RESUMO
BACKGROUND: Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma. METHODS: In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. RESULTS: Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling. CONCLUSIONS: Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Doença de Hodgkin/tratamento farmacológico , Imunoterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Brentuximab Vedotin , Feminino , Doença de Hodgkin/metabolismo , Doença de Hodgkin/terapia , Humanos , Imunoconjugados/uso terapêutico , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Nivolumabe , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Recidiva , Células de Reed-Sternberg/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Transplante de Células-TroncoRESUMO
BACKGROUND: Programmed death 1 (PD-1) signaling in the tumor microenvironment dampens immune responses to cancer, and blocking this axis induces antitumor effects in several malignancies. Clinical studies of PD-1 blockade are only now being initiated in pediatric patients, and little is known regarding programmed death-ligand 1 (PD-L1) expression in common childhood cancers. The authors characterized PD-L1 expression and tumor-associated immune cells (TAICs) (lymphocytes and macrophages) in common pediatric cancers. METHODS: Whole slide sections and tissue microarrays were evaluated by immunohistochemistry for PD-L1 expression and for the presence of TAICs. TAICs were also screened for PD-L1 expression. RESULTS: Thirty-nine of 451 evaluable tumors (9%) expressed PD-L1 in at least 1% of tumor cells. The highest frequency histotypes comprised Burkitt lymphoma (80%; 8 of 10 tumors), glioblastoma multiforme (36%; 5 of 14 tumors), and neuroblastoma (14%; 17 of 118 tumors). PD-L1 staining was associated with inferior survival among patients with neuroblastoma (P = .004). Seventy-four percent of tumors contained lymphocytes and/or macrophages. Macrophages were significantly more likely to be identified in PD-L1-positive versus PD-L1-negative tumors (P < .001). CONCLUSIONS: A subset of diagnostic pediatric cancers exhibit PD-L1 expression, whereas a much larger fraction demonstrates infiltration with tumor-associated lymphocytes. PD-L1 expression may be a biomarker for poor outcome in neuroblastoma. Further preclinical and clinical investigation will define the predictive nature of PD-L1 expression in childhood cancers both at diagnosis and after exposure to chemoradiotherapy. Cancer 2017;123:3807-3815. © 2017 American Cancer Society.
Assuntos
Antígeno B7-H1/análise , Linfócitos do Interstício Tumoral , Macrófagos , Proteínas de Neoplasias/análise , Neoplasias/química , Neoplasias Ósseas/química , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Linfoma de Burkitt/química , Linfoma de Burkitt/imunologia , Linfoma de Burkitt/patologia , Criança , Glioblastoma/química , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias/patologia , Neuroblastoma/química , Neuroblastoma/imunologia , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Osteossarcoma/química , Osteossarcoma/imunologia , Osteossarcoma/patologia , Rabdomiossarcoma/química , Rabdomiossarcoma/imunologia , Rabdomiossarcoma/patologia , Sarcoma de Ewing/química , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/patologia , Análise Serial de TecidosRESUMO
Inflammation is associated with several diseases of the prostate including benign enlargement and cancer, but a causal relationship has not been established. Our objective was to characterize the prostate inflammatory microenvironment after infection with a human prostate-derived bacterial strain and to determine the effect of inflammation on prostate cancer progression. To this end, we mimicked typical human prostate infection with retrograde urethral instillation of CP1, a human prostatic isolate of Escherichia coli. CP1 bacteria were tropic for the accessory sex glands and induced acute inflammation in the prostate and seminal vesicles, with chronic inflammation lasting at least 1 year. Compared to controls, infection induced both acute and chronic inflammation with epithelial hyperplasia, stromal hyperplasia, and inflammatory cell infiltrates. In areas of inflammation, epithelial proliferation and hyperplasia often persist, despite decreased expression of androgen receptor (AR). Inflammatory cells in the prostates of CP1-infected mice were characterized at 8 weeks post-infection by flow cytometry, which showed an increase in macrophages and lymphocytes, particularly Th17 cells. Inflammation was additionally assessed in the context of carcinogenesis. Multiplex cytokine profiles of inflamed prostates showed that distinct inflammatory cytokines were expressed during prostate inflammation and cancer, with a subset of cytokines synergistically increased during concurrent inflammation and cancer. Furthermore, CP1 infection in the Hi-Myc mouse model of prostate cancer accelerated the development of invasive prostate adenocarcinoma, with 70% more mice developing cancer by 4.5 months of age. This study provides direct evidence that prostate inflammation accelerates prostate cancer progression and gives insight into the microenvironment changes induced by inflammation that may accelerate tumour initiation or progression.
Assuntos
Adenocarcinoma/patologia , Progressão da Doença , Escherichia coli/fisiologia , Próstata/microbiologia , Próstata/patologia , Neoplasias da Próstata/patologia , Microambiente Tumoral/fisiologia , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatologia , Animais , Proliferação de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Escherichia coli/isolamento & purificação , Humanos , Hiperplasia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/fisiopatologia , Prostatite/metabolismo , Prostatite/patologia , Prostatite/fisiopatologia , Receptores Androgênicos/metabolismo , Células Th17/patologiaRESUMO
BACKGROUND: Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. METHODS: In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. RESULTS: As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. CONCLUSIONS: Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Neoplasias/metabolismo , Nivolumabe , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a key negative regulator of T cell activation. A complex integration of positive and negative co-stimulatory signals in the well-defined B7:CD28/CTLA-4 pathway modulates the generation and maintenance of immune responses. Inhibiting negative regulation through binding of CTLA-4 has been shown to promote stimulation of adaptive immunity and potentiation of T cell activation. CTLA-4-blocking antibodies have demonstrated efficacy in various murine malignancy models when administered as monotherapy; additionally, they have shown synergistic anti-tumor activity when utilized with other agents, such as vaccines, chemotherapy, and radiation. Preclinical studies have supported the rationale for current clinical development of anti-CTLA-4 antibodies, including ipilimumab and tremelimumab, as novel therapeutic strategies to augment anti-tumor immunity in cancer. Both ipilimumab and tremelimumab have been evaluated extensively in melanoma; notably, ipilimumab was recently approved as monotherapy for the treatment of advanced melanoma. Tremelimumab is currently undergoing evaluation in phase II trials as monotherapy in melanoma and malignant mesothelioma, while ipilimumab is under clinical investigation in phase II and III trials in various tumor types, including in melanoma, prostate, and lung cancers as monotherapy and with other therapeutic modalities, such as chemotherapy and radiation. In this review, we will provide a detailed overview of preclinical advances that have delineated many features of CTLA-4 and have helped define its role in T cell response. We will also highlight clinical application of anti-CTLA-4 therapy in cancer and describe knowledge gaps that future studies may address.
Assuntos
Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Pesquisa Translacional Biomédica , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Biomarcadores Tumorais/metabolismo , Modelos Animais de Doenças , Humanos , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
BACKGROUND: The FDA recently approved an anti-CTLA-4 antibody (Iplimumab) for the treatment of metastatic melanoma. This decision was based on Phase III results, which demonstrate that blocking this immune checkpoint provides a survival advantage in patients with advanced disease. As a single agent, ipilimumab is also being clinically evaluated in advanced (metastatic, castrate-resistant) prostate cancer and two randomized, placebo-controlled Phase III studies have recently completed accrual. METHODS: We used a well-described genetically engineered mouse (GEM), autochronous prostate cancer model (Pro-TRAMP) to explore the relative sequencing and dosing of anti-CTLA-4 antibody when combined with a cell-based, GM-CSF-secreting vaccine (GVAX). RESULTS: Our results show that combined treatment results in a dramatic increase in effector CD8 T cells in the prostate gland, and enhanced tumor-antigen directed lytic function. These effects are maximized when CTLA-4 blockade is applied after, but not before, vaccination. Additional experiments, using models of metastatic disease, show that incorporation of low-dose cyclophosphamide into this combined treatment regimen results in an additional pre-clinical benefit. CONCLUSIONS: Together these studies define a combination regimen using anti-CTLA-4/GVAX immunotherapy and low-dose chemotherapy for potential translation to a clinical trial setting.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia/métodos , Neoplasias da Próstata/terapia , Animais , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/citologia , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Ciclofosfamida/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Ipilimumab , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Metástase Neoplásica , Neoplasias da Próstata/imunologia , Fatores de TempoRESUMO
BACKGROUND: The CD8 T-cell response to prostate and other cancers is often functionally diminished or absent. This may occur via deletion of tumor-specific T cells, through acquisition of an anergic phenotype, or via active suppression mediated by another population of cells. METHODS: We used a double transgenic model in which mice express CD8 T cells specific for a prostate/prostate cancer antigen to study the response of CD8 T cells to evolving autochronous prostate tumors in TRAMP mice. CD8 T cells were analyzed for functionality by measuring IFN-γ production via flow cytometry and via an in vivo CTL killing assay. In addition, pathological scoring of the prostates of the double transgenic mice was compared to scoring of tumor burden prostates of ProTRAMP mice. RESULTS: Tumor-specific CD8 T cells were not grossly deleted in these animals, but evidenced a clearly non-functional phenotype. Interestingly, full lytic function was rapidly recovered upon removal from tumor-bearing mice. CONCLUSIONS: These data indicate a role for continuous antigen exposure in the maintenance of tumor-specific CD8 T-cell tolerance to prostate cancer.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal/imunologia , Carcinoma de Células Pequenas/imunologia , Neoplasia Prostática Intraepitelial/imunologia , Neoplasias da Próstata/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/transplante , Carcinoma Ductal/patologia , Carcinoma de Células Pequenas/patologia , Sobrevivência Celular , Transplante de Células , Modelos Animais de Doenças , Feminino , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/patologiaRESUMO
Lymphocyte Activation Gene-3 (LAG-3) is a transmembrane protein that binds MHC class II, enhances regulatory T cell activity, and negatively regulates cellular proliferation, activation, and homeostasis of T cells. Programmed Death 1 (PD-1) also negatively regulates T cell function. LAG-3 and PD-1 are both transiently expressed on CD8 T cells that have been stimulated during acute activation. However, both LAG-3 and PD-1 remain on CD8 T cells at high levels after stimulation within tolerizing environments. Our previous data demonstrated that blockade of either LAG-3 or PD-1 using mAb therapy in combination with vaccination restores the function of tolerized Ag-specific CD8 T cells in models of self and tumor tolerance. It is unclear whether tolerized CD8 T cells coexpress PD-1 and LAG-3 or whether PD-1 and LAG-3 mark functionally distinct populations of CD8 T cells. In this study, we describe three populations of CD8 T cells activated under tolerizing conditions based on LAG-3 and PD-1 staining, each with distinct phenotypic and functional characteristics. From a mechanistic perspective, both Ag concentration and proinflammatory signals control the expression of LAG-3 and PD-1 phenotypes on CD8 T cells under activating and tolerizing conditions. These results imply that signaling through the PD-1 and LAG-3 pathways have distinct functional consequences to CD8 T cells under tolerizing conditions and manipulation of both Ag and cytokine signaling can influence CD8 tolerance through LAG-3 and PD-1.
Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação/imunologia , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Transferência Adotiva , Animais , Antígenos/análise , Antígenos CD/análise , Antígenos de Diferenciação/análise , Linfócitos T CD8-Positivos/transplante , Citocinas , Tolerância Imunológica/imunologia , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1 , Transdução de Sinais/imunologia , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
Tumors express a wide variety of both mutated and nonmutated Ags. Whether these tumor Ags are broadly recognized as self or foreign by the immune system is currently unclear. Using an autochthonous prostate cancer model in which hemagglutinin (HA) is specifically expressed in the tumor (ProHA x TRAMP mice), as well as an analogous model wherein HA is expressed in normal tissues as a model self-Ag (C3HA(high)), we examined the transcriptional profile of CD4 T cells undergoing Ag-specific division. Consistent with our previous data, transfer of Ag-specific CD4 T cells into C3HA(high) resulted in a functionally inactivated CD4 T cell profile. Conversely, adoptive transfer of an identical CD4 T cell population into ProHA x TRAMP mice resulted in the induction of a regulatory phenotype of the T cell (Treg) both at the transcriptional and functional level. Interestingly, this Treg skewing was a property of even early-stage tumors, suggesting Treg induction as an important tolerance mechanism during tumor development.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Neoplasias/imunologia , Animais , Antígenos/imunologia , Linfócitos T CD4-Positivos/citologia , Proliferação de Células , Regulação para Baixo , Fatores de Transcrição Forkhead/imunologia , Perfilação da Expressão Gênica , Camundongos , Neoplasias/genética , Fenótipo , Ratos , Transcrição Gênica/genética , Regulação para CimaRESUMO
IL-17-secreting CD8 T cells (Tc17) have been described in several settings, but little is known regarding their functional characteristics. While Tc1 cells produced IFN-gamma and efficiently killed targets, Tc17 cells lacked lytic function in vitro. Interestingly, the small numbers of IFN-gamma-positive or IL-17/IFN-gamma-double-positive cells generated under Tc17 conditions also lacked lytic activity and expressed a similar pattern of cell surface proteins to IL-17-producing cells. As is the case for Th17 (CD4) cells, STAT3 is important for Tc17 polarization, both in vitro and in vivo. Adoptive transfer of highly purified, Ag-specific IL-17-secreting Tc17 cells into Ag-bearing hosts resulted in near complete conversion to an IFN-gamma-secreting phenotype and substantial pulmonary pathology, demonstrating functional plasticity. Tc17 also accumulated to a greater extent than did Tc1 cells, suggesting that adoptive transfer of CD8 T cells cultured in Tc17 conditions may have therapeutic potential for diseases in which IFN-gamma-producing cells are desired.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Interleucina-17/biossíntese , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Citometria de Fluxo , Expressão Gênica/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Lymphocyte activation gene-3 (LAG-3) is a cell-surface molecule with diverse biologic effects on T cell function. We recently showed that LAG-3 signaling is important in CD4+ regulatory T cell suppression of autoimmune responses. Here, we demonstrate that LAG-3 maintains tolerance to self and tumor antigens via direct effects on CD8+ T cells using 2 murine systems. Naive CD8+ T cells express low levels of LAG-3, and expression increases upon antigen stimulation. Our data show increased levels of LAG-3 protein on antigen-specific CD8+ T cells within antigen-expressing organs or tumors. In vivo antibody blockade of LAG-3 or genetic ablation of the Lag-3 gene resulted in increased accumulation and effector function of antigen-specific CD8+ T cells within organs and tumors that express their cognate antigen. Most notably, combining LAG-3 blockade with specific antitumor vaccination resulted in a significant increase in activated CD8+ T cells in the tumor and disruption of the tumor parenchyma. A major component of this effect was CD4 independent and required LAG-3 expression by CD8+ T cells. Taken together, these data demonstrate a direct role for LAG-3 on CD8+ T cells and suggest that LAG-3 blockade may be a potential cancer treatment.
Assuntos
Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/imunologia , Tolerância Imunológica/imunologia , Tolerância a Antígenos Próprios/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Antígenos CD/genética , Linfócitos T CD8-Positivos/citologia , Linhagem Celular , Proliferação de Células , Humanos , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subpopulações de Linfócitos T/citologia , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
IMPORTANCE: Nivolumab, a monoclonal antibody that inhibits programmed cell death 1, is approved by the US Food and Drug Administration for treating advanced melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and other malignancies. Data on long-term survival among patients receiving nivolumab are limited. OBJECTIVES: To analyze long-term overall survival (OS) among patients receiving nivolumab and identify clinical and laboratory measures associated with tumor regression and OS. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of the phase 1 CA209-003 trial (with expansion cohorts), which was conducted at 13 US medical centers and included 270 patients with advanced melanoma, RCC, or NSCLC who received nivolumab and were enrolled between October 30, 2008, and December 28, 2011. The analyses were either specified in the original protocol or included in subsequent protocol amendments that were implemented between 2008 and 2012. Statistical analysis was performed from October 30, 2008, to November 11, 2016. INTERVENTION: In the CA209-003 trial, patients received nivolumab (0.1-10.0 mg/kg) every 2 weeks in 8-week cycles for up to 96 weeks, unless they developed progressive disease, achieved a complete response, experienced unacceptable toxic effects, or withdrew consent. MAIN OUTCOMES AND MEASURES: Safety and activity of nivolumab; OS was a post hoc end point with a minimum follow-up of 58.3 months. RESULTS: Of 270 patients included in this analysis, 107 (39.6%) had melanoma (72 [67.3%] male; median age, 61 [range, 29-85] years), 34 (12.6%) had RCC (26 [76.5%] male; median age, 58 [range, 35-74] years), and 129 (47.8%) had NSCLC (79 [61.2%] male; median age, 65 [range, 38-85] years). Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC. In a multivariable analysis, the presence of liver (odds ratio [OR], 0.31; 95% CI, 0.12-0.83; P = .02) or bone metastases (OR, 0.31; 95% CI, 0.10-0.93; P = .04) was independently associated with reduced likelihood of survival at 5 years, whereas an Eastern Cooperative Oncology Group performance status of 0 (OR, 2.74; 95% CI, 1.43-5.27; P = .003) was independently associated with an increased likelihood of 5-year survival. Overall survival was significantly longer among patients with treatment-related AEs of any grade (median, 19.8 months; 95% CI, 13.8-26.9 months) or grade 3 or more (median, 20.3 months; 95% CI, 12.5-44.9 months) compared with those without treatment-related AEs (median, 5.8 months; 95% CI, 4.6-7.8 months) (P < .001 for both comparisons based on hazard ratios). CONCLUSIONS AND RELEVANCE: Nivolumab treatment was associated with long-term survival in a subset of heavily pretreated patients with advanced melanoma, RCC, or NSCLC. Characterizing factors associated with long-term survival may inform treatment approaches and strategies for future clinical trial development. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00730639.
RESUMO
BACKGROUND: Cancer immunotherapy refers to an array of strategies intended to treat progressive tumors by augmenting a patient's anti-tumor immune response. As immunotherapy is eventually incorporated into oncology treatment paradigms, it is important to understand how these therapies interact with established cancer treatments such as chemotherapy or Radiotherapy (RT). To address this, we utilized a well-established, autochthonous murine model of prostate cancer to test whether RT could augment (or diminish) the CD4 T cell response to a tumor vaccine. METHODS: Transgenic mice that develop spontaneous prostate cancer (TRAMP) which also express a unique tumor associated antigen (Influenza hemagglutinin) under the control of a prostate-specific promoter were given local RT in combination with immunotherapy. The immunological outcome of this combinatorial strategy was assayed by monitoring the effector response of adoptively transferred, prostate-specific CD4 T cells. RESULTS: Neither RT nor immunotherapy alone was capable of priming an anti-tumor immune response in animals with evolving tumors. The combination of immunotherapy with RT resulted in anti-tumor T cell activation--this effect was profoundly dependent on the relative timing of RT and immunotherapy. Anti-tumor immune responses occurred when immunotherapy was administered 3-5 weeks post-RT, but such responses were undetectable when immunotherapy was administered either earlier (peri-radiotherapy) or later. CONCLUSIONS: The therapeutic temporal window of immunotherapy post-RT suggests that highly aggressive, immuno-suppressive tumors might be most sensitive to immunotherapy in a fairly narrow time window; these results should help to guide future development of clinical combinatorial strategies.
Assuntos
Vacinas Anticâncer/farmacologia , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/terapia , Animais , Antígenos Glicosídicos Associados a Tumores/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Terapia Combinada , Modelos Animais de Doenças , Hemaglutininas Virais/metabolismo , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Orthomyxoviridae/imunologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Fatores de TempoRESUMO
For men who have hormone-refractory prostate cancer, current treatment options are somewhat limited, with docetaxel the only agent showing a significant prolongation of survival. Several groups have investigated therapeutic approaches involving stimulation of an immune response against progressive prostate cancer. Several features of prostate cancer suggest that it may be a good target for immunotherapy. Constant pressure by the immune system forces tumors to evolve multiple ways to escape immune assault, however, and it is thus unlikely that single-agent immunotherapy for prostate cancer will achieve maximal clinical benefit. Most likely, successful immunotherapy will eventually require either the combination of multiple immunologic approaches or the combination of immunologic approaches with conventional therapy.
Assuntos
Imunoterapia , Neoplasias da Próstata/terapia , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Masculino , Proteínas de Neoplasias/imunologia , Antígeno Prostático Específico/imunologia , Antígeno Prostático Específico/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologiaRESUMO
Recent advances in cancer treatment with checkpoint blockade of receptors such as CTLA-4 and PD-1 have demonstrated that combinations of agents with complementary immunomodulatory effects have the potential to enhance antitumor activity as compared to single agents. We investigated the efficacy of immune-modulatory interleukin-21 (IL-21) combined with checkpoint blockade in several syngeneic mouse tumor models. After tumor establishment, mice were administered recombinant mouse IL-21 (mIL-21) alone or in combination with blocking monoclonal antibodies against mouse PD-1 or CTLA-4. In contrast to monotherapy, IL-21 enhanced antitumor activity of mCTLA-4 mAb in four models and anti-PD-1 mAb in two models, with evidence of synergy for one or both of the combination treatments in the EMT-6 and MC38 models. The enhanced efficacy was associated with increased intratumoral CD8+ T cell infiltrates, CD8+ T cell proliferation, and increased effector memory T cells, along with decreased frequency of central memory CD8+ T cells. In vivo depletion of CD8+ T cells abolished the antitumor activities observed for both combination and monotherapy treatments, further supporting a beneficial role for CD8+ T cells. In all studies, the combination therapies were well tolerated. These results support the hypothesis that the combination of recombinant human IL-21 with CTLA-4 or PD-1 monoclonal antibodies could lead to improved outcomes in cancer patients.
RESUMO
Implantation of DA-3 mammary tumor cells into BALB/c mice results in tumor growth, metastatic lesions, and death. These cells were transfected with genes encoding for either the transmembrane (DA-3/TM) or secreted (DA-3/sec) form of human mucin 1 (MUC1). Although the gene for the secreted form lacks the transmembrane and cytoplasmic domains, the 5' sequences of these mucins are identical; however, the gene for the secreted mucin isoform ends with a sequence encoding for a unique 11 amino acid peptide. The DA-3/TM or DA-3 cells transfected with the neomycin vector only (DA-3/neo) have the same in vivo growth characteristics as the parent cell line. In contrast, DA-3/sec cells fail to grow when implanted in immunocompetent BALB/c animals. DA-3/sec cells implanted in nude mice resulted in tumor development verifying the tumorigenic potential of these cells. Pre-exposure of BALB/c mice to DA-3/sec cells afforded protection against challenge with DA-3/TM or DA-3/neo mammary tumors and the unrelated tumors K7, an osteosarcoma, and RENCA, a renal cell carcinoma. Partial protection against subsequent tumor challenges was also achieved by substituting the 11 amino acid peptide found only in the secreted MUC1 isoform, for the live DA-3/sec cells. Notably, the efficacy of this peptide is not strain restricted because it also retarded the growth of Lewis lung carcinoma cells in C57 BL/6 mice. These findings reveal that a unique peptide present in the secreted MUC1 has immunoenhancing properties and may be a potential agent for use in immunotherapy.
Assuntos
Adjuvantes Imunológicos/farmacologia , Antineoplásicos/farmacologia , Mucina-1/farmacologia , Fragmentos de Peptídeos/farmacologia , Animais , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mucina-1/fisiologia , Neoplasias Experimentais/prevenção & controle , Oligodesoxirribonucleotídeos/farmacologia , Fragmentos de Peptídeos/fisiologiaRESUMO
PURPOSE: Cancer cells can exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity. In part, this may occur through overexpression of PD-1 and PD-1 pathway ligands (PD-L1 and PD-L2) in the tumor microenvironment. PD-1 blockade has produced significant antitumor activity in solid tumors, and similar evidence has emerged in hematologic malignancies. METHODS: In this phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma, T-cell lymphoma, and multiple myeloma received the anti-PD-1 monoclonal antibody nivolumab at doses of 1 or 3 mg/kg every 2 weeks. This study aimed to evaluate the safety and efficacy of nivolumab and to assess PD-L1/PD-L2 locus integrity and protein expression. RESULTS: Eighty-one patients were treated (follicular lymphoma, n = 10; diffuse large B-cell lymphoma, n = 11; other B-cell lymphomas, n = 10; mycosis fungoides, n = 13; peripheral T-cell lymphoma, n = 5; other T-cell lymphomas, n = 5; multiple myeloma, n = 27). Patients had received a median of three (range, one to 12) prior systemic treatments. Drug-related adverse events occurred in 51 (63%) patients, and most were grade 1 or 2. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma, diffuse large B-cell lymphoma, mycosis fungoides, and peripheral T-cell lymphoma, respectively. Median time of follow-up observation was 66.6 weeks (range, 1.6 to 132.0+ weeks). Durations of response in individual patients ranged from 6.0 to 81.6+ weeks. CONCLUSION: Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Aberrações Cromossômicas , Cromossomos Humanos Par 9 , Linfoma de Células B/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma de Células T/genética , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Micose Fungoide/tratamento farmacológico , Micose Fungoide/genética , Micose Fungoide/patologia , Nivolumabe , Pneumonia/induzido quimicamente , Proteína 2 Ligante de Morte Celular Programada 1/genética , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Retratamento , Linfócitos T/efeitos dos fármacos , Linfócitos T/fisiologia , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. METHODS AND MATERIALS: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. RESULTS: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. CONCLUSIONS: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.
Assuntos
Adenocarcinoma/terapia , Vacinas Anticâncer/uso terapêutico , Tomografia Computadorizada de Feixe Cônico/métodos , Imunoterapia Adotiva/métodos , Radioterapia Conformacional/métodos , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Transferência Adotiva/métodos , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Terapia Combinada/métodos , Terapia Combinada/mortalidade , Hemaglutininas/imunologia , Hemaglutininas/metabolismo , Imunoterapia Adotiva/mortalidade , Linfócitos do Interstício Tumoral/citologia , Masculino , Camundongos , Camundongos Transgênicos , Gradação de Tumores , Micrometástase de Neoplasia/prevenção & controle , Órgãos em Risco/diagnóstico por imagem , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Cintilografia , Dosagem Radioterapêutica , Radioterapia Conformacional/mortalidade , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Reguladores/citologia , Carga Tumoral , Bexiga Urinária/diagnóstico por imagemRESUMO
Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4(+) and CD8(+) T cells in three distinct transplantable tumors. Dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3(-/-)Pdcd1(-/-) mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.
Assuntos
Antígenos CD/fisiologia , Linfócitos T CD4-Positivos/imunologia , Neoplasias Experimentais/imunologia , Receptor de Morte Celular Programada 1/fisiologia , Evasão Tumoral/imunologia , Animais , Anticorpos/uso terapêutico , Antígenos CD/imunologia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Tolerância Imunológica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Receptor de Morte Celular Programada 1/imunologia , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
Relative upregulation of the Ikaros family transcription factor Helios in natural regulatory T cells (Tregs) has been reported by several groups. However, a role for Helios in regulatory T cells has not yet been described. Here, we show that Helios is upregulated in CD4(+)CD25(+) regulatory T cells. Chromatin-immunoprecipitation (ChIP) experiments indicated that Helios binds to the FoxP3 promoter. These data were further corroborated by experiments showing that knocking-down Helios with siRNA oligonucleotides results in down-regulation of FoxP3. Functionally, we found that suppression of Helios message in CD4(+)CD25(+) T cells significantly attenuates their suppressive function. Taken together, these data suggest that Helios may play an important role in regulatory T cell function and support the concept that Helios may be a novel target to manipulate Treg activity in a clinical setting.