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1.
Front Immunol ; 12: 632890, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33732254

RESUMEN

Coronavirus disease-19 (COVID-19) in children is usually mild but some are susceptible to a Kawasaki disease (KD)-like multisystem inflammatory syndrome in children (MIS-C) in the convalescent stage, posing a need to differentiate the phenotype, susceptibility, autoimmunity, and immunotherapy between KD and MIS-C, particularly in the upcoming mass vaccination of COVID-19. Patients with MIS-C are prone to gastrointestinal symptoms, coagulopathy, and shock in addition to atypical KD syndrome with fever, mucocutaneous lesions, lymphadenopathy, and/or cardiovascular events. MIS-C manifests KD-like symptoms that alert physicians to early recognize and adopt the KD treatment regimen for patients with MIS-C. MIS-C linked to COVID-19 teaches us infection-associated autoimmune vasculitis and vice versa. Studies on genetic susceptibility have identified certain human leukocyte antigen (HLA) locus and toll-like receptor (TLR) associated with KD and/or COVID-19. Certain HLA subtypes, such as HLA-DRB1 and HLA-MICA A4 are associated with KD. HLA-B*46:01 is proposed to be the risk allele of severe COVID-19 infection, and blood group O type is a protective factor of COVID-19. The autoimmune vasculitis of KD, KD shock syndrome (KDSS), or MIS-C is mediated by a genetic variant of HLA, FcγR, and/or antibody-dependent enhancement (ADE) resulting in hyperinflammation with T helper 17 (Th17)/Treg imbalance with augmented Th17/Th1 mediators: interleukin-6 (IL-6), IL-10, inducible protein-10 (IP-10), Interferon (IFNγ), and IL-17A, and lower expression of Treg-signaling molecules, FoxP3, and transforming growth factor (TGF-ß). There are certain similarities and differences in phenotypes, susceptibility, and pathogenesis of KD, KDSS, and MIS-C, by which a physician can make early protection, prevention, and precision treatment of the diseases. The evolution of immunotherapies for the diseases has shown that intravenous immunoglobulin (IVIG) alone or combined with corticosteroids is the standard treatment for KD, KDSS, and MIS-C. However, a certain portion of patients who revealed a treatment resistance to IVIG or IVIG plus corticosteroids, posing a need to early identify the immunopathogenesis, to protect hosts with genetic susceptibility, and to combat Th17/Treg imbalance by anti-cytokine or pro-Treg for reversal of the hyperinflammation and IVIG resistance. Based on physiological and pathological immunity of the diseases under genetic susceptibility and host milieu conditions, a series of sequential regimens are provided to develop a so-called "Know thyself, enemy (pathogen), and ever-victorious" strategy for the prevention and immunotherapy of KD and/or MIS-C.


Asunto(s)
Autoinmunidad , /terapia , Predisposición Genética a la Enfermedad/genética , Inmunoterapia/métodos , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome Mucocutáneo Linfonodular/terapia , Fenotipo , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/terapia , Adolescente , Corticoesteroides/uso terapéutico , /virología , Niño , Preescolar , Citocinas/sangre , Femenino , Antígenos HLA/genética , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Lactante , Masculino , Síndrome Mucocutáneo Linfonodular/genética , Síndrome de Respuesta Inflamatoria Sistémica/genética , Síndrome de Respuesta Inflamatoria Sistémica/virología
2.
Nat Commun ; 12(1): 1453, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674603

RESUMEN

A major roadblock prohibiting effective cellular immunotherapy of pancreatic ductal adenocarcinoma (PDAC) is the lack of suitable tumor-specific antigens. To address this challenge, here we combine flow cytometry screenings, bioinformatic expression analyses and a cyclic immunofluorescence platform. We identify CLA, CD66c, CD318 and TSPAN8 as target candidates among 371 antigens and generate 32 CARs specific for these molecules. CAR T cell activity is evaluated in vitro based on target cell lysis, T cell activation and cytokine release. Promising constructs are evaluated in vivo. CAR T cells specific for CD66c, CD318 and TSPAN8 demonstrate efficacies ranging from stabilized disease to complete tumor eradication with CD318 followed by TSPAN8 being the most promising candidates for clinical translation based on functionality and predicted safety profiles. This study reveals potential target candidates for CAR T cell based immunotherapy of PDAC together with a functional set of CAR constructs specific for these molecules.


Asunto(s)
Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Moléculas de Adhesión Celular/metabolismo , Inmunoterapia/métodos , Neoplasias Pancreáticas/metabolismo , Tetraspaninas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/terapia , Animales , Antígenos de Neoplasias/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/terapia , Moléculas de Adhesión Celular/genética , Línea Celular Tumoral , Citocinas/metabolismo , Proteínas Ligadas a GPI/metabolismo , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Factores Inmunológicos , Activación de Linfocitos , Ratones , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Linfocitos T/inmunología , Tetraspaninas/genética
3.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-33670942

RESUMEN

Immunotherapy is a highly emerging form of breast cancer therapy that enables clinicians to target cancers with specific receptor expression profiles. Two popular immunotherapeutic approaches involve chimeric antigen receptor-T cells (CAR-T) and bispecific antibodies (BsAb). Briefly mentioned in this review as well is the mRNA vaccine technology recently popularized by the COVID-19 vaccine. These forms of immunotherapy can highly select for the tumor target of interest to generate specific tumor lysis. Along with improvements in CAR-T, bispecific antibody engineering, and therapeutic administration, much research has been done on novel molecular targets that can especially be useful for triple-negative breast cancer (TNBC) immunotherapy. Combining emerging immunotherapeutics with tumor marker discovery sets the stage for highly targeted immunotherapy to be the future of cancer treatments. This review highlights the principles of CAR-T and BsAb therapy, improvements in CAR and BsAb engineering, and recently identified human breast cancer markers in the context of in vitro or in vivo CAR-T or BsAb treatment.


Asunto(s)
Neoplasias de la Mama/terapia , Inmunoterapia/métodos , Animales , Anticuerpos Biespecíficos/inmunología , Anticuerpos Biespecíficos/uso terapéutico , Biomarcadores de Tumor , Neoplasias de la Mama/inmunología , Linfocitos T CD8-positivos/inmunología , /inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Femenino , Humanos , Inmunoterapia Adoptiva/métodos , Terapia Molecular Dirigida , Receptores Quiméricos de Antígenos/inmunología , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/terapia , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunología
5.
J Vis Exp ; (168)2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33645559

RESUMEN

The efficacy of photoimmunotherapy can be evaluated more accurately with an orthotopic mouse model than with a subcutaneous one. A pleural dissemination model can be used for the evaluation of treatment methods for intrathoracic diseases such as lung cancer or malignant pleural mesothelioma. Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer treatment strategy that combines the specificity of tumor-targeting antibodies with toxicity caused by a photoabsorber (IR700Dye) after exposure to NIR light. The efficacy of NIR-PIT has been reported using various antibodies; however, only a few reports have shown the therapeutic effect of this strategy in an orthotopic model. In the present study, we demonstrate an example of efficacy evaluation of the pleural disseminated lung cancer model, which was treated using NIR-PIT.


Asunto(s)
Inmunoterapia/métodos , Neoplasias Pulmonares/terapia , Fármacos Fotosensibilizantes/uso terapéutico , Fototerapia/métodos , Neoplasias Pleurales/terapia , Animales , Terapia Combinada , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoconjugados/uso terapéutico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Neoplasias Pleurales/inmunología , Neoplasias Pleurales/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Medicine (Baltimore) ; 100(12): e25262, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33761725

RESUMEN

INTRODUCTION: Myxofibrosarcoma (MFS) is a locally aggressive tumor and has the potential to be fatal because of distant metastasis. Immunotherapy targeting either programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) has recently shown a curative effect on multiple cancers including melanoma, non-small cell lung cancer, and renal cell carcinoma. Although the immunotherapy has been applied in sarcoma, there is little information about the efficiency to treat metastatic MFS. PATIENT CONCERNS: A 42-year-old male presented to the clinic with a mass in the left thigh. Mass resection and ligament replacement surgery were performed. DIAGNOSES: The patient was diagnosed as high-grade MFS (federation nationale des centres de lutte contre le cancer, Grade 3) with pulmonary metastasis. INTERVENTIONS: In the past few years, he was treated with surgery, chemoradiotherapy, and Anlotinib (an angiogenesis inhibitor), but the metastatic lesion continued to progress. About 40% to 50% of tumor cells in his pulmonary tissues were showed positive PD-L1 expression and his tumor mutational burden was 215Muts. Thus, he received Camrelizumab (PD-1 inhibitor). OUTCOMES: Six months after the initiating immunotherapy of Camrelizumab, the size of pulmonary lesions showed marked shrinkage, indicating a partial response. After a follow-up of 18 months, the patient remained in good condition without progressive disease. CONCLUSION: This case described here demonstrated that immunotherapy of PD-1 inhibitor is a promising treatment option for refractory MFS with PD-L1 positive or tumor mutational burden -high, which could contribute to effective tumor response.


Asunto(s)
Inmunoterapia/métodos , Neoplasias Pulmonares , Mixosarcoma , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias de los Tejidos Blandos , Adulto , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Disección/métodos , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Masculino , Mixosarcoma/patología , Mixosarcoma/cirugía , Clasificación del Tumor , Estadificación de Neoplasias , Supervivencia sin Progresión , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/cirugía , Muslo/patología , Muslo/cirugía , Resultado del Tratamiento
7.
Life Sci ; 273: 119150, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33662426

RESUMEN

As a transmembrane protein, CD47 plays an important role in mediating cell proliferation, migration, phagocytosis, apoptosis, immune homeostasis, inhibition of NO signal transduction and other related reactions. Upon the interaction of innate immune checkpoint CD47-SIRPα occurrence, they send a "don't eat me" signal to the macrophages. This signal ultimately helps tumors achieve immune escape by inhibiting macrophage contraction to prevent tumor cells from phagocytosis. Therefore, the importance of CD47-SIRPα immune checkpoint inhibitors in tumor immunotherapy has attracted more attention in recent years. Based on the cognitive improvement of the effect with CD47 in tumor microenvironment and tumor characteristics, the pace of tumor treatment strategies for CD47-SIRPα immune checkpoint inhibitors has gradually accelerated. In this review, we introduced the high expression of CD47 in cancer cells to avoid phagocytosis by immune cells and the importance of CD47 in the structure of cancer microenvironment and the maintenance of cancer cell characteristics. Given the role of the innate immune system in tumorigenesis and development, an improved understanding of the anti-tumor process of innate immune checkpoint inhibitors can lay the foundation for more effective combinations with other anti-tumor treatment strategies.


Asunto(s)
Antígenos de Diferenciación/inmunología , Antígeno CD47/inmunología , Inmunidad Innata/inmunología , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Receptores Inmunológicos/inmunología , Animales , Humanos , Inmunoterapia/métodos , Macrófagos , Neoplasias/inmunología , Fagocitosis , Escape del Tumor , Microambiente Tumoral
8.
Biomed Eng Online ; 20(1): 24, 2021 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-33653371

RESUMEN

Osteosarcoma (OS) is the most common primary bone malignancy that affects children and young adults. OS is characterized by a high degree of malignancy, strong invasiveness, rapid disease progression, and extremely high mortality rate; it is considered as a serious threat to the human health globally. The incidence of OS is common in the metaphysis of long tubular bones, but rare in the spine, pelvis, and sacrum areas; moreover, majority of the OS patients present with only a single lesion. OS has a bimodal distribution pattern, that is, its incidence peaks in the second decade of life and in late adulthood. We examine historical and current literature to present a succinct review of OS. In this review, we have discussed the types, clinical diagnosis, and modern and future treatment methods of OS. The purpose of this article is to inspire new ideas to develop more effective therapeutic options.


Asunto(s)
Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/terapia , Estadificación de Neoplasias/métodos , Osteosarcoma/diagnóstico por imagen , Osteosarcoma/terapia , Antineoplásicos/farmacología , Progresión de la Enfermedad , Terapia Genética/métodos , Humanos , Inmunoterapia/métodos , Imagen por Resonancia Magnética , Radioterapia/métodos , Tomografía Computarizada por Rayos X
9.
Allergol. immunopatol ; 49(1): 58-61, ene.-feb. 2021. tab, graf
Artículo en Inglés | IBECS | ID: ibc-199226

RESUMEN

BACKGROUND: Allergen-specific immunotherapy is a potentially disease-modifying therapy that is effective for the treatment of patients with allergic diseases. Although the pain caused by the administration of subcutaneous immunotherapy with allergens (SCITA) is considered to be minimal, no studies assessing that pain for the treatment of only pediatric patients have been reported. OBJECTIVES: This research aimed to evaluate the pain associated with SCITA for pediatric patients followed at our Immunoallergology Department. METHODS: During four consecutive weeks, the nurse who administered the injection completed a questionnaire recording the child's assessment of the pain associated with SCITA; these questionnaires were randomized before any analyses were done. Two different pain evaluation scales were used, with the choice of scale being determined based on the child's age: the self-reporting faces scale (score: 0-10; 5 to 8 years old) and the numeric scale (score: 0-10; >8 years old). Demographic and clinical data, as well as any adverse reactions, were documented. RESULTS: We included 46 pediatric patients (mean age: 12.3±2.6 years; 69.5% male), most of whom were suffering from rhinitis/rhinoconjunctivitis and undergoing subcutaneous immunotherapy with mites. Seven local adverse reactions were recorded, and all were mild. Ten patients did not mention any pain associated with SCITA. Of the 36 patients who mentioned some pain, 33 mentioned mild pain (scores between 1 and 3); only three mentioned moderate pain (scores between 4 and 6). For both scales, the median score obtained was 1. The maximum pain reported had a score of 6. No significant differences were observed between different groups of patients. CONCLUSIONS: In this study, SCITA was shown to be a mildly painful procedure that is associated with only a few local reactions. Therefore, SCITA should be considered as a safe option for the treatment of most pediatric patients suffering from allergies


No disponible


Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Desensibilización Inmunológica/métodos , Alérgenos/uso terapéutico , Inmunoterapia/métodos , Manejo del Dolor/métodos , Inyecciones Subcutáneas/métodos , Encuestas y Cuestionarios , Rinitis/inmunología , Rinitis/terapia , Asma/inmunología , Asma/terapia , Dimensión del Dolor/métodos
10.
Cell Prolif ; 54(3): e12979, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33522069

RESUMEN

OBJECTIVE: Due to limited immunological profiles of high-grade serous ovarian cancer (HGSOC), we aimed to characterize its molecular features to determine whether a specific subset that can respond to immunotherapy exists. MATERIALS AND METHODS: A training cohort of 418 HGSOC samples from TCGA was analysed by consensus non-negative matrix factorization. We correlated the expression patterns with the presence of immune cell infiltrates, immune regulatory molecules and other genomic or epigenetic features. Two independent cohorts containing 482 HGSOCs and in vitro experiments were used for validation. RESULTS: We identified immune and non-immune groups where the former was enriched in signatures that reflect immune cells, infiltration and PD-1 signalling (all, P < 0.001), and presented with a lower chromosomal aberrations but increased neoantigens, tumour mutation burden, and microsatellite instability (all, P < 0.05); this group was further refined into two microenvironment-based subtypes characterized by either immunoactivation or carcinoma-associated fibroblasts (CAFs) and distinct prognosis. CAFs-immune subtype was enriched for factors that mediate immunosuppression and promote tumour progression, including highly expressed stromal signature, TGF-ß signalling, epithelial-mesenchymal transition and tumour-associated M2-polarized macrophages (all, P < 0.001). Robustness of these immune-specific subtypes was verified in validation cohorts, and in vitro experiments indicated that activated-immune subtype may benefit from anti-PD1 antibody therapy (P < 0.05). CONCLUSION: Our findings revealed two immune subtypes with different responses to immunotherapy and indicated that some HGSOCs may be susceptible to immunotherapies or combination therapies.


Asunto(s)
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Neoplasias Ováricas/patología , Microambiente Tumoral/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Cistadenocarcinoma Seroso/tratamiento farmacológico , Transición Epitelial-Mesenquimal/inmunología , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Inmunoterapia/métodos , Neoplasias Ováricas/genética , Pronóstico , Microambiente Tumoral/inmunología
12.
J Surg Oncol ; 123(3): 718-729, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33595888

RESUMEN

Immunotherapy has emerged as an important treatment modality throughout oncology with a particularly important role in the treatment of lung cancer. Early signals showed responses could be achieved in nonsmall cell lung cancer and small cell lung cancer and these monoclonal antibodies have become standards of care for advanced stage disease. They have also shown promise in earlier-stage disease as complements to radiation or surgery, offering the potential for durable, meaningful survival gains.


Asunto(s)
Inmunoterapia/métodos , Neoplasias Pulmonares/terapia , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Ensayos Clínicos Fase III como Asunto , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Ensayos Clínicos Controlados Aleatorios como Asunto
13.
J Surg Oncol ; 123(3): 789-797, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33595889

RESUMEN

Surgical resection is the treatment for early cutaneous melanoma and is often curative. Some patients, however, will subsequently relapse. High-risk features in the primary tumor and regional lymph node metastasis highlight patient subsets that are at increased risk for recurrent disease. Immunotherapy in the form of checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab have been shown to improve recurrence-free survival for node-positive melanoma in the adjuvant setting and will be the focus of this review.


Asunto(s)
Inmunoterapia/métodos , Melanoma/terapia , Neoplasias Cutáneas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Humanos , Melanoma/inmunología , Melanoma/patología , Melanoma/cirugía , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía
14.
J Surg Oncol ; 123(3): 798-806, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33595890

RESUMEN

While surgical resection, local and cytotoxic therapies have long formed the basis of cancer care, immunotherapy now plays a key role in supplementing and even replacing these agents in the first line. Here we review the early success of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 blockade and discuss biomarkers of therapeutic response. We next highlight a select group of novel targets in Phase III trials both as monotherapies and in combination with PD-1 inhibitors. Finally, we discuss innovations which seek to improve outcomes in therapy-resistant solid tumors.


Asunto(s)
Inmunoterapia/métodos , Neoplasias/terapia , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Ensayos Clínicos Fase III como Asunto , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Ensayos Clínicos Controlados Aleatorios como Asunto
15.
J Surg Oncol ; 123(3): 760-774, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33595891

RESUMEN

Immune checkpoint inhibition (ICI) has transformed the management of metastatic colorectal cancer (mCRC) with mismatch-repair deficiency (dMMR) and microsatellite instability (MSI-H), though this constitutes on average less than 5% of mCRC, and ICI is ineffective in preserved MMR/microsatellite stable disease (pMMR/MSS). Here we review the efficacy of ICI in dMMR/MSI-H mCRC, poor response to ICI in pMMR/MSS mCRC, role for ICI in locally advanced disease, biomarkers of response, novel immunotherapies, and future directions in targeting resistance mechanisms.


Asunto(s)
Neoplasias Colorrectales/terapia , Inmunoterapia/métodos , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Humanos , Metástasis de la Neoplasia , Ensayos Clínicos Controlados Aleatorios como Asunto
16.
J Surg Oncol ; 123(3): 751-759, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33595893

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer with an urgent need for better medical therapies. Efforts have been made to investigate the efficacy of immunotherapy, particularly given the hallmarks of immune suppression and exhaustion in PDAC tumors. Here, we review the molecular components responsible for the immune-privileged state in PDAC and provide an overview of the immunotherapeutic strategies for PDAC including vaccine therapy, checkpoint blockade, myeloid-targeted therapy, and immune agonist therapy.


Asunto(s)
Carcinoma Ductal Pancreático/terapia , Inmunoterapia/métodos , Neoplasias Pancreáticas/terapia , Animales , Vacunas contra el Cáncer/uso terapéutico , Carcinoma Ductal Pancreático/inmunología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Humanos , Neoplasias Pancreáticas/inmunología , Ensayos Clínicos Controlados Aleatorios como Asunto
17.
J Surg Oncol ; 123(3): 775-781, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33595894

RESUMEN

Merkel cell carcinoma (MCC) is an aggressive form of skin cancer which, while chemosensitive, has high rates of relapse and chemoresistance, limiting the impact of chemotherapy. An immunogenic tumor, the management of advanced MCC has changed dramatically with the introduction of checkpoint inhibitors. This review will focus on the impact of immunotherapy in unresectable and metastatic MCC, ongoing research in the adjuvant and neoadjuvant settings, and future directions of immune-based strategies for this challenging cancer.


Asunto(s)
Carcinoma de Células de Merkel/terapia , Inmunoterapia/métodos , Neoplasias Cutáneas/terapia , Carcinoma de Células de Merkel/inmunología , Ensayos Clínicos como Asunto , Terapia Combinada , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Cutáneas/inmunología
18.
Nat Commun ; 12(1): 1087, 2021 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-33597530

RESUMEN

The introduction of immune checkpoint inhibitors has demonstrated significant improvements in survival for subsets of cancer patients. However, they carry significant and sometimes life-threatening toxicities. Prompt prediction and monitoring of immune toxicities have the potential to maximise the benefits of immune checkpoint therapy. Herein, we develop a digital nanopillar SERS platform that achieves real-time single cytokine counting and enables dynamic tracking of immune toxicities in cancer patients receiving immune checkpoint inhibitor treatment - broader applications are anticipated in other disease indications. By analysing four prospective cytokine biomarkers that initiate inflammatory responses, the digital nanopillar SERS assay achieves both highly specific and highly sensitive cytokine detection down to attomolar level. Significantly, we report the capability of the assay to longitudinally monitor 10 melanoma patients during immune inhibitor blockade treatment. Here, we show that elevated cytokine concentrations predict for higher risk of developing severe immune toxicities in our pilot cohort of patients.


Asunto(s)
Inmunoterapia/métodos , Melanoma/terapia , Monitorización Inmunológica/métodos , Espectrometría Raman/métodos , Quimiocina CX3CL1/inmunología , Quimiocina CX3CL1/metabolismo , Estudios de Cohortes , Citocinas/inmunología , Citocinas/metabolismo , Factor Estimulante de Colonias de Granulocitos/inmunología , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , /inmunología , Ipilimumab/efectos adversos , Ipilimumab/inmunología , Ipilimumab/uso terapéutico , Melanoma/inmunología , Melanoma/metabolismo , Microscopía Confocal/métodos , Proyectos Piloto , Reproducibilidad de los Resultados
19.
Nat Commun ; 12(1): 832, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547304

RESUMEN

The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1+TIM-3+ T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3+ cytotoxic CD8 T cells and immunosuppressive regulatory T cells (Treg cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes Treg cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon ß and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.


Asunto(s)
Adenocarcinoma/terapia , Neoplasias del Colon/terapia , Galectinas/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Proteína Relacionada con TNFR Inducida por Glucocorticoide/inmunología , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Animales , Anticuerpos/farmacología , Antineoplásicos Inmunológicos/farmacología , Neoplasias del Colon/genética , Neoplasias del Colon/inmunología , Neoplasias del Colon/mortalidad , Galectinas/antagonistas & inhibidores , Galectinas/genética , Proteína Relacionada con TNFR Inducida por Glucocorticoide/agonistas , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Receptor 2 Celular del Virus de la Hepatitis A/genética , Humanos , Inmunoterapia/métodos , Células Jurkat , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/mortalidad , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos BALB C , Receptor de Muerte Celular Programada 1/genética , Unión Proteica , Transducción de Señal , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/terapia , Análisis de Supervivencia , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología
20.
Front Immunol ; 12: 627186, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33613575

RESUMEN

After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.


Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Linfocitos B/inmunología , Carcinoma de Células Renales/diagnóstico , Inmunoterapia/métodos , Ipilimumab/uso terapéutico , Neoplasias Renales/diagnóstico , Nivolumab/uso terapéutico , Linfocitos T/inmunología , Anticuerpos Antivirales/sangre , Carcinoma de Células Renales/tratamiento farmacológico , Células Cultivadas , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Neoplasias Renales/tratamiento farmacológico , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias
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