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1.
Medicine (Baltimore) ; 100(29): e26672, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34398032

RESUMO

BACKGROUND: To date, there have been no reported trials that directly compare pembrolizumab/carrelizumab monotherapy versus pembrolizumab/carrelizumab and chemotherapy in the first-line treatment setting of advanced/metastatic non-small cell lung cancer (NSCLC). We performed a Bayesian network meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of pembrolizumab/carrelizumab versus pembrolizumab/carrelizumab and chemotherapy in previously treated patients with NSCLC. METHODS: The following search terms would be used in PUBMED, Scopus, EMBASE, and Cochrane Library databases on July 20, 2021, as the search algorithm: (pembrolizumab) OR (carrelizumab) OR (programmed death-1) AND (non-small cell lung cancer) OR (NSCLC). All RCTs that reported the outcomes of pembrolizumab/carrelizumab with or without chemotherapy compared with those of pembrolizumab/carrelizumab alone for patients with NSCLC were considered eligible for inclusion in this meta-analysis. The primary outcomes of interest were overall survival, progression-free survival, objective response rate based on the Response Evaluation Criteria in Solid Tumors for complete and partial responses, and treatment-related adverse events including immune-related adverse events. Secondary outcomes included overall survival, progression-free survival, objective response rate, and treatment-related adverse events for the FDA-approved doses. CONCLUSIONS: The results of our review will be reported strictly following the PRISMA criteria and the review will add to the existing literature by showing compelling evidence and improved guidance in clinic settings. ETHICAL APPROVAL: As this study is on the basis of published or registered previous studies, ethical approval and informed consent of patients are not required.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Projetos de Pesquisa
2.
Cancer Sci ; 112(9): 3585-3597, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34252986

RESUMO

Diffuse large B cell lymphoma (DLBCL) heterogeneity promotes recurrence and anti-CD20-based therapeutic resistance. Previous studies have shown that downregulation of MS4A1/CD20 expression after chemoimmunotherapy with rituximab leads to rituximab resistance. However, the mechanisms of CD20 loss remain unknown. We identified that pyruvate dehydrogenase kinase 4 (PDK4) is markedly elevated in DLBCL cells derived from both patients and cell lines with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) resistance. We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression. Collectively, this is the first study showing that targeting PDK4 has the potential to overcome rituximab resistance in DLBCL.


Assuntos
Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/administração & dosagem , Reprogramação Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glicoproteínas/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Rituximab/administração & dosagem , Transdução de Sinais/genética , Adolescente , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Transfecção , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
3.
Molecules ; 26(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34299401

RESUMO

Bevacizumab (BCZ) is a recombinant humanized monoclonal antibody against the vascular endothelial growth factor, which is involved in the angiogenesis process. Pathologic angiogenesis is observed in several diseases including ophthalmic disorders and cancer. The multiple administrations of BCZ can cause adverse effects. In this way, the development of controlled release systems for BCZ delivery can promote the modification of drug pharmacokinetics and, consequently, decrease the dose, toxicity, and cost due to improved efficacy. This review highlights BCZ formulated in organic nanoparticles providing an overview of the physicochemical characterization and in vitro and in vivo biological evaluations. Moreover, the main advantages and limitations of the different approaches are discussed. Despite difficulties in working with antibodies, those nanocarriers provided advantages in BCZ protection against degradation guaranteeing bioactivity maintenance.


Assuntos
Bevacizumab/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Bevacizumab/administração & dosagem , Bevacizumab/química , Humanos , Nanopartículas/química
4.
Am Surg ; 87(6): 849-854, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34060947

RESUMO

BACKGROUND: Talimogene laherparepvec (TVEC) is an injectable attenuated oncolytic herpes simplex virus (HSV-1) used in the treatment of loco regionally metastatic melanoma. Lesions managed by TVEC are generally considered unresectable at time of initiation of intralesional therapy; however, a subset of patients go on to have surgical resection of loco regionally controlled disease. We sought to review our experience with surgical excision of treated lesions to offer an insight into the radiologic correlate, treatment effect, and pathological findings of intralesional TVEC therapy. METHODS: This is a retrospective descriptive case series of patients who underwent TVEC injection at Mayo Clinic, Rochester, MN, between October 2016 and July 2020. Institutional Institutional Review Board approval was obtained. RESULTS: Twenty-one patients underwent intralesional TVEC, met inclusion criteria, and were included in this series. Seven went on to surgical excision of the injected lesions after an initial course of TVEC. Of those 7 patients, 4 had residual melanoma in the specimen on final pathology, while 3 had a complete pathologic response. All 3 patients who had no residual disease on pathology continued to have fluorodeoxyglucose (FDG) avidity on preoperative positron emission tomography scan of the excised lesions. DISCUSSION: Despite ongoing FDG avidity on PET scan, patients who have well-controlled disease and stability over time of the injected lesions may benefit from surgical excision following a course of TVEC. This may render the patient clinically disease free and/or allow them a reprieve from TVEC treatment.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Produtos Biológicos/administração & dosagem , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/cirurgia , Adulto , Idoso , Terapia Combinada , Fluordesoxiglucose F18 , Herpesvirus Humano 1 , Humanos , Injeções Intralesionais , Masculino , Melanoma/diagnóstico por imagem , Pessoa de Meia-Idade , Minnesota , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Neoplasias Cutâneas/diagnóstico por imagem , Ultrassonografia
5.
Am J Nurs ; 121(7): 25, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34156377

RESUMO

Pembrolizumab (Keytruda) has been approved to treat metastatic or locally advanced esophageal or gastroesophageal junction cancer. It is used in combination with platinum- and fluoropyrimidine-based chemotherapy.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos
8.
Cancer Sci ; 112(8): 3041-3049, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34101947

RESUMO

Near-infrared photoimmunotherapy (NIR-PIT) is a cell selective cancer therapy that uses an antibody-photoabsorber (IRDye700DX, IR700) conjugate (APC) and NIR light. NIR-PIT targeting epidermal growth factor receptor (EGFR) in head and neck cancer (HNC) was conditionally approved in Japan in 2020. APC-bound tumors can be detected using endoscopic fluorescence imaging, whereas NIR light can be delivered using endoscopic fiber optics. The aims of this study were: (1) to assess the feasibility of endoscopic NIR-PIT in an orthotopic HNC model using a CD44-expressing MOC2-luc cell line; and (2) to evaluate quantitative fluorescence endoscopic imaging prior to and during NIR-PIT. The results were compared in 3 experimental groups: (1) untreated controls, (2) APC injection without light exposure (APC-IV), and (3) APC injection followed by NIR light exposure (NIR-PIT). APC injected groups showed significantly higher fluorescence signals for IR700 compared with the control group prior to therapeutic NIR light exposure, and the fluorescence signal significantly decreased in the NIR-PIT group after light exposure. After treatment, the NIR-PIT group showed significantly attenuated bioluminescence compared with the control and the APC-IV groups. Histology demonstrated diffuse necrotic death of the cancer cells in the NIR-PIT group alone. In conclusion, endoscopically delivered light combined with quantitative fluorescence imaging can be used to "see and treat" HNC. This method could also be applied to other types of cancer approachable with endoscopy.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Neoplasias de Cabeça e Pescoço/terapia , Receptores de Hialuronatos/antagonistas & inibidores , Indóis/administração & dosagem , Compostos de Organossilício/administração & dosagem , Administração Intravenosa , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Endoscopia , Estudos de Viabilidade , Feminino , Neoplasias de Cabeça e Pescoço/imunologia , Imunoterapia , Indóis/química , Indóis/farmacologia , Camundongos , Imagem Óptica , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Fototerapia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Nanomedicine ; 16: 4017-4030, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34140769

RESUMO

Purpose: This study was aimed at developing the trispecific antibodies (anti-EGFR/anti-FAP/anti-mPEG, TsAb) or dual bispecific antibodies (anti-EGFR/anti-mPEG and anti-FAP/anti-mPEG) docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micelles (mPEG-lsbPMs) for improving the targeting efficiency and therapeutic efficacy. Methods: mPEG-lsbPMs were simply prepared via thin film method. The trispecific antibodies or bispecific antibodies bound the mPEG-lsbPMs by anti-mPEG Fab fragment. The formulations were characterized by DLS and TEM; in vitro and in vivo studies were also conducted to evaluate the cellular uptake, cell cytotoxicity and therapeutic efficacy. Results: The particle sizes of mPEG-lsbPMs with or without the antibodies were around 100 nm; the formulations showed high encapsulation efficiencies of 97.12%. The TsAb and dual bispecific antibodies were fabricated and demonstrated their targeting ability. Two EGFR-overexpressed cell lines (HT-29 and MIA PaCa-2) were co-cultured with FAP-overexpressed WS1 cells (HT-29/WS1; MIA PaCa-2/WS1) to mimic a tumor coexisting in the tumor microenvironment. Cellular binding study revealed that the binding of anti-FAP micelles to three co-culture ratios (4:1, 1:1, and 1:4) of HT-29/EGFR to WS1/FAP was significantly higher than that for TsAb micelles and dual (1:1) micelles, and the binding of those targeting antibodies to WS1/FAP and MIA PaCa-2/EGFR was equally efficacious resulting in a similar binding amount of the TsAb and dual BsAbs (1:1) with the co-culture of MIA PaCa-2/EGFR and WS1/FAP at a 1:1 ratio. Antitumor efficacy study showed that treatment with DTX-loaded mPEG-lsbPMs modified with or without BsAbs, dual BsAbs (1:1), and TsAbs was enhanced in inhibiting tumor growth compared with that for Tynen® while showing fewer signs of adverse effects. Conclusion: Active targeting of both tumors and TAF-specific antigens was able to increase the affinity of DTX-loaded mPEG-lsbPMs toward tumor cells and TAFs leading to successive uptake by tumor cells or TAFs which enhanced their chemotherapeutic efficacy against antigen-positive cancer cells.


Assuntos
Anticorpos Biespecíficos/farmacologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Docetaxel/administração & dosagem , Portadores de Fármacos/química , Animais , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/química , Antineoplásicos Imunológicos/farmacocinética , Fibroblastos Associados a Câncer/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Cocultura , Docetaxel/farmacocinética , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Humanos , Injeções Intradérmicas , Lecitinas/química , Masculino , Camundongos Nus , Micelas , Tamanho da Partícula , Polietilenoglicóis/química , Ratos Sprague-Dawley , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Anticancer Res ; 41(6): 3131-3137, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083307

RESUMO

BACKGROUND/AIM: Our multicenter phase II TAS-CC3 study demonstrated favorable median progression-free survival (PFS) and overall survival (OS) of 32 metastatic colorectal cancer (mCRC) patients treated with TAS-102 + bevacizumab as 3rd-line treatment. PATIENTS AND METHODS: We investigated the predictive and prognostic values of pre-treatment blood inflammation-based scores, including the neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR) and lymphocyte-to-monocyte ratio (LMR) on disease-control (DC), PFS and OS by a post-hoc analysis. RESULTS: Receiver operating characteristic curve analyses of the 3 inflammation-based scores versus DC showed the best predictive performance for LMR, followed by NLR and PLR. The high-LMR group had a significantly higher DC rate than the low group (87.5 vs. 43.8%). The high-LMR group showed significantly longer survival than the low group (4.9 vs. 2.3 m for median PFS) (21.0 vs. 6.1 m for median OS). CONCLUSION: The pre-treatment LMR is a valid predictive and prognostic biomarker for mCRC patients undergoing TAS-102 and bevacizumab treatment.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Linfócitos/patologia , Monócitos/patologia , Metástase Neoplásica/tratamento farmacológico , Pirrolidinas/uso terapêutico , Timina/uso terapêutico , Trifluridina/uso terapêutico , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem
11.
Medicine (Baltimore) ; 100(19): e25862, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34106633

RESUMO

RATIONALE: Meningeal melanocytoma is a rare benign melanocytic tumor of the central nervous system. We report for the first time a case of meningeal melanocytoma treated with immunotherapy. PATIENT CONCERNS: A 70-year-old man with no medical history was admitted to the Emergency Room. He suffered from a motor and sensory deficit in his left lower limb and a bilateral upper arm neuralgia. DIAGNOSES: A contrast-enhanced magnetic resonance imaging (MRI) was performed. It showed a C7-T1 bleeding intramedullary tumor. Laminectomy was decided and performed. The results of the pathologic examination showed a melanocytic tumor harboring GNAQ mutation. Meningeal melanocytoma was the final diagnosis. INTERVENTIONS: The patient was treated with 10 radiotherapy sessions and 6 cycles of nivolumab. A year later, the patient experienced neuralgia again with severe pain and an increasing sensory motor deficit. He underwent a second surgery that was incomplete. As the tumor kept growing, he received temozolomide. But the 6th cycle had to be interrupted due to bedsore infection in the hip area. OUTCOMES: Disease progression finally led to the patient's death 3 years after diagnosis. LESSONS: This case report is the first about a patient with meningeal melanocytoma treated with immunotherapy. Treatment based on biomolecular mutations will probably change spinal melanocytoma therapeutic approach in the next few years.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Quimiorradioterapia Adjuvante/métodos , Melanoma/terapia , Neoplasias Meníngeas/terapia , Nivolumabe/uso terapêutico , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Humanos , Laminectomia/métodos , Masculino , Melanócitos/patologia , Melanoma/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Nivolumabe/administração & dosagem
12.
Nat Rev Clin Oncol ; 18(9): 558-576, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34006998

RESUMO

Immune-checkpoint inhibitors and chimeric antigen receptor (CAR) T cells are revolutionizing oncology and haematology practice. With these and other immunotherapies, however, systemic biodistribution raises safety issues, potentially requiring the use of suboptimal doses or even precluding their clinical development. Delivering or attracting immune cells or immunomodulatory factors directly to the tumour and/or draining lymph nodes might overcome these problems. Hence, intratumoural delivery and tumour tissue-targeted compounds are attractive options to increase the in situ bioavailability and, thus, the efficacy of immunotherapies. In mouse models, intratumoural administration of immunostimulatory monoclonal antibodies, pattern recognition receptor agonists, genetically engineered viruses, bacteria, cytokines or immune cells can exert powerful effects not only against the injected tumours but also often against uninjected lesions (abscopal or anenestic effects). Alternatively, or additionally, biotechnology strategies are being used to achieve higher functional concentrations of immune mediators in tumour tissues, either by targeting locally overexpressed moieties or engineering 'unmaskable' agents to be activated by elements enriched within tumour tissues. Clinical trials evaluating these strategies are ongoing, but their development faces issues relating to the administration methodology, pharmacokinetic parameters, pharmacodynamic end points, and immunobiological and clinical response assessments. Herein, we discuss these approaches in the context of their historical development and describe the current landscape of intratumoural or tumour tissue-targeted immunotherapies.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Citocinas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Humanos , Fatores Imunológicos/administração & dosagem , Imunoterapia/tendências , Injeções Intralesionais , Camundongos , Terapia de Alvo Molecular/métodos , Neoplasias/patologia , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Distribuição Tecidual , Microambiente Tumoral/imunologia
13.
Cancer Sci ; 112(8): 3029-3040, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34058788

RESUMO

Integrin associated protein (CD47) is an important target in immunotherapy, as it is expressed as a "don't eat me" signal on many tumor cells. Interference with its counter molecule signal regulatory protein alpha (SIRPα), expressed on myeloid cells, can be achieved with blocking Abs, but also by inhibiting the enzyme glutaminyl cyclase (QC) with small molecules. Glutaminyl cyclase inhibition reduces N-terminal pyro-glutamate formation of CD47 at the SIRPα binding site. Here, we investigated the impact of QC inhibition on myeloid effector cell-mediated tumor cell killing by epidermal growth factor receptor (EGFR) Abs and the influence of Ab isotypes. SEN177 is a QC inhibitor and did not interfere with EGFR Ab-mediated direct growth inhibition, complement-dependent cytotoxicity, or Ab-dependent cell-mediated cytotoxicity (ADCC) by mononuclear cells. However, binding of a human soluble SIRPα-Fc fusion protein to SEN177 treated cancer cells was significantly reduced in a dose-dependent manner, suggesting that pyro-glutamate formation of CD47 was affected. Glutaminyl cyclase inhibition in tumor cells translated into enhanced Ab-dependent cellular phagocytosis by macrophages and enhanced ADCC by polymorphonuclear neutrophilic granulocytes. Polymorphonuclear neutrophilic granulocyte-mediated ADCC was significantly more effective with EGFR Abs of human IgG2 or IgA2 isotypes than with IgG1 Abs, proposing that the selection of Ab isotypes could critically affect the efficacy of Ab therapy in the presence of QC inhibition. Importantly, QC inhibition also enhanced the therapeutic efficacy of EGFR Abs in vivo. Together, these results suggest a novel approach to specifically enhance myeloid effector cell-mediated efficacy of EGFR Abs by orally applicable small molecule QC inhibitors.


Assuntos
Aminoaciltransferases/antagonistas & inibidores , Antígenos de Diferenciação/química , Antineoplásicos Imunológicos/administração & dosagem , Antígeno CD47/metabolismo , Neoplasias/tratamento farmacológico , Receptores Imunológicos/química , Bibliotecas de Moléculas Pequenas/administração & dosagem , Animais , Antígenos de Diferenciação/metabolismo , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cetuximab/administração & dosagem , Cetuximab/farmacologia , Sinergismo Farmacológico , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Neoplasias/metabolismo , Panitumumabe/administração & dosagem , Panitumumabe/farmacologia , Ligação Proteica/efeitos dos fármacos , Receptores Imunológicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Transfusion ; 61(7): 2054-2063, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33960433

RESUMO

BACKGROUND: Daratumumab, a human anti-CD38 monoclonal antibody used to treat multiple myeloma, interferes with pretransfusion testing and can mask alloantibodies. Incidence of alloimmunization in patients on daratumumab has not been well characterized, and optimal transfusion guidelines regarding prophylactic antigen matching, accounting for both patient safety and efficiency, have not been well established for these patients. METHODS: Records of patients who received daratumumab between January 1, 2014 and July 2, 2019 were reviewed. Daratumumab interference with pretransfusion testing was managed by testing with reagent red blood cells (RBCs) treated with 0.2 M dithiothreitol. When daratumumab was present during antibody testing, patients were transfused with RBC units prophylactically matched for D, C, c, E, e, and K antigens per hospital policy. RESULTS: Out of 90 patients identified, 52 received a total of 638 RBC transfusions (average of 12.3 units per patient, SD 17.2, range 1-105, median 5 among those transfused). Alloantibodies existing before daratumumab initiation were identified in seven patients. No new alloantibodies were detected in any patients after starting daratumumab treatment. CONCLUSIONS: The incidence of alloimmunization in patients receiving daratumumab is low. Whether this is due to the effect of daratumumab, underlying pathophysiology, or other factors, is unknown. Because these patients require a large number of RBC transfusions overall and have little observed alloimmunization, phenotype matching (beyond RhD) may be unnecessary. Since the use of dithiothreitol cannot rule out the presence of anti-K, we recommend transfusion of ABO-compatible units, prophylactically matched for the D and K antigens only.


Assuntos
Anticorpos Monoclonais/imunologia , Antineoplásicos Imunológicos/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Artefatos , Incompatibilidade de Grupos Sanguíneos/sangue , Tipagem e Reações Cruzadas Sanguíneas , Transfusão de Sangue , Eritrócitos/imunologia , Isoanticorpos/sangue , Mieloma Múltiplo/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Antígenos de Grupos Sanguíneos/imunologia , Incompatibilidade de Grupos Sanguíneos/diagnóstico , Incompatibilidade de Grupos Sanguíneos/epidemiologia , Tipagem e Reações Cruzadas Sanguíneas/métodos , Terapia Combinada , Ditiotreitol/farmacologia , Eritrócitos/efeitos dos fármacos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Incidência , Isoanticorpos/biossíntese , Isoanticorpos/imunologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Transplante Autólogo
15.
Cancer Invest ; 39(6-7): 473-481, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34014777

RESUMO

AIM: The aim of this study is to evaluate the efficacy and toxicity of trastuzumab emtansine (T-DM1) in cases with metastatic breast cancer (mBC) in different lines of treatment. METHOD: Retrospective analysis of T-DM1 results of human epidermal growth factor receptor 2 (Her2) positive 414 cases with mBC from 31 centers in Turkey. FINDINGS: Except 2, all of the cases were female with a median age of 47. T-DM1 had been used as second-line therapy in 37.7% of the cases and the median number of T-DM1 cycles was 9. Progression-free survival (PFS) and overall survival (OS) times were different according to the line of treatment. The median OS was found as 43, 41, 46, 23 and 17 months for 1st, 2nd, 3rd, 4th and 5th line, respectively (p = 0.032) while the median PFS was found as 37, 12, 8, 8 and 8 months, respectively (p = 0.0001). Treatment was well tolerated by the patients. The most common grade 3-4 adverse effects were thrombocytopenia (2.7%) and increased serum gamma-glutamyl transferase (2%). DISCUSSION: The best of our knowledge this is the largest real-life experience about the safety and efficacy of T-DM1 use in cases with mBC after progression of Her2 targeted treatment. This study suggests and supports that T-DM1 is more effective in earlier lines of treatment and is a reliable option for mBC.


Assuntos
Ado-Trastuzumab Emtansina/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2/genética , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Turquia
16.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946818

RESUMO

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.


Assuntos
Adenocarcinoma/secundário , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias de Próstata Resistentes à Castração/terapia , Adenocarcinoma/terapia , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Ensaios Clínicos como Assunto , Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos , Previsões , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Masculino , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Estudos Multicêntricos como Assunto , Proteínas de Neoplasias/antagonistas & inibidores , Compostos Organoplatínicos/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Medicina de Precisão/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Taxoides/administração & dosagem
17.
Theranostics ; 11(13): 6293-6314, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995659

RESUMO

Radioimmunotherapy (RIT) is FDA-approved for the clinical management of liquid malignancies, however, its use for solid malignancies remains a challenge. The putative benefit of RIT lies in selective targeting of antigens expressed on the tumor surface using monoclonal antibodies, to systemically deliver cytotoxic radionuclides. The past several decades yielded dramatic improvements in the quality, quantity, recent commercial availability of alpha-, beta- and Auger Electron-emitting therapeutic radiometals. Investigators have created new or improved existing bifunctional chelators. These bifunctional chelators bind radiometals and can be coupled to antigen-specific antibodies. In this review, we discuss approaches to develop radiometal-based RITs, including the selection of radiometals, chelators and antibody platforms (i.e. full-length, F(ab')2, Fab, minibodies, diabodies, scFv-Fc and nanobodies). We cite examples of the performance of RIT in the clinic, describe challenges to its implementation, and offer insights to address gaps toward translation.


Assuntos
Radioimunoterapia/métodos , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Quelantes/administração & dosagem , Quelantes/metabolismo , Química Click , Ensaios Clínicos como Assunto , Fracionamento da Dose de Radiação , Sistemas de Liberação de Medicamentos , Previsões , Humanos , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Linfoma não Hodgkin/radioterapia , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/radioterapia , Especificidade de Órgãos , Medicina de Precisão , Tolerância a Radiação , Compostos Radiofarmacêuticos/administração & dosagem , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Anticorpos de Cadeia Única/administração & dosagem , Anticorpos de Cadeia Única/uso terapêutico , Anticorpos de Domínio Único/administração & dosagem , Anticorpos de Domínio Único/uso terapêutico , Radioisótopos de Ítrio/administração & dosagem , Radioisótopos de Ítrio/uso terapêutico
18.
Cancer Immunol Immunother ; 70(9): 2727-2735, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33837852

RESUMO

Transurethral resection of the tumor (TUR-B) followed by adjuvant intravesical treatment with cytostatic drugs or Bacillus Calmette-Guérin (BCG) as standard therapy of non-muscle-invasive bladder cancer (NMIBC) is associated with a high recurrence rate of about 60-70%, considerable side effects and requires close monitoring. Alternative treatment options are warranted. Two patients with epithelial cell adhesion molecule (EpCAM)-positive recurrent non-muscle invasive bladder cancer were treated the first time by an intravesical administration of the trifunctional bispecific EpCAM targeting antibody catumaxomab (total dosage of 470 and 1120 µg, respectively). The binding and killing activity of catumaxomab in urine milieu was evaluated in vitro. In contrast to its previous systemic application catumaxomab was well tolerated without any obvious signs of toxicity. Relevant cytokine plasma levels were not detected and no significant systemic drug release was observed. The induction of a human anti-mouse-antibody (HAMA) reaction was either absent or untypically weak contrary to the high immunogenicity of intraperitoneal applied catumaxomab. Tumor cells that were detectable in urine patient samples disappeared after catumaxomab therapy. Endoscopically confirmed recurrence-free intervals were 32 and 25 months. Our data suggest that intravesical administration of catumaxomab in NMIBC is feasible, safe and efficacious, thus arguing for further clinical development of catumaxomab in this indication.


Assuntos
Anticorpos Biespecíficos/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cistoscopia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Ligação Proteica , Retratamento , Resultado do Tratamento , Microambiente Tumoral/imunologia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/imunologia
19.
Curr Opin Oncol ; 33(4): 368-371, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33882527

RESUMO

PURPOSE OF REVIEW: Small bowel adenocarcinoma (SBA) is a rare disease, for which few studies have been conducted so far. Therefore, most treatment recommendations have been extrapolated from trials in colorectal cancer. In this review, we revise available data that could improve the management of SBA, with a particular focus on systemic therapy. RECENT FINDINGS: For advanced/irresectable disease, first-line doublet chemotherapy remains standard of care. It is uncertain whether extending treatment to triplet chemotherapy brings added benefit. Pembrolizumab is an accepted treatment modality for mismatch repair-deficient tumors, yet might also be active in microsatellite stable tumors. More trials with immunotherapy are underway. Although there is no place for anti-EGFR monotherapy, the addition of cetuximab to chemotherapy should be investigated further. Two trials suggest an added value of bevacizumab to chemotherapy, yet larger trials are needed to confirm these data. For localized disease, the role of (neo)adjuvant chemotherapy is under investigation. SUMMARY: For decades, patients with SBA have probably been treated suboptimal by basing treatment recommendations on data from colorectal cancer. An effort for SBA-specific trials and/or inclusion of SBA patients in basket trials is of utmost importance in order to improve outcome for these patients.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Intestino Delgado/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Antineoplásicos Imunológicos/administração & dosagem , Quimioterapia Adjuvante , Ensaios Clínicos Fase II como Assunto , Humanos , Neoplasias Intestinais/imunologia , Neoplasias Intestinais/patologia , Intestino Delgado/imunologia , Inibidores de Proteínas Quinases/administração & dosagem , Doenças Raras/tratamento farmacológico
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