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1.
Medicine (Baltimore) ; 98(41): e17348, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593084

RESUMO

Immune checkpoint inhibitors (ICIs) like cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and programmed death cell protein 1 (anti-PD1) have revolutionized cancer treatment. As ICI use becomes widespread, more immune-related adverse events (irAE's) are being reported. Our aim was to investigate the frequency and nature of new irAE's as well as report the frequency of flare-ups of pre-existing autoimmune conditions occurring after ICI therapy.We performed a retrospective chart review of all patients treated for cancer with anti-PD1 or anti-CTLA4 or combination therapy at our tertiary care center from January 2014 to April 2016. Demographic data, cancer type and stage, irAE's (new immune disorders and disease flares of pre-existing autoimmune disorders on ICI therapy), and drug treatment information were extracted.We identified 220 patients treated with ICI therapy during the study period out of which 27% (60/220) developed irAE's. 11% in anti-CTLA4 group and 16% among anti-PD1 treated patients developed irAE's. IrAE's resulted in discontinuation of cancer therapy in 28% of those who developed irAE's. 21.4% had a flare of their autoimmune disease but only 1 required discontinuation of immunotherapy.IrAE's are an important emerging clinical disease entity for specialists to be aware of. Our study shows that ICI's can be safely used in patients with pre-existing autoimmune conditions with close monitoring. However, there is still a large unmet need to have a better understanding of how to systematically evaluate and manage patients with irAE's as well as for identifying the predictors of irAE's.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doenças do Sistema Imunitário/induzido quimicamente , Imunoterapia/efeitos adversos , Melanoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Humanos , Doenças do Sistema Imunitário/imunologia , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos
2.
Zhonghua Gan Zang Bing Za Zhi ; 27(9): 732-736, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31594104

RESUMO

The treatment of late stage hepatocellular carcinoma (HCC) presently remains a great challenge. A very few drugs have been recently approved for clinical use except sorafenib and lenvatinib. After decades of failure and experience with molecular targeted and immunosuppressive therapy, immune checkpoint inhibitors are becoming one of the potentially effective therapies for patients with HCC, whose tumor is in the middle and late stages. Moreover, immune checkpoint is one of the main mechanisms of tumor immune evasion; of which programmed cell death protein 1 and its ligand (PD1/PD-L1) are important immune checkpoint targets, and its related pathway has shown to have an antitumor effect in a variety of solid or hematologic tumors and its inhibitors can effectively exert antitumor immunosuppressive effects. This review summarizes the current role of PD1/PD-L1 inhibitors in the treatment of late stage HCC, and explores the forecasting value of combined therapy strategy for HCC.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Humanos , Receptor de Morte Celular Programada 1/metabolismo
3.
Med Oncol ; 36(11): 94, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31605245

RESUMO

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a variety of solid tumors; nonetheless, they have not been well investigated and are still recognized as a relative contraindication for patients with a liver transplantation (LT) history, since ICIs treatment might potentially lead to graft rejection. The program death-1 (PD-1) and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways are implicated in the tolerance of transplanted organ, as well as blockade of the pathways, which contribute to eliminating tumors and may inadvertently lead to peripheral transplant rejection. Currently, no guidelines are available regarding the treatment for ICIs patients with a prior LT history. Therefore, this study was carried out to review the recent studies, attempting to introduce the ICIs-related graft rejection after LT from various aspects. We believed that ICIs could be given for the well-informed patients receiving LT and developed recurrence in a controlled setting. Typically, these patients should be treated according to a clinical care path or a prospective clinical trial, so as obtain a persistent anti-tumor immune response in the meantime of avoiding graft rejection, adjust the immunosuppression, reduce the possibility of graft loss following rejection, and have the opportunity to develop biomarkers for tumor response and transplant rejection.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Rejeição de Enxerto/induzido quimicamente , Transplante de Fígado , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Rejeição de Enxerto/imunologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
4.
Anticancer Res ; 39(9): 4995-5001, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519606

RESUMO

BACKGROUND/AIM: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) combined with non-myeloablative chemotherapy (NMA) has been shown to prolong survival in patients with metastatic disease. MATERIALS AND METHODS: Tissue harvesting was performed form a variety of sites. TILs were isolated, expanded and infused with bolus high-dose IL-2. RESULTS: Between 2008 and 2018, 242 lesions were resected for TILs harvesting from a range of sites form 196 patients without mortality and with minimal morbidity. Of those harvested, 75 were unable to complete therapy because of clinical deterioration during the wait period. Of 121 evaluable treated patients, there was no effect of metastatic site biopsied on the mean fold TIL expansion. Those receiving prior ipilimumab had a higher TIL fold expansion but a lower TIL fold expansion than those exposed to anti-PD1 therapy. CONCLUSION: Harvesting may be safely performed with successful TIL expansion from most sites. Prior check point inhibitory immunotherapy may potentially influence TIL fold expansion.


Assuntos
Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Melanoma/terapia , Adolescente , Adulto , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Feminino , Humanos , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto Jovem
5.
Zhonghua Wai Ke Za Zhi ; 57(10): 77-82, 2019 Oct 01.
Artigo em Chinês | MEDLINE | ID: mdl-31510736

RESUMO

Programmed cell death protein 1 (PD-1/CD279) and cytotoxic T Lymphocyte Antigen-4 (CTLA-4) are important immune checkpoints, through the role of the corresponding ligands and inhibit T cell activation and production of cytokines, in maintaining the body's vital role in peripheral tolerance. The use of anti-CTLA-4/PD-1 /PD-L1 monoclonal antibodies to block the tumor signaling pathway has shown excellent anti-tumor efficacy in a variety of solid tumors, and it is expected that immunotherapy will be available for the treatment of 60% advanced tumors in the next decade. Esophageal cancer is one of the major causes of cancer-related deaths worldwide, and its 5-year survival rate is generally low. Currently, radiotherapy, chemotherapy, and surgery are the standard treatments for esophageal cancer, and there is no effective treatment scheme for patients with esophageal cancer who fail to respond to standard treatment. Due to the diversity of somatic cell gene mutations and the generation of neo-antigens in esophageal cancer, immunotherapy has become a feasible treatment scheme to improve the prognosis of esophageal cancer. In this situation, the application of immunotherapy for esophageal cancer or more specific immune checkpoint inhibitors has gradually become the focus of the treatment of esophageal cancer. Nowadays, the research of immune checkpoint inhibitors, such as ipilimumab, tremelimumab, pembrolizumab, nivolumab and avelumab on esophageal cancer is proceeding at an amazing speed. The phase Ⅰ b clinical study of immunotherapy for esophageal cancer, which previously attracted great interest, has been replaced by the phase Ⅲ clinical study, and the results of the relevant studies also show a good prospect for the application of immune checkpoint inhibitors for esophageal cancer. However, the prediction of therapeutic effect and the selection of the best candidates still need to be further studied.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Esofágicas/imunologia , Humanos , Imunoterapia/métodos , Prognóstico
7.
Cancer Immunol Immunother ; 68(9): 1493-1500, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31501955

RESUMO

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.


Assuntos
Imunoterapia/métodos , Melanoma/metabolismo , Ligante OX40/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Ligante OX40/genética , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise de Sobrevida , Resultado do Tratamento
8.
Cancer Immunol Immunother ; 68(9): 1527-1535, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31535160

RESUMO

BACKGROUND: Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. METHODS: Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. RESULTS: The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n = 38; PD-1 inhibitor monotherapy, n = 20; chemotherapy alone, n = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17-0.80, P = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42-0.94, P = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31-1.10, P = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45-0.83, P = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). CONCLUSIONS: Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/terapia , Imunoterapia/métodos , Idoso , Neoplasias do Sistema Biliar/mortalidade , China , Terapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
9.
Cancer Sci ; 110(11): 3415-3423, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513320

RESUMO

Anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy, which is one of the most promising cancer therapies, is licensed for treating various tumors. Programmed death-ligand 1, which is expressed on the surface of cancer cells, leads to the inhibition of T lymphocyte activation and immune evasion if it binds to the receptor PD-1 on CTLs. Anti-PD-1/PD-L1 Abs inhibit interactions between PD-1 and PD-L1 to restore antitumor immunity. Although certain patients achieve effective responses to anti-PD-1/PD-L1 therapy, the efficacy of treatment is highly variable. Clinical trials of anti-PD-1/PD-L1 therapy combined with radiotherapy/chemotherapy are underway with suggestive evidence of favorable outcome; however, the molecular mechanism is largely unknown. Among several molecular targets that can influence the efficacy of anti-PD-1/PD-L1 therapy, PD-L1 expression in tumors is considered to be a critical biomarker because there is a positive correlation between the efficacy of combined treatment protocols and PD-L1 expression levels. Therefore, understanding the mechanisms underlying the regulation of PD-L1 expression in cancer cells, particularly the mechanism of PD-L1 expression following DNA damage, is important. In this review, we consider recent findings on the regulation of PD-L1 expression in response to DNA damage signaling in cancer cells.


Assuntos
Antígeno B7-H1/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Neoplasias/metabolismo , Medicina de Precisão , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Comunicação Celular , Pontos de Checagem do Ciclo Celular , Morte Celular/fisiologia , Dano ao DNA , Fragmentação do DNA , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/efeitos da radiação , Humanos , Ativação Linfocitária , Proteínas de Membrana/metabolismo , Instabilidade de Microssatélites , Mutação , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Nucleotidiltransferases/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA Mensageiro/metabolismo , Evasão Tumoral , Regulação para Cima
10.
Cancer Immunol Immunother ; 68(10): 1585-1596, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31515670

RESUMO

Patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) have shown benefit from anti-PD-1 therapies. However, not all patients experience tumor shrinkage, durable responses or prolonged survival, demonstrating the need to find response markers. In blood samples from NSCLC and RCC patients obtained before and after anti-PD-1 treatment, we studied leukocytes by complete blood cell count, lymphocyte subsets using flow cytometry and plasma concentration of nine soluble mediators, in order to find predictive biomarkers of response and to study changes produced after anti-PD-1 therapy. In baseline samples, discriminant analysis revealed a combination of four variables that helped differentiate stable disease-response (SD-R) from progressive disease (PD) patients: augmented frequency of central memory CD4+ T cells and leukocyte count was associated with response while increased percentage of PD-L1+ natural killer cells and naïve CD4+ T cells was associated with lack of response. After therapy, differential changes between responders and non-responders were found in leukocytes, T cells and TIM-3+ T cells. Patients with progressive disease showed an increase in the frequency of TIM-3 expressing CD4+ and CD8+ T cells, whereas SD-R patients showed a decrease in these subsets. Our findings indicate that a combination of immune variables from peripheral blood (PB) could be useful to distinguish response groups in NSCLC and RCC patients treated with anti-PD-1 therapy. Frequency of TIM-3+ T cells showed differential changes after treatment in PD vs SD-R patients, suggesting that it may be an interesting marker for monitoring progression during therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Idoso , Proteína C-Reativa/análise , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Renais/imunologia , Feminino , Receptor Celular 2 do Vírus da Hepatite A/sangue , Humanos , Neoplasias Renais/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade
11.
Magy Onkol ; 63(3): 233-238, 2019 Sep 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31533144

RESUMO

Survival of patients with lung cancer is unfavorable. Distant metastasis is detected in more than half of the patients at diagnosis. In advanced stages, platinum-based chemotherapy has been the main therapeutic approach for a long time, however, in 2004 targeted therapies emerged. Recently, PDL1/ PD-1 inhibitors have been introduced in the treatment of metastatic lung cancers, for which the therapeutic criteria are increasingly outlined. Based on international and Hungarian data, it is likely that determination of PD-L1 expression in the primary tumor samples may be sufficient for the establishment of therapeutic indication, if PD-L1 expression of tumor cells remains the sole criterion. However, if the combined positive score, which takes into account PD-L1 expression of both tumor and immune cells, will be introduced as a therapeutic criterion, testing of all the actual tumor samples may be required to initiate treatment, as conventional oncotherapies may affect the PD-L1 expression of immune cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Humanos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo
12.
Drugs Today (Barc) ; 55(8): 485-494, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31461085

RESUMO

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent type of malignancy in Caucasians worldwide. Several factors have been correlated with aggressiveness and likelihood of recurrence and distant metastases, which are challenging to control. Metastatic disease has a dismal prognosis, and standard chemotherapy has failed to significantly improve outcomes. Recently, it has been recognized that cSCCs are highly mutated tumors with a denoting potential likelihood of response to immune checkpoint blockade. Cemiplimab is an anti-programmed cell death protein 1 (PD-1) antibody recently approved for the treatment of unresectable locally advanced or metastatic cSCC by the U.S. Food and Drug Administration (FDA) and the European Commission with a compelling response rate and an acceptable safety profile.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia
13.
JAMA ; 322(8): 764-774, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31454018

RESUMO

Importance: Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease. Observations: Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of ≥50%) and 40% among patients with ALK-positive tumors. Conclusions and Relevance: Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Pontos de Checagem do Ciclo Celular , Genes erbB-1 , Humanos , Imunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Intervalo Livre de Progressão , Taxa de Sobrevida
14.
Clin Exp Rheumatol ; 37 Suppl 118(3): 114-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31464670

RESUMO

OBJECTIVES: To analyse the worldwide occurrence of sicca/Sjögren's (SS) syndrome associated with the use of immune checkpoint inhibitors (ICI) in patients with cancer. METHODS: The ImmunoCancer International Registry (ICIR) is a Big Data-Sharing multidisciplinary network composed by 40 specialists in Rheumatology, Internal Medicine, Immunology and Oncology from 18 countries focused on the clinical and basic research of the immune-related adverse events (irAEs) related to cancer immunotherapies. For this study, patients who were investigated for a clinical suspicion of SS after being exposed to ICI were included. RESULTS: We identified 26 patients (11 women and 15 men, with a mean age at diagnosis of 63.57 years). Underlying cancer included lung (n=12), renal (n=7), melanoma (n=4), and other (n=3) neoplasia. Cancer immunotherapies consisted of monotherapy (77%) and combined regimens (23%). In those patients receiving monotherapy, all patients were treated with PD-1/PD-L1 inhibitors (nivolumab in 9, pembrolizumab in 7 and durvalumab in 4); no cases associated with CTLA-4 inhibitors were identified. The main SS-related features consisted of dry mouth in 25 (96%) patients, dry eye in 17 (65%), abnormal ocular tests in 10/16 (62%) and abnormal oral diagnostic tests in 12/14 (86%) patients. Minor salivary gland biopsy was carried out in 15 patients: histopathological findings consisted of mild chronic sialadenitis in 8 (53%) patients and focal lymphocytic sialadenitis in the remaining 7 (47%); a focus score was measured in 5 of the 6 patients (mean of 1.8, range 1-4). Immunological markers included positive ANA in 13/25 (52%), anti-Ro/ SS-A in 5/25 (20%), RF in 2/22 (9%), anti-La/SS-B in 2/25 (8%), low C3/C4 levels in 1/17 (6%) and positive cryoglobulins in 1/10 (10%). Classification criteria for SS were fulfilled by 10 (62%) out of 16 patients in whom the two key classificatory features were carried out. Among the 26 patients, there were only 3 (11%) who presented exclusively with sicca syndrome without organ-specific autoimmune manifestations. Therapeutic management included measures directed to treat sicca symptoms and therapies against autoimmune-mediated manifestations (glucocorticoids in 42%, second/third-line therapies in 31%); therapeutic response for systemic features was observed in 8/11 (73%). No patient died due to autoimmune involvement. CONCLUSIONS: Patients with Sjögren's syndrome triggered by ICI display a very specific profile different from that reported in idiopathic primary SS, including more frequent occurrence in men, a higher mean age, a predominant immunonegative serological profile, and a notable development of organ-specific autoimmune involvement in spite of the poor immunological profile. The close association found between sicca/Sjögren's syndrome and primarily PD-1 blockade requires further specific investigation.


Assuntos
Antígeno B7-H1 , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Síndrome de Sjogren , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Glândulas Salivares Menores , Síndrome de Sjogren/imunologia
16.
Cancer Immunol Immunother ; 68(9): 1417-1428, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31422446

RESUMO

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4+ and CD8+ T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Eosinófilos/imunologia , Imunoterapia/métodos , Interleucina-2/uso terapêutico , Melanoma/terapia , Neoplasias Cutâneas/terapia , Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inflamação , Ativação Linfocitária , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/imunologia , Regulação para Cima
17.
Cancer Immunol Immunother ; 68(9): 1467-1477, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31451841

RESUMO

BACKGROUND: The lethal effects of multiple antigen-specific cellular therapy (MASCT) may be enhanced by blocking PD-1 in vitro and vascular endothelial growth factor receptor 2 inhibitor (apatinib). We analyzed the pooled data from our phase I/II trials to determine the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in advanced solid tumors. METHODS: Patients with advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The safety profile was the primary end point. The secondary end points were antitumor response, progression-free survival (PFS), and overall survival (OS). The circulating T cells were quantified before and after aMASCT infusion. RESULTS: Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate (34.2% and 18.8%) and PFS (median 6.0 and 4.5 months, P = 0.002) were improved in the aMASCT plus apatinib group compared with the aMASCT group; however, the OS was not improved (median 10.0 and 8.2 months, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent and favorable prognostic factor of PFS and OS. The circulating T cells increased and Tregs decreased in both groups after one cycle of aMASCT treatment. CONCLUSIONS: Treatment with aMASCT plus apatinib was safe and effective for the management of advanced solid tumors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Células Dendríticas/imunologia , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Piridinas/uso terapêutico , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos de Neoplasias/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Células Dendríticas/transplante , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Prospectivos , Piridinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Análise de Sobrevida
18.
Cancer Immunol Immunother ; 68(10): 1689-1700, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31375885

RESUMO

Immunotherapy aims to activate the immune system to fight cancer in a very specific and targeted manner. Despite the success of different immunotherapeutic strategies, in particular antibodies directed against checkpoints as well as adoptive T-cell therapy, the response of patients is limited in different types of cancers. This attributes to escape of the tumor from immune surveillance and development of acquired resistances during therapy. In this review, the different evasion and resistance mechanisms that limit the efficacy of immunotherapies targeting tumor-associated antigens presented by major histocompatibility complex molecules on the surface of the malignant cells are summarized. Overcoming these escape mechanisms is a great challenge, but might lead to a better clinical outcome of patients and is therefore currently a major focus of research.


Assuntos
Imunoterapia/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Evasão Tumoral , Apresentação do Antígeno , Antígenos HLA-G/fisiologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos
19.
Gynecol Oncol ; 155(1): 51-57, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31421916

RESUMO

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC), yet little is known about their effects on subsequent treatment. Preclinical studies suggest immunotherapy may enhance response to chemotherapy. We sought to evaluate the impact of ICIs on subsequent therapies and survival in recurrent OC. METHODS: A retrospective review was conducted to identify women with recurrent OC who received ICI from 01/2013 to 5/2017 and ≥1 subsequent treatment. Treatment duration after ICI was calculated using time-to-event analysis. Kaplan-Meier survival analysis and Cox proportional hazards models were used to calculate overall survival (OS) from first treatment after ICI and to assess survival differences by clinical benefit from ICI, defined by long (≥24 weeks) versus short (<24 weeks) ICI treatment duration. RESULTS: Of 79 evaluable women identified, 66 (84%) had platinum-resistant OC. Median age at diagnosis was 57 years. Median time from diagnosis to ICI was 39.7 months, with median of 4 prior treatments (range, 1-12). Median number of treatments after ICI was 2 (range, 1-8). Median duration of first-line treatment after ICI was 3.7 months (95% CI, 2.9-6.0) and declined with each subsequent line. The most common therapies after ICI were taxanes, platinum-based regimens, and pegylated liposomal doxorubicin. Bevacizumab was used in 47 women (59%). Median OS after ICI was 18.3 months (95% CI, 11.8-22.7) and did not differ between long versus short ICI. CONCLUSIONS: In this heavily pretreated population of patients with recurrent OC, therapies after ICI resulted in promising survival, suggesting that ICI may improve efficacy of subsequent chemotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Antígeno B7-H1/antagonistas & inibidores , Bevacizumab/administração & dosagem , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , New York/epidemiologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos , Adulto Jovem
20.
Expert Opin Investig Drugs ; 28(8): 695-708, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31359805

RESUMO

Introduction: Immunotherapy has revolutionized the treatment of cancer. Given this growing success, at the same time, there are significant limitations and unanswered questions concerning response rates, duration of therapy, why some patients respond and others do not, and if combining different immune-agents would overcome this lack of response, increase the chance of success and postpone acquired resistance. Areas covered: The comprehension of how to properly modulate the immune pathways, the molecular and the immunological bases of the disease, will be fundamental to guide the development of therapeutic interventions and combinations that will be more suitable for treatment of cancer patients. In this review, we discuss the strategies of immunotherapy combinations in order to develop more effective immunotherapy programs, with a particular focus on melanoma and renal cancer patients, as well as the combination of immunotherapy and chemotherapy. Expert Opinion: Given the complexity of immune activation, combinatorial approaches are needed, and due to the considerable variability in tumor biology across patients and tumor types, patient selection and biomarkers need to be further explored. In summary, combined therapies have shown promising success, but additional and continuous research to identify the safety, efficacy, optimal combination, dosage and timing are still required.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Imunoterapia/métodos , Neoplasias/terapia , Animais , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Humanos , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Melanoma/imunologia , Melanoma/terapia , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
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