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1.
Cancer Immunol Immunother ; 68(10): 1661-1669, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31606777

RESUMO

BACKGROUND: We previously found that PD-L1 expression is increased on tumor cells following vaccination treatments that lead to increased tumor-specific T cells that secrete IFNγ. Indoleamine 2,3-dioxygenase (IDO) is another IFNγ inducible gene that has potent immunosuppressive effects. There have been reports of IDO expression in prostate cancer; however, it is unknown whether IDO expression might similarly increase in prostate tumors following T-cell-based immunotherapy. METHODS: Blood samples from normal male blood donors (n = 12) and patients with different stages of prostate cancer (n = 89), including patients with metastatic, castration-resistant prostate cancer treated with a DNA vaccine and/or pembrolizumab, were evaluated for IDO activity by kynurenine and tryptophan levels. Metastatic tissue biopsies obtained pre- and post-treatments were evaluated for IDO expression. IDO suppression of vaccine-induced T-cell function was assessed by ELISPOT. RESULTS: Overall, IDO activity was increased in patients with more advanced prostate cancer. This activity, and IDO expression as detected immunohistochemically, increased following treatment with either a DNA vaccine encoding the prostatic acid phosphatase (PAP) tumor antigen or PD-1 blockade with pembrolizumab. Increased IDO activity after treatment was associated with the absence of clinical effect, as assessed by lack of PSA decline following treatment. Increased antigen-specific T-cell response, as measured by IFNγ release, to the vaccine target antigen was detected following in vitro stimulation of peripheral blood cells with 1-methyltryptophan. CONCLUSIONS: These findings suggest that IDO expression is a mechanism of immune evasion used by prostate cancer and that future clinical trials using T-cell-based immune strategies might best include IDO inhibition.


Assuntos
Vacinas Anticâncer/administração & dosagem , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Linfócitos T/efeitos dos fármacos
2.
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
3.
Medicine (Baltimore) ; 98(38): e17257, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567999

RESUMO

Recent availability of immune checkpoint inhibitors has facilitated research involving programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1). However, the incidence and clinical implication of PD-1 and PD-L1 expression in prostate cancer remain poorly understood. The current study aimed to determine the status of PD-1/PD-L1 expression in prostate cancer specimens and its prognostic significance.We immunohistochemically stained for PD-1 and PD-L1 in our tissue microarray (TMA) consisting of radical prostatectomy specimens. The expression of PD-1/PD-L1 was designated as positive when moderate to strong staining or weak staining was seen in at least 1% or 10%, respectively, of tumor cells and/or associated immune cells. We then evaluated the relationship between the expression of each protein and clinicopathological features available for our patient cohort.PD-1 and PD-L1 were positive in 3 (1.5%) and 1 (0.5%) of 201 non-neoplastic prostate tissues, and also in 17 (7.7%) and 29 (13.2%) of 220 prostate cancers, respectively. PD-1 and PD-L1 were also expressed in tumor-infiltrating lymphocytes/macrophages in 172 (78.2%) and 33 (15.0%) cases, respectively. PD-L1 expression in tumor cells was more often seen in high pT stage (pT2: 10.8% vs pT3/4: 20.4%; P = .072; pT2/3a: 11.4% vs pT3b/4: 31.6%; P = .013) or lymph node-positive (pN0: 10.1% vs pN1: 27.3%; P = .086) cases, whereas PD-1 expression in tumor cells was not significantly associated with pT/pN stage. In addition, there were no statistically significant associations between PD-1/PD-L1 expression in tumor cells or tumor-infiltrating lymphocytes/macrophages versus patient age, preoperative prostate-specific antigen level, or Gleason score. Kaplan-Meier analysis coupled with log-rank test further revealed no significant associations between PD-1/PD-L1 expression in tumor cells (P = .619/P = .315), tumor-infiltrating lymphocytes/macrophages (P = .954/P = .155), or either or both of them (P = .964/P = .767) versus disease recurrence after radical prostatectomy.PD-1/PD-L1 expression was detected in a subset of prostate cancers. In particular, PD-L1 expression was considerably up-regulated in nonorgan-confined tumors. However, PD-1/PD-L1 expression in our TMA was found to be not very helpful in predicting tumor recurrence in prostate cancer patients who underwent radical prostatectomy.


Assuntos
Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Próstata/metabolismo , Antígeno B7-H1/imunologia , Biomarcadores , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Análise Serial de Tecidos
4.
Nature ; 574(7779): 565-570, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645726

RESUMO

Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement.


Assuntos
Antígenos B7/química , Antígenos B7/metabolismo , Glicoproteínas de Membrana/metabolismo , Linfócitos T/metabolismo , Animais , Anticorpos Bloqueadores/imunologia , Anticorpos Bloqueadores/farmacologia , Antígenos B7/antagonistas & inibidores , Antígenos B7/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Cristalografia por Raios X , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Feminino , Histidina/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
5.
Cancer Immunol Immunother ; 68(10): 1635-1648, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31549214

RESUMO

Pancreatic cancer has been termed a 'recalcitrant cancer' due to its relative resistance to chemotherapy and immunotherapy. This resistance is thought to be due in part to the dense fibrotic tumor microenvironment and lack of tumor infiltrating CD8 + T cells. The gastrointestinal peptide, gastrin, has been shown to stimulate growth of pancreatic cancer by both a paracrine and autocrine mechanism. Interruption of gastrin at the CCK receptor may reduce tumor-associated fibrosis and alter tumor immune cells. Polyclonal Ab Stimulator (PAS) is a vaccine that targets gastrin and has been shown to prolong survival of patients with pancreatic cancer. Here, we report that PAS vaccination monotherapy elicits both a humoral and cellular immune response when used in immune competent mice-bearing pancreatic tumors and that PAS monotherapy produced a marked T-cell activation and influx of CD8 + lymphocytes into pancreatic tumors. Isolated peripheral lymphocytes elicited cytokine release upon re-stimulation with gastrin in vitro demonstrating specificity of immune activation for the target peptide. Combination therapy with PAS and PD-1 Ab activated CD4 -/CD8 - TEMRA cells important in T-cell-mediated tumor death and memory. Tumors of mice treated with PAS (250 µg) or PAS (100 and 250 µg) in combination with a PD-1 Ab were significantly smaller compared to tumors from PBS or PD-1 Ab-treated mice. When PAS was given in combination with PD-1 Ab, tumors had less fibrosis, fewer inhibitory Treg lymphocytes, and fewer tumor-associated macrophages. These findings reveal a novel approach to improve treatment strategies for pancreatic cancer.


Assuntos
Vacinas Anticâncer/imunologia , Gastrinas/imunologia , Neoplasias Pancreáticas/terapia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral , Vacinação , Animais , Linhagem Celular Tumoral , Memória Imunológica , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Linfócitos T/imunologia
6.
Zhonghua Zhong Liu Za Zhi ; 41(9): 641-647, 2019 Sep 23.
Artigo em Chinês | MEDLINE | ID: mdl-31550852

RESUMO

Over the past decades, although the clinical efficacy of advanced head and neck squamous cell carcinoma (HNSCC) has been moderately improved by the combination of cetuximab and chemotherapy, no remarkable treatment has emerged. The prognosis of HNSCC is still unsatisfied. With the deeper exploration of tumor immunological therapy, immunocheckpoint inhibitors such as monoclonal antibodies targeting on programmed cell death protein 1 (PD-1)/ cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have shown appreciable anti-tumor effect on cancers such as melanoma and non-small cell lung cancer. Some successful clinical studies on HNSCC have also been reported, which provide a new opportunity for the improvement of HNSCC prognosis.Here we systemically review the progress of checkpoint inhibitors and its combination therapy in HNSCC, some immunotherapy efficacy-related biomarkers are also discussed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Antígeno CTLA-4/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Receptor de Morte Celular Programada 1/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
7.
Semin Oncol ; 46(3): 261-270, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31537299

RESUMO

Deficient DNA mismatch repair causes a robust mutator phenotype known as microsatellite instability (MSI). MSI is a feature of Lynch syndrome-related cancers and is also found in approximately 15% of sporadic gastric, colorectal, and endometrial cancers. Epigenetic inactivation of the MLH1 gene is often associated with sporadic MSI cancers. Recent next-generation sequencing (NGS)-based analyses have comprehensively characterized MSI-positive (MSI+) cancers, and several approaches for detecting the MSI phenotype of tumors using NGS have been developed. The FDA has recently granted accelerated approval to an anti-PD-1 antibody, pembrolizumab, for use in pediatric and adult patients with MSI+ solid tumors. Genome-wide analyses using NGS have revealed that hypermutation defined as >10 somatic mutations per megabase appears to be more prevalent than previously estimated, affecting approximately 17% of adult cancers. These results potentially expand the use of immunotherapy, which is thought to be effective in cancers with an increased mutational burden. Therefore, evaluation of MSI and MSI-associated molecular changes in tumors has emerged as clinically important. MSI is a valuable diagnostic marker of Lynch syndrome and a potential predictive marker for chemotherapy and immunotherapy efficacy. Here, we provide an update on MSI-associated cancers, focusing on findings obtained by genome-wide analyses using NGS, and the predictive role of MSI in immune checkpoint immunotherapy.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL/genética , Neoplasias/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Medicina de Precisão , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
8.
Chemotherapy ; 64(2): 62-80, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31387102

RESUMO

BACKGROUND: Immune checkpoints are critical regulatory pathways of the immune system which finely tune the response to biological threats. Among them, the CD-28/CTLA-4 and PD-1/PD-L1 axes play a key role in tumour immune escape and are well-established targets of cancer immunotherapy. SUMMARY: The clinical experience accumulated to date provides unequivocal evidence that anti-CTLA-4, PD-1, or PD-L1 monoclonal antibodies, used as monotherapy or in combination regimes, are effective in a variety of advanced/metastatic types of cancer, with improved clinical outcomes compared to conventional chemotherapy. However, the therapeutic success is currently restricted to a limited subset of patients and reliable predictive biomarkers are still lacking. Key Message: The identification and characterization of additional co-inhibitory pathways as novel pharmacological targets to improve the clinical response in refractory patients has led to the development of different immune checkpoint inhibitors, the activities of which are currently under investigation. In this review, we discuss recent literature data concerning the mechanisms of action of next-generation monoclonal antibodies targeting LAG-3, TIM-3, and TIGIT co-inhibitory molecules that are being explored in clinical trials, as single agents or in combination with other immune-stimulating agents.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias/tratamento farmacológico , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Ensaios Clínicos como Assunto , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Microambiente Tumoral
9.
Cancer Sci ; 110(10): 3079-3088, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432594

RESUMO

Chimeric antigen receptor-engineered T (CAR-T)-cell therapy holds significant promise for the treatment of hematological malignancies, especially for B-cell leukemia and lymphoma. However, its efficacy against non-hematological malignancies has been limited as a result of several biological problems characteristic of the tumor microenvironment of solid tumors. One of the main hurdles is the heterogeneous nature of tumor-associated antigens (TAA) expressed in solid tumors. Another hurdle is the inefficient activation and limited persistence of CAR-T cells, mainly as a result of T-cell exhaustion caused by immunosuppressive factors in the tumor microenvironment. In the present study, to address these problems, we engineered CAR-T cells to produce antagonistic anti-programmed cell death protein 1 (PD-1) single-chain variable fragment (scFv), by which PD-1-dependent inhibitory signals in CAR-T cells and adjacent tumor-specific non-CAR-T cells are attenuated. In mouse solid tumor models, PD-1 scFv-producing CAR-T cells induced potent therapeutic effects superior to those of conventional CAR-T cells, along with a significant reduction of apoptotic cell death not only in CAR-T cells themselves but also in TAA-specific T cells in the tumor tissue. In addition, the treatment with anti-PD-1 scFv-producing CAR-T cells resulted in an increased concentration of PD-1 scFv in tumor tissue but not in sera, suggesting an induction of less severe systemic immune-related adverse events. Hence, the present study developed anti-PD-1 scFv-producing CAR-T cell technology and explored its cellular mechanisms underlying potent antitumor efficacy.


Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Anticorpos de Cadeia Única/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Técnicas de Cocultura , Masculino , Camundongos , Neoplasias/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Carbohydr Polym ; 222: 114993, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31320068

RESUMO

ß-glucans trigger the proinflammatory responses of innate immune cells to enhance the host defense. A variety of ß-glucans were identified as strong immune stimulator and exerted antitumor activities. Our previous work indicates that a ß-1,3/1,6-glucan (BG136) derived from marina alga Durvillaea antarctica promotes the proinflammatory responses in macrophage cell line RAW264.7. In the present study, we further explored its antitumor effects in vivo as an immune stimulator. The data shows that BG136 alone decreases the tumor burdens in DLD1 xenograft and AOM-DSS induced tumor models. BG136 also augments the antitumor effects of PD-1 antibody in B16 syngeneic tumor model. BG136 increases macrophage phagocytosis, enhances cytokine/chemokine secretion and modulates the systemic and intratumoral immune cell composition. Collectively, these data suggest that BG136 might act as an immune stimulator to exert antitumor effects in vivo.


Assuntos
Adjuvantes Imunológicos/farmacologia , Glucanos/farmacologia , Neoplasias/imunologia , Animais , Linhagem Celular Tumoral , Citocinas/imunologia , Humanos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Feófitas/metabolismo , Fagocitose/efeitos dos fármacos , Receptor de Morte Celular Programada 1/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
Crit Rev Oncol Hematol ; 142: 35-43, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31357142

RESUMO

Programmed cell death-1 (PD-1) receptor and its ligands physiologically regulate the activity of the adaptive immune system to limit excessive inflammatory processes, thus preventing normal tissue damage. Tumor cells escape from the host immune surveillance using this pathway, rendering it relevant therapeutic target. Despite the relevant clinical efficacy observed in patients with solid and hematological malignancies, the clinical benefit of these novel treatments is limited to a relatively restricted number of patients. A wide amount of genomic and immune related features is currently under investigation as potential predictive biomarkers for treatment selection. The results obtained so far are encouraging but still imperfect. Combination strategies using different immunotherapeutic agents or with other treatments (such as chemotherapy) are being investigated, showing promising but still not completely satisfactory results. This review aims to shed light on the main principles of targeting PD-1 in breast cancer, from biology through its functional and clinical implications.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Imunoterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Feminino , Humanos , Receptor de Morte Celular Programada 1/imunologia
12.
Medicine (Baltimore) ; 98(27): e16324, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277179

RESUMO

BACKGROUND: Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) drugs treatment-related adverse events (AEs) are not uniform based on current study for patients with cancer. The study aimed to provide a complete toxicity profile and toxicity spectrum for anti-PD-1 and anti-PD-L1 drugs. METHODS: All systematic reviews (SRs) with meta-analyses (MAs) relate to the anti-PD-1 and anti-PD-L1 drugs and SRs will be searched in the database of PubMed, Embase, Cochrane Library, and Web of Science from inception to February 2019. Eligible publications must have reported site, organ, or system level data on treatment-related AEs. The following will extract from each SRs: first author, year of publication, country of origin, number of origin study, number of patients enrolled, participant characteristics, duration of cancer diagnosis, cancer types, detailed description of treatment, and occurrence of AEs. Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) and A Measurements Tool to Assess Systematic Reviews 2 (AMSTAR-2) will be used to assess the reporting and methodological quality of SRs/MAs. The characteristics of the included SRs/MAs and their quality will descriptively summarized using systematically structured tables. A network meta-analysis (NMAs) approach versus a narrative synthesis will be used to examine data synthesis considered. Odds ratios and 95% credibility intervals will be used as summary statistics. Evidence mapping (EM) method will to present the evidence landscape related to anti-PD-1 and anti-PD-L1 drugs treatment-related AEs for patients with cancer. DISCUSSION: The results of the overview will be submitted to a peer-reviewed journal for publication. ETHICS AND DISSEMINATION: Because this study is not a clinical study, and we will search and evaluate only existing sources of literature. So, ethical approval is not required.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/imunologia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/imunologia , Humanos , Metanálise como Assunto , Revisão Sistemática como Assunto
13.
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
14.
Nat Immunol ; 20(9): 1231-1243, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358999

RESUMO

Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Glicoproteínas de Membrana/metabolismo , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , ADP-Ribosil Ciclase 1/genética , Animais , Anticorpos/imunologia , Linfócitos T CD8-Positivos/patologia , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Imunoterapia/métodos , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/imunologia
15.
Cancer Sci ; 110(9): 2711-2721, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31294893

RESUMO

The percentage of programmed death ligand 1 (PD-L1) positivity in cancer cells, named as the tumor proportion score, is considered to be a predictive biomarker for anti-PD-1/PD-L1 therapy in lung cancer. PD-L1 is expressed on not only cancer cells but also on immune cells, including macrophages. Although previous studies related to PD-L1/2 expression in cancer tissues have been generally based on single immunohistochemistry (IHC), in the present study, we attempted to evaluate accurate PD-L1/2 expression in cancer cells in lung adenocarcinoma cells using double IHC to also evaluate macrophages. Of the 231 patients, PD-L1 expression was negative in 169 patients (73.2%), 1%-49% positive in 47 patients (20.3%), and ≥50% positive in 15 patients (6.5%). Interestingly, PD-L1 positivity was decreased when using double IHC compared with the estimation by single IHC. High PD-L1 expression was associated with high-grade cancer cells and in higher stage cancer. PD-L2 was negative in 109 patients (47.2%), 1%-49% positive in 50 patients (21.6%), and ≥50% positive in 72 patients (31.2%). The number of PD-L2-positive patients was increased in cases that had an epidermal growth factor receptor (EGFR) mutation and in lower stage cancer. Thirty-five patients (15.2%) were positive for both PD-L1 and PD-L2, whereas 81 patients (35.1%) were negative for both PD-L1 and PD-L2. Log-rank analysis showed that progression-free survival and overall survival were significantly the longest in the PD-L1-negative and PD-L2-positive groups (P < .0001 and P = .0120). We observed lower PD-L1 or PD-L2 expression in lung adenocarcinoma than previously reported. Double IHC for macrophages may help clinicians to evaluate PD-L1 or PD-L2 expression specifically in cancer cells.


Assuntos
Adenocarcinoma de Pulmão/patologia , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/análise , Neoplasias Pulmonares/patologia , Proteína 2 Ligante de Morte Celular Programada 1/análise , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/imunologia , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imuno-Histoquímica/métodos , Pulmão/citologia , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Resultado do Tratamento
16.
Anticancer Res ; 39(7): 3917-3921, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262921

RESUMO

AIM: To evaluate the efficacy and safety of re-treatment with anti-programmed death (PD)-L1 antibody (atezolizumab) after anti-PD-1 antibody (nivolumab/pembrolizumab) treatment in advanced non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: We retrospectively reviewed 18 NSCLC patients who received atezolizumab after anti-PD-1 antibody treatment. Data on patient characteristics, number of cycles of anti-PD-1 antibody and atezolizumab, regimens between anti-PD-1 antibody and atezolizumab, best response, and immune-related adverse events (irAEs) were collected and analyzed. RESULTS: Nine patients a had high (≥50%) PD-L1 expression. The median number of cycles of atezolizumab was 3 (range=2-7). The median progression-free survival was 2.9±1.8 months. Seven (38.9%) and 11 (61.1%) patients had stable and progressive disease, respectively. No patient achieved partial or complete response. There were no significant differences in the occurrence of irAEs between anti-PD-1 antibodies and atezolizumab. CONCLUSION: Preliminary results showed that patients previously treated with anti PD-1 antibodies received only limited benefit from subsequent atezolizumab.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Retratamento , Estudos Retrospectivos , Resultado do Tratamento
17.
Biophys Chem ; 253: 106213, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31276987

RESUMO

The interaction event between programmed death receptor-1 (PD-1) and its ligand (PD-L1) functions as an essential immune checkpoint against cytotoxic T effector cell activation. Previously, a number of small-molecule inhibitors and antibody drugs have been successfully developed to block the PD1/PDL1 signaling axis for breast cancer immunotherapy. Here, we attempt to directly disrupt the formation of PD-1/PD-L1 complex by using a self-inhibitory peptide (SIP) strategy. In the procedure, the complex crystal structure is examined systematically with energetic analysis and alanine scanning. Two double-stranded segments I and II in PD-L1 active finger are identified as hotspot regions; they directly interact with the amphipathic pocket of PD-1 to form the complex system. The segments are derived from PD-L1 to define two SIP peptides, namely, DS-I and DS-II, which are thought to have capability of rebinding at the complex interface, thus disrupting PD-1/PD-L1 interaction as a new immune checkpoint blockade. A further analysis reveals that the free linear DS-I and DS-II peptides are highly flexible without protein context support, which would incur a large entropy penalty (unfavorable indirect readout effect) when rebinding to PD-1. Next, intramolecular cyclization is applied to constraining the intrinsically disordered conformation of free DS-II peptide into native ordered double-stranded configuration, which can be substantiated by molecular dynamics simulation and circular dichroism spectroscopy. Several cyclized counterparts of linear DS-II peptide are designed and their affinities to PD-1 are determined using fluorescence polarization assays. As might be expected, three designed cyclic peptides DS-II[c111-127], ΔDS-II[c111-127] and ΔDS-II[c110-128] exhibit considerably increased potency (Kd = 28.0 ±â€¯4.2, 17.5 ±â€¯3.1 and 11.6 ±â€¯2.3 µM, respectively) relative to linear DS-II peptide (Kd = 109 ±â€¯15 µM).


Assuntos
Antígeno B7-H1/imunologia , Neoplasias da Mama/terapia , Imunoterapia , Peptídeos/imunologia , Receptor de Morte Celular Programada 1/imunologia , Antígeno B7-H1/química , Neoplasias da Mama/imunologia , Dicroísmo Circular , Ciclização , Feminino , Humanos , Simulação de Dinâmica Molecular , Peptídeos/síntese química , Peptídeos/química , Receptor de Morte Celular Programada 1/química , Conformação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Linfócitos T Citotóxicos/imunologia
18.
Int J Clin Oncol ; 24(10): 1171-1181, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321613

RESUMO

Immune checkpoint inhibitors targeting the cytotoxic T lymphocyte-associated antigen-4 and programmed cell death-1 receptors have transformed the treatment of melanoma and other cancers. These therapies are associated with a number of side effects, including immune-related adverse events. Sarcoidosis-like granulomas (SLGs) are important immune checkpoint inhibitor-related reactions to recognize as SLGs can mimic disease progression and accordingly impact treatment decisions. We systematically review reports of immune checkpoint inhibitor-induced SLGs in cancer patients and discuss potential underlying pathophysiological mechanisms.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Granuloma/induzido quimicamente , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sarcoidose/induzido quimicamente , Antígeno CTLA-4/imunologia , Granuloma/patologia , Humanos , Receptor de Morte Celular Programada 1/imunologia , Sarcoidose/patologia
19.
Oncology ; 97(4): 228-235, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31216560

RESUMO

BACKGROUND: Immuno-oncological (IO) therapies such as PD-1 and PD-L1 antibodies have been introduced in the treatment of advanced non-small cell lung cancer (NSCLC) since 2015 based on randomized trials showing unprecedented advantages in overall survival (OS) with hazard ratios (HRs) between 0.5 and 0.7. The impact of these treatments on OS in routine clinical practice and the role of tumor mass have not been studied. METHODS: 557 consecutive patients with inoperable stage III or stage IV NSCLC diagnosed in our certified lung cancer center from 2006 to 2018 were included if they had received at least one line of systemic treatment. OS of immuno-oncologically treated patients (IO patients, n = 144) who received treatment with a PD-1 antibody (nivolumab [n = 77] or pembrolizumab [n = 51]) or a PD-L1 antibody (atezolizumab [n = 4] or durvalumab [n = 12]) was compared to historic controls treated before availability of IO treatment (n = 413) using case-control analysis. IO patients and historic controls were individually matched for stage, performance state, histology, smoking status, gender, age, and initial treatment mode (palliative vs. definitive radio-chemotherapy). RESULTS: Case-control analysis of 91 matched pairs showed significantly longer OS in IO patients compared to historic controls (21.2 vs. 10.9 months, HR 0.526, CI 0.373-0.723). The benefit was more pronounced in patients with lower tumor stage (HR 0.48 [stage III], 0.40 [IVA], 0.63 [IVB]) or smaller tumor size (HR 0.38 [RECIST ≤57 mm], 0.40 [RECIST 58-94 mm], 0.59 [RECIST 95-141 mm], 0.75 [RECIST ≥142 mm]). CONCLUSIONS: IO patients showed significant benefit in OS with HRs comparable to those reported in phase III trials. The benefit tended to be greater in patients with lower tumor mass.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento
20.
Nat Commun ; 10(1): 2782, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31239444

RESUMO

Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N6-methyladenosine (m6A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. FTO level is increased in human melanoma and enhances melanoma tumorigenesis in mice. FTO is induced by metabolic starvation stress through the autophagy and NF-κB pathway. Knockdown of FTO increases m6A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m6A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m6A demethylase in promoting melanoma tumorigenesis and anti-PD-1 resistance, and suggest that the combination of FTO inhibition with anti-PD-1 blockade may reduce the resistance to immunotherapy in melanoma.


Assuntos
Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Anticorpos Monoclonais/administração & dosagem , Melanoma/enzimologia , Melanoma/terapia , Adenosina/genética , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Animais , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Desmetilação , Feminino , Humanos , Imunoterapia , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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