/uso terapêutico , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Terapia Combinada , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Humanos , Interleucina-1/antagonistas & inibidores , Neoplasias/imunologia , Terapia Viral Oncolítica , Inibidores de Proteínas Quinases/uso terapêutico , Radioimunoterapia , Linfócitos T/transplante
14.
Cancer Sci ; 110(5): 1653-1664, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30801908

RESUMO

Podoplanin is a type I transmembrane sialomucin-like glycoprotein that is highly expressed in malignant mesothelioma. The rat-human chimeric antibody NZ-12 has high affinity for human podoplanin and antibody-dependent cellular cytotoxicity and is applicable for radioimmunotherapy (RIT) to enhance the antitumor effect. In the present study, we evaluated the in vivo and in vitro properties of radiolabeled NZ-12 and the antitumor effect of RIT with 90 Y-labeled NZ-12 in an NCI-H226 (H226) malignant mesothelioma xenograft mouse model. 111 In-labeled NZ-12 bound specifically to H226 cells with high affinity, and accumulation was high in H226 tumors but low in major organs. RIT with 90 Y-labeled NZ-12 significantly suppressed tumor growth and prolonged survival without body weight loss and obvious adverse effects. Higher podoplanin expression levels were observed in human mesothelioma specimens, suggesting higher tumor accumulation of 90 Y-labeled NZ-12 in patients compared with the H226 tumor xenografts. Our findings suggest that 90 Y-labeled NZ-12 is a promising RIT agent as a new therapeutic option for malignant mesothelioma that warrants further clinical studies to evaluate the dosimetry and efficacy in patients.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Neoplasias Pulmonares/radioterapia , Glicoproteínas de Membrana/metabolismo , Mesotelioma/radioterapia , Radioimunoterapia/métodos , Radioisótopos de Ítrio/química , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Citotoxicidade Celular Dependente de Anticorpos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Radioisótopos de Índio/química , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Masculino , Mesotelioma/diagnóstico por imagem , Mesotelioma/metabolismo , Camundongos , Camundongos Nus , Ratos , Resultado do Tratamento , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Vis Exp ; (143)2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30774125

RESUMO

While radioimmunotherapy (RIT) is a promising approach for the treatment of cancer, the long pharmacokinetic half-life of radiolabeled antibodies can result in high radiation doses to healthy tissues. Perhaps not surprisingly, several different strategies have been developed to circumvent this troubling limitation. One of the most promising of these approaches is pretargeted radioimmunotherapy (PRIT). PRIT is predicated on decoupling the radionuclide from the immunoglobulin, injecting them separately, and then allowing them to combine in vivo at the target tissue. This approach harnesses the exceptional tumor-targeting properties of antibodies while skirting their pharmacokinetic drawbacks, thereby lowering radiation doses to non-target tissues and facilitating the use of radionuclides with half-lives that are considered too short for use in traditional radioimmunoconjugates. Over the last five years, our laboratory and others have developed an approach to in vivo pretargeting based on the inverse electron-demand Diels-Alder (IEDDA) reaction between trans-cyclooctene (TCO) and tetrazine (Tz). This strategy has been successfully applied to pretargeted positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging with a variety of antibody-antigen systems. In a pair of recent publications, we have demonstrated the efficacy of IEDDA-based PRIT in murine models of pancreatic ductal adenocarcinoma and colorectal carcinoma. In this protocol, we describe protocols for PRIT using a 177Lu-DOTA-labeled tetrazine radioligand ([177Lu]Lu-DOTA-PEG7-Tz) and a TCO-modified variant of the colorectal cancer targeting huA33 antibody (huA33-TCO). More specifically, we will describe the construction of huA33-TCO, the synthesis and radiolabeling of [177Lu]Lu-DOTA-PEG7-Tz, and the performance of in vivo biodistribution and longitudinal therapy studies in murine models of colorectal carcinoma.


Assuntos
Reação de Cicloadição/métodos , Radioimunoterapia/métodos , Animais , Modelos Animais de Doenças , Humanos , Camundongos
16.
Clin Transl Oncol ; 21(8): 992-1004, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30644044

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 , Prognóstico
17.
Appl Radiat Isot ; 145: 251-257, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30686576

RESUMO

At the time of publication, radiopharmaceuticals labelled with thorium-227 are in clinical trials in Europe for the treatment of various types of cancer. In part I of this two-part series the primary standardisation of an aqueous solution of 227Th was reported. In part II, the activity derived from the recommended absolute γ-ray emission intensities have been compared to that from the primary standardisation techniques. This comparison showed a negative bias of 4% in the determined activity per unit mass with an 11% spread in the activities determined for the eight most intense γ-ray emissions (Iγ > 1%) from the 227Th α decay. Using the standardised 227Th, measurements of the characteristic γ-ray emissions from the 223Ra excited states were made using a calibrated HPGe γ-ray spectrometer. This has enabled the absolute intensities of 70 γ ray emissions from the 227Th α-decay to be experimentally determined. A significant improvement over the precision of the recommended normalisation scaling factor has been made, with a value of 12.470 (35) % determined. Typically, the precision of the intensities has been improved by an order of magnitude or greater than current recommended values. The correlation matrices for pairs of the most intense γ-ray emission intensities are presented.


Assuntos
Compostos Radiofarmacêuticos/uso terapêutico , Tório/uso terapêutico , Partículas alfa/uso terapêutico , Calibragem , Raios gama/uso terapêutico , Humanos , Neoplasias/radioterapia , Radioimunoterapia/métodos , Radioimunoterapia/normas , Compostos Radiofarmacêuticos/normas , Rádio (Elemento)/química , Padrões de Referência , Contagem de Cintilação , Espectrometria gama , Tório/normas
18.
Immunotherapy ; 11(4): 297-309, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606066

RESUMO

AIM: Melanoma brain metastases (MBM) are associated with a dismal prognosis. Few clinical trials evaluated the impact of immunotherapy (IT) and targeted therapy (TT) alone or in combination with surgery and radiotherapy in this population. PATIENTS & METHODS: Retrospective analysis of data from 163 patients diagnosed with MBM between January 2014 and December 2016. Prognostic factors of overall survival were analyzed using Kaplan-Meier survival curves, classification and regression tree and multivariate Cox regression analysis. RESULTS: The median follow-up was 25 months; median overall survival (mOS) for all patients was 7 months. For patients receiving IT, the mOS was 13 months and 7 months for patients receiving TT or chemotherapy (CT). The mOS for patients treated with surgery/radiosurgery in combination with IT, TT and CT was 25, 14 and 11 months, respectively. CONCLUSION: New systemic therapies, especially IT, improve mOS in patients with MBM, particularly when combined with surgery/radiosurgery upfront.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Melanoma/terapia , Radioimunoterapia , Radiocirurgia , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Seguimentos , Humanos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
19.
Immunotherapy ; 11(2): 101-118, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30511887

RESUMO

AIM: We investigated a promising cooperative combination of radiotherapy (RT) and programmed death ligand 1 (PD-L1) monoclonal antibodies (mAb) in both local and abscopal tumors. MATERIALS & METHODS: C57BL/6 mice were randomly grouped and received RT, α-PD-L1 mAb or combination therapy 13 days after implantation of Lewis lung carcinoma cells. Flow cytometry and immunohistochemistry analyses demonstrated CD8+ T-cell infiltration and PD-L1 expression in tumor issue. Cytometric bead arrays were used to examine cytokine levels. RESULTS: Our studies revealed that administration of 8 Gy × 3 F with α-PD-L1 mAb promoted both local and distant control. Only local hypofractionated RT enhanced CD8+ T-cell infiltration with increased PD-L1 expression at distant foci, which might occur via serum IFN-γ modulation. Addition of α-PD-L1 mAb reduced PD-L1 expression and further increased CD8+ T-cell infiltration. CONCLUSION: We identified a novel mechanism through which combination therapy enhanced the abscopal effect.


Assuntos
Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Lewis/terapia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Radioimunoterapia/métodos , Animais , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Movimento Celular , Terapia Combinada , Citometria de Fluxo , Humanos , Interferon gama/sangue , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias
20.
Clin Cancer Res ; 25(2): 881-891, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30254080

RESUMO

PURPOSE: The impact of androgen receptor (AR) activity in breast cancer biology is unclear. We characterized and tested a novel therapy to an AR-governed target in breast cancer.Experimental Design: We evaluated the expression of prototypical AR gene products human kallikrein 2 (hK2) and PSA in breast cancer models. We screened 13 well-characterized breast cancer cell lines for hK2 and PSA production upon in vitro hormone stimulation by testosterone [dihydrotestosterone (DHT)]. AR-positive lines were further evaluated by exposure to estrogen (17ß-Estradiol) and the synthetic progestin D-Norgestrel. We then evaluated an anti-hK2-targeted radiotherapy platform (hu11B6), labeled with alpha (α)-particle emitting Actinium-225, to specifically treat AR-expressing breast cancer xenografts under hormone stimulation. RESULTS: D-Norgestrel and DHT activated the AR pathway, while 17ß-Estradiol did not. Competitive binding for AR protein showed similar affinity between DHT and D-Norgestrel, indicating direct AR-ligand interaction. In vivo production of hK2 was sufficient to achieve site-specific delivery of therapeutic radionuclide to tumor tissue at >20-fold over background muscle uptake; effecting long-term local tumor control. CONCLUSIONS: [225Ac]hu11B6 targeted radiotherapy was potentiated by DHT and by D-Norgestrel in murine xenograft models of breast cancer. AR activity in breast cancer correlates with kallikrein-related peptidase-2 and can be activated by D-Norgestrel, a common contraceptive, and AR induction can be harnessed for hK2-targeted breast cancer α-emitter radiotherapy.


Assuntos
Partículas alfa/uso terapêutico , Neoplasias da Mama/metabolismo , Imunoconjugados/administração & dosagem , Receptores Androgênicos/metabolismo , Transdução de Sinais , Animais , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Feminino , Hexoquinase/antagonistas & inibidores , Humanos , Imunoconjugados/farmacocinética , Camundongos , Terapia de Alvo Molecular , Radioimunoterapia , Radiometria , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
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