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Many approaches to identify therapeutically relevant neoantigens couple tumor sequencing with bioinformatic algorithms and inferred rules of tumor epitope immunogenicity. However, there are no reference data to compare these approaches, and the parameters governing tumor epitope immunogenicity remain unclear. Here, we assembled a global consortium wherein each participant predicted immunogenic epitopes from shared tumor sequencing data. 608 epitopes were subsequently assessed for T cell binding in patient-matched samples. By integrating peptide features associated with presentation and recognition, we developed a model of tumor epitope immunogenicity that filtered out 98% of non-immunogenic peptides with a precision above 0.70. Pipelines prioritizing model features had superior performance, and pipeline alterations leveraging them improved prediction performance. These findings were validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T cell binding. This data resource enables identification of parameters underlying effective anti-tumor immunity and is available to the research community.
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Antígenos de Neoplasias/inmunología , Epítopos/inmunología , Neoplasias/inmunología , Alelos , Presentación de Antígeno/inmunología , Estudios de Cohortes , Humanos , Péptidos/inmunología , Receptor de Muerte Celular Programada 1 , Reproducibilidad de los ResultadosRESUMEN
Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and costimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC-mediated response during inflammatory disease, such as GVHD.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Proteínas Portadoras/inmunología , Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Animales , Autofagia/inmunología , Proteínas Relacionadas con la Autofagia , Antígeno B7-1/biosíntesis , Antígeno B7-2/biosíntesis , Antígenos CD40/biosíntesis , Proteínas Portadoras/genética , Proliferación Celular , Células Cultivadas , Colitis/inmunología , Cisteína Endopeptidasas/biosíntesis , Modelos Animales de Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Trasplante de Células Madre Hematopoyéticas , Proteínas de Homeodominio/genética , Proteínas Inmediatas-Precoces/biosíntesis , Inflamación/inmunología , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Activación de Linfocitos/inmunología , Lisosomas/patología , Proteínas de la Membrana/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Trasplante Homólogo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND: Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose. METHODS: This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing. FINDINGS: Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0-19·4; cohort B1 22·0 months [21·4-22·7], cohort B2 18·2 months [17·0-18·9], cohort C1 17·9 months [14·3-19·7], cohort C2 15·9 months [12·7-16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3-4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2). INTERPRETATION: APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population. FUNDING: Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.
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Adenocarcinoma/tratamiento farmacológico , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígenos CD40/antagonistas & inhibidores , Desoxicitidina/análogos & derivados , Nivolumab/administración & dosificación , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/inmunología , Adenocarcinoma/secundario , Anciano , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígenos CD40/inmunología , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , Paclitaxel/efectos adversos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , GemcitabinaRESUMEN
Immunotherapy is emerging as a new treatment modality in breast cancer. After long-standing use of endocrine therapy and targeted biological therapy, improved understanding of immune evasion by cancer cells and the discovery of selective immune checkpoint inhibitors have created novel opportunities for treatment. Single-drug therapies with monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have shown little efficacy in patients with metastatic breast cancer, in part because of the low number of tumour-infiltrating lymphocytes in most breast cancers. There is growing interest in the development of combinations of immunotherapy and molecularly targeted therapies for metastatic breast cancer. In this Personal View, we review the available data and ongoing efforts to establish the safety and efficacy of immunotherapeutic approaches in combination with HER2-targeted therapy, inhibitors of cyclin-dependent kinases 4 and 6, angiogenesis inhibitors, poly(ADP-ribose) polymerase inhibitors, as well as chemotherapy and radiotherapy.
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Neoplasias de la Mama/tratamiento farmacológico , Inmunoterapia , Terapia Molecular Dirigida , Receptor ErbB-2/antagonistas & inhibidores , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Terapia Combinada , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Femenino , Humanos , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor ErbB-2/genéticaRESUMEN
Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Albúminas , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Humanos , Nivolumab/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
As the field of cancer immunotherapy continues to advance at a fast pace, treatment approaches and drug development are evolving rapidly to maximize patient benefit. New agents are commonly evaluated for activity in patients who had previously received a programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor as standard of care or in an investigational study. However, because of the kinetics and patterns of response to PD-1/PD-L1 blockade, and the lack of consistency in the clinical definitions of resistance to therapy, the design of clinical trials of new agents and interpretation of results remains an important challenge. To address this unmet need, the Society for Immunotherapy of Cancer convened a multistakeholder taskforce-consisting of experts in cancer immunotherapy from academia, industry, and government-to generate consensus clinical definitions for resistance to PD-(L)1 inhibitors in three distinct scenarios: primary resistance, secondary resistance, and progression after treatment discontinuation. The taskforce generated consensus on several key issues such as the timeframes that delineate each type of resistance, the necessity for confirmatory scans, and identified caveats for each specific resistance classification. The goal of this effort is to provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance.
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Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Biomarcadores de Tumor , Femenino , Humanos , Masculino , Neoplasias/inmunología , Neoplasias/terapiaRESUMEN
This corrects the article DOI: 10.1038/nrd.2018.167.
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A variant of the autophagy gene ATG16L1 is associated with Crohn's disease, an inflammatory bowel disease (IBD), and poor survival in allogeneic hematopoietic stem cell transplant recipients. We demonstrate that ATG16L1 in the intestinal epithelium is essential for preventing loss of Paneth cells and exaggerated cell death in animal models of virally triggered IBD and allogeneic hematopoietic stem cell transplantation. Intestinal organoids lacking ATG16L1 reproduced this loss in Paneth cells and displayed TNFα-mediated necroptosis, a form of programmed necrosis. This cytoprotective function of ATG16L1 was associated with the role of autophagy in promoting mitochondrial homeostasis. Finally, therapeutic blockade of necroptosis through TNFα or RIPK1 inhibition ameliorated disease in the virally triggered IBD model. These findings indicate that, in contrast to tumor cells in which autophagy promotes caspase-independent cell death, ATG16L1 maintains the intestinal barrier by inhibiting necroptosis in the epithelium.
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Apoptosis , Autofagia , Proteínas Portadoras/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Animales , Proteínas Relacionadas con la Autofagia , Infecciones por Caliciviridae/patología , Infecciones por Caliciviridae/virología , Supervivencia Celular , Citoprotección , Células Epiteliales/metabolismo , Células Epiteliales/patología , Eliminación de Gen , Enfermedad Injerto contra Huésped/patología , Enfermedad Injerto contra Huésped/terapia , Trasplante de Células Madre Hematopoyéticas , Homeostasis , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Mutación/genética , Necrosis , Norovirus/fisiología , Organoides/patología , Células de Paneth/metabolismo , Células de Paneth/patología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Immunotherapy is rapidly becoming a standard of care for many cancers. However, colorectal cancer had been generally resistant to immunotherapy, despite features in common with sensitive tumors. Observations of substantial clinical activity for checkpoint blockade in colorectal cancers with defective mismatch repair (microsatellite instability-high tumors) have reignited interest in the search for immunotherapies that could be extended to the larger microsatellite stable (MSS) population. The Cancer Research Institute and Fight Colorectal Cancer convened a group of scientists, clinicians, advocates, and industry experts in colorectal cancer and immunotherapy to compile ongoing research efforts, identify gaps in translational and clinical research, and provide a blueprint to advance immunotherapy. We identified lack of a T-cell inflamed phenotype (due to inadequate T-cell infiltration, inadequate T-cell activation, or T-cell suppression) as a broad potential explanation for failure of checkpoint blockade in MSS. The specific cellular and molecular underpinnings for these various mechanisms are unclear. Whether biomarkers with prognostic value, such as the immunoscores and IFN signatures, would also predict benefit for immunotherapies in MSS colon cancer is unknown, but if so, these and other biomarkers for measuring the potential for an immune response in patients with colorectal cancer will need to be incorporated into clinical guidelines. We have proposed a framework for research to identify immunologic factors that may be modulated to improve immunotherapy for colorectal cancer patients, with the goal that the biomarkers and treatment strategies identified will become part of the routine management of colorectal cancer. Cancer Immunol Res; 5(11); 942-9. ©2017 AACR.
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Neoplasias Colorrectales/terapia , Inmunoterapia , Animales , Neoplasias Colorrectales/inmunología , HumanosRESUMEN
On September 25-28, 2016, in New York City, the Second International Cancer Immunotherapy Conference was cohosted by the Cancer Research Institute, the American Association for Cancer Research, the Association for Cancer Immunotherapy, and the European Academy of Tumor Immunology. This exciting conference brought together more than 1,400 participants, including scientists, clinicians, investors, and regulators, to discuss the latest scientific advances within the field of cancer immunotherapy. This conference report reviews the chief themes that emerged during the 4-day meeting. Cancer Immunol Res; 4(12); 996-1000. ©2016 AACR.
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Inmunoterapia , Neoplasias/terapia , Animales , Humanos , Mutación , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/metabolismo , Medicina de Precisión , Microambiente TumoralRESUMEN
The inaugural International Cancer Immunotherapy Conference, cohosted by the Cancer Research Institute (CRI), the American Association for Cancer Research (AACR), the Association for Cancer Immunotherapy (CIMT), and the European Academy of Tumor Immunology (EATI), was held in New York City on September 1619, 2015. The conference brought together nearly 1,400 scientists, clinicians, regulators, patient advocates, and other stakeholders to discuss the latest scientific developments in cancer immunology and immunotherapy, as well as the regulatory hurdles facing new drug development. This conference report summarizes the main themes that emerged during the 4-day meeting.
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Inmunoterapia , Neoplasias/terapia , Animales , Vacunas contra el Cáncer/administración & dosificación , Ensayos Clínicos como Asunto , Humanos , Neoplasias/inmunología , Neoplasias/mortalidad , Resultado del TratamientoRESUMEN
With the recent FDA approvals of pembrolizumab and nivolumab, and a host of additional immunomodulatory agents entering clinical development each year, the field of cancer immunotherapy is changing rapidly. Strategies that can assist researchers in choosing the most promising drugs and drug combinations to move forward through clinical development are badly needed in order to reduce the likelihood of late-stage clinical trial failures. On October 5, 2014, the Cancer Immunotherapy Consortium of the Cancer Research Institute, a collaborative think tank composed of stakeholders from academia, industry, regulatory agencies, and patient interest groups, met to discuss strategies for de-risking immunotherapy development, with a focus on integrating preclinical and clinical studies, and conducting smarter early-phase trials, particularly for combination therapies. Several recommendations were made, including making better use of clinical data to inform preclinical research, obtaining adequate tissues for biomarker studies, and choosing appropriate clinical trial endpoints to identify promising drug candidates and combinations in nonrandomized early-phase trials.