RESUMEN
Background: Biliary tract cancer stands as a prevalent illness, posing significant risks to human health, where immune cells are pivotal in both its development and recovery processes. Due to the diverse functionalities exhibited by different immune cell phenotypes within the organism, and the relatively limited research on their relationship with biliary tract cancer, this study employed Mendelian randomization (MR) to explore their potential association, thereby aiding in a better understanding of the causal link between immune cell phenotypes and biliary tract cancer. Methods: In this study, the causative association of 731 immunophenotype with biliary tract cancer was established using publicly accessible genome-wide association study (GWAS) genetic data through two-sample MR analysis. Sensitivity analyses assess horizontal pleiotropy and heterogeneity of the study findings. Results: Among the 731 immunophenotypes examined, a total of 26 immune cell phenotypes were found to exhibit positive results, indicating a significant association with the risk of biliary tract cancer. We confirmed that among these 26 types of immune cells, there are primarily 13 types of B cells; three types of classical dendritic cells (CDCs), including CD80 on myeloid DC, HLA DR on myeloid DC, and Myeloid DC %DC; one type of mature stage T cell,CD4RA on TD CD4+; six types of regulatory T cells; and three types of myeloid cells.
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Neoplasias del Sistema Biliar , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Fenotipo , Humanos , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/inmunología , Predisposición Genética a la Enfermedad , Inmunofenotipificación , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) has enhanced survival outcomes for certain patients with advanced biliary tract carcinoma (BTC). Pinpointing those who would benefit most from immunotherapy remains elusive. We investigated the predictive value of the modified Gustave Roussy Immune Score (mGRIm-s) in BTC patients treated with ICIs. METHODS: Data from 110 patients at Chinese People's Liberation Army General Hospital, spanning September 2015 to April 2021, were analyzed. The median follow-up duration was 38.7 months as of December 2023. Risk factors included low albumin, high lactate dehydrogenase, and an elevated neutrophil-lymphocyte ratio. Patients were stratified into low (patients with no risk factors) and high (patients with at least one risk factor) mGRIm-s groups based on these factors. RESULTS: Survival outcomes post-immunotherapy favored the low mGRIm-s group, with significantly improved progression-free survival (PFS) and overall survival (OS) (8.50 months vs. 3.70 months and 21.60 months vs. 8.00 months). COX regression confirmed an elevated risk in the high mGRIm-s group. Subgroup analysis highlighted a notable survival advantage for low mGRIm-s patients receiving first-line immunotherapy. CONCLUSIONS: This study underscores mGRIm-s's potential in predicting immunotherapy response in BTC, paving the way for more targeted approaches.
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Neoplasias del Sistema Biliar , Inhibidores de Puntos de Control Inmunológico , Humanos , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Anciano , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias del Sistema Biliar/inmunología , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/mortalidad , Adulto , Estudios Retrospectivos , Inmunoterapia/métodos , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Pancreatic and biliary tract cancers are digestive system tumors with dismal prognosis and limited treatment options. The effectiveness of conventional surgical interventions, radiation therapy, and systemic therapy is restricted in these cases. Furthermore, clinical trials have shown that immunotherapy using immune checkpoint inhibitors has only demonstrated modest clinical results when applied to patients with pancreatobiliary tumors. This highlights the importance of implementing combination immunotherapy approaches or exploring alternative therapeutic strategies to improve treatment outcomes. MATERIALS AND METHODS: We reviewed the relevant literature on chimeric antigen receptor (CAR)-T cell therapy for pancreatobiliary cancers from PubMed/Medline and ClinicalTrials.gov and retrieved the relevant data accordingly. Attention was additionally given to the examination of grey literature with the aim of obtaining additional details regarding ongoing clinical trials. We mainly focused on abstracts and presentations and e-posters and slides of recent important annual meetings (namely ESMO Immuno-Oncology Congress, ESMO Congress, ASCO Virtual Scientific Program, ASCO Gastrointestinal Cancers Symposium). RESULTS: CAR-T cell therapy has emerged as a promising and evolving treatment approach for pancreatic and biliary tract cancer. This form of adoptive cell therapy utilizes genetic engineering to modify the expression of specific antibodies on the surface of T cells enabling them to target specific cancer-associated antigens and to induce potent anti-tumor activity. The aim of this review is to provide an updated summary of the available evidence from clinical trials that have explored the application of CAR-T cell therapy in treating pancreatobiliary cancers. CONCLUSIONS: While the utilization of CAR-T cell therapy in pancreatobiliary cancers is still in its initial phases with only a limited amount of clinical data available, the field is advancing rapidly, incorporating novel technologies to mitigate potential toxicities and enhance antigen-directed tumor eradication.
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Neoplasias del Sistema Biliar , Ensayos Clínicos como Asunto , Inmunoterapia Adoptiva , Neoplasias Pancreáticas , Receptores Quiméricos de Antígenos , Humanos , Neoplasias del Sistema Biliar/terapia , Neoplasias del Sistema Biliar/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/inmunología , Receptores Quiméricos de Antígenos/inmunologíaAsunto(s)
Inmunoterapia Adoptiva , Neoplasias Hepáticas , Neoplasias Pancreáticas , Receptores Quiméricos de Antígenos , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/inmunología , Receptores Quiméricos de Antígenos/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/inmunología , Neoplasias del Sistema Biliar/terapia , Neoplasias del Sistema Biliar/inmunología , Resultado del Tratamiento , Inmunoterapia/métodosRESUMEN
Biliary tract cancers continue to increase in incidence and have a high mortality rate. Most of the patients present with advanced-stage disease. The discovery of targetable genomic alterations addressing IDH, FGFR, HER2, BRAFV600 E, and others has led to the identification and validation of novel therapies in biliary cancer. Recent advances demonstrating an improved outcome with the addition of immune checkpoint inhibitors to chemotherapy have established a new first-line care standard. In case of contraindications to the use of checkpoint inhibitors and the absence of targetable alterations, chemotherapy remains to be the standard of care.
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Neoplasias del Sistema Biliar , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Terapia Molecular Dirigida , Humanos , Neoplasias del Sistema Biliar/terapia , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/inmunología , Neoplasias del Sistema Biliar/genética , Terapia Molecular Dirigida/métodos , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
The role of ß-catenin and Dickkopf-1 (DKK1) is dependent on the specific immunobiology of T cell inflammation in biliary tract cancer (BTC). We aimed to analyze the role of DKK1 or ß-catenin as a prognostic factor in BTC, and determine the clinical associations of ß-catenin and DKK1 with CD8+ tumor-infiltrating lymphocytes (TIL). We used data from The Cancer Genome Atlas Research Network and the clinicopathological data of 145 patients with BTC who had undergone primary radical resection between 2006 and 2016. CD8+ TIL expression was a significant predictor of favorable overall survival (OS) and relapse-free survival (RFS) (median OS, 34.9 months in high-TIL, 16.7 months in low-TIL, P < 0.0001 respectively; median RFS, 27.1 months in high-TIL, 10.0 months in low-TIL, P < 0.0001 respectively). In the high-CD8+ TIL BTC group, the tumor expression of ß-catenin and DKK1 had a significant negative impact on either OS or RFS. In the low-TIL BTC group, there were no differences according to ß-catenin and DKK1 expression. Cox regression multivariate analysis demonstrated that CD8+ TIL and ß-catenin retained significant association with OS. Among patients with resected BTC, the ß-catenin and DKK1 protein and high CD8+ TIL levels were associated with poor and good clinical outcomes, respectively.
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Neoplasias del Sistema Biliar/química , Biomarcadores de Tumor/análisis , Linfocitos T CD8-positivos/inmunología , Péptidos y Proteínas de Señalización Intercelular/análisis , Linfocitos Infiltrantes de Tumor/inmunología , beta Catenina/análisis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Biliar/inmunología , Neoplasias del Sistema Biliar/mortalidad , Neoplasias del Sistema Biliar/cirugía , Bases de Datos Genéticas , Femenino , Humanos , Inmunohistoquímica , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , Estudios Retrospectivos , Factores de Tiempo , Microambiente TumoralRESUMEN
BACKGROUND: The gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims to investigate the relationship between the gut microbiome and the clinical response to anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced hepatobiliary cancers. METHODS: Patients with unresectable hepatocellular carcinoma or advanced biliary tract cancers who have progressed from first-line chemotherapy (gemcitabine plus cisplatin) were enrolled. Fresh stool samples were collected before and during anti-PD-1 treatment and analyzed with metagenomic sequencing. Significantly differentially enriched taxa and prognosis associated taxa were identified. The Kyoto Encyclopedia of Genes and Genomes database and MetaCyc database were further applied to annotate the differentially enriched taxa to explore the potential mechanism of the gut microbiome influencing cancer immunotherapy. RESULTS: In total, 65 patients with advanced hepatobiliary cancers receiving anti-PD-1 treatment were included in this study. Seventy-four taxa were significantly enriched in the clinical benefit response (CBR) group and 40 taxa were significantly enriched in the non-clinical benefit (NCB) group. Among these taxa, patients with higher abundance of Lachnospiraceae bacterium-GAM79 and Alistipes sp Marseille-P5997, which were significantly enriched in the CBR group, achieved longer progression-free survival (PFS) and overall survival (OS) than patients with lower abundance. Higher abundance of Ruminococcus calidus and Erysipelotichaceae bacterium-GAM147 enriched in the CBR group was also observed in patients with better PFS. In contrast, worse PFS and OS were found in patients with higher abundance of Veillonellaceae, which was significantly enriched in the NCB group. Functional annotation indicated that the taxa enriched in the CBR group were associated with energy metabolism while the taxa enriched in the NCB group were associated with amino acid metabolism, which may modulate the clinical response to immunotherapy in hepatobiliary cancers. In addition, immunotherapy-related adverse events were affected by the gut microbiome diversity and relative abundance. CONCLUSIONS: We demonstrate that the gut microbiome is associated with the clinical response to anti-PD-1 immunotherapy in patients with hepatobiliary cancers. Taxonomic signatures enriched in responders are effective biomarkers to predict the clinical response and survival benefit of immunotherapy, which might provide a new therapeutic target to modulate the response to cancer immunotherapy.
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Neoplasias del Sistema Biliar/tratamiento farmacológico , Carcinoma Hepatocelular/tratamiento farmacológico , ADN Bacteriano/genética , Microbioma Gastrointestinal , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias del Sistema Biliar/inmunología , Neoplasias del Sistema Biliar/microbiología , Neoplasias del Sistema Biliar/patología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/microbiología , Carcinoma Hepatocelular/patología , ADN Bacteriano/análisis , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/microbiología , Neoplasias Hepáticas/patología , Masculino , Metagenómica , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND AND OBJECTIVES: We evaluated the changes in natural killer cell activity (NKA) during the entire treatment period of patients with resectable biliopancreatic cancers and investigated the predictors of the failure of recovery of NKA after surgery. METHODS: A total of 202 patients who underwent curative resection for biliopancreatic cancer were enrolled in the study. NKA levels were measured six times during the treatment period. We investigated whether there was any difference in postoperative NKA recovery according to the period-by-time NKA value. RESULTS: NKA decreased after surgery (mean, 40 pg/ml) compared to the NKA value at admission (200.2 pg/ml), then began to increase from 3 weeks after surgery (139.7 pg/ml) and rose to normal NKA levels at 5 weeks (217.1 pg/ml). The pattern of NKA changes was distinct according to the NKA values at admission. In multivariate analysis, NKA values of less than 250 pg/ml at admission (odds ratio = 5.898, p = 0.044) were a predictor of NKA recovery failure 5 weeks after surgery. CONCLUSIONS: NKA rapidly decreased after curative surgery for biliopancreatic cancer and recovered to normal levels about 5 weeks later. Clinicians should be aware and cautious that patients with low NKA at admission may fail to recover NKA postoperatively.
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Neoplasias de los Conductos Biliares/patología , Neoplasias del Sistema Biliar/patología , Procedimientos Quirúrgicos del Sistema Biliar/métodos , Células Asesinas Naturales/inmunología , Pancreatectomía/métodos , Neoplasias Pancreáticas/patología , Recuperación de la Función , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/inmunología , Neoplasias de los Conductos Biliares/cirugía , Neoplasias del Sistema Biliar/inmunología , Neoplasias del Sistema Biliar/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/cirugía , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: This study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers. METHODS: Three cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel. RESULTS: Based on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank p<0.01). In the non-ICI cohort, the CNV risk score was not associated with PFS or OS. Furthermore, the results indicated that 53% of patients with low CNV risk scores achieved durable clinical benefit; in contrast, 88% of patients with high CNV risk scores could not benefit from combination therapy (p<0.05). CONCLUSIONS: The CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.
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Neoplasias del Sistema Biliar/tratamiento farmacológico , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Variaciones en el Número de Copia de ADN , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Beijing , Neoplasias del Sistema Biliar/sangre , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/inmunología , Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/sangre , Ensayos Clínicos como Asunto , Análisis Mutacional de ADN , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Masculino , Persona de Mediana Edad , Mutación , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Sistema Biliar/terapia , Inmunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/inmunología , Neoplasias del Sistema Biliar/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificaciónRESUMEN
BACKGROUND: As the prognosis of biliary tract cancer (BTC) is extremely poor and treatment options are limited, new treatment modalities are urgently needed. We designed a phase II clinical trial to investigate the immune responses and clinical benefits of OCV-C01, an HLA-A*24:02-restricted three-peptide cancer vaccine targeting VEGFR1, VEGFR2, and KIF20A. PATIENTS AND METHODS: Participants were patients with advanced BTC who had unresectable tumours and were refractory to standard chemotherapy. OCV-C01 was injected weekly until the discontinuance criteria were met. RESULTS: Six participants, including four patients positive for HLA-A*24:02, were enrolled in this study for assessment of efficacy. Four out of six patients exhibited vaccine-specific T-cell responses to one or more of three antigens. Log-rank tests revealed that vaccine-specific T cell responses contributed significantly to overall survival. CONCLUSION: The cancer vaccine had positive effects on survival, indicating that this approach warrants further clinical studies.
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Neoplasias del Sistema Biliar/tratamiento farmacológico , Vacunas contra el Cáncer/administración & dosificación , Cinesinas/antagonistas & inhibidores , Vacunas de Subunidad/administración & dosificación , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Biliar/inmunología , Neoplasias del Sistema Biliar/metabolismo , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Supervivencia sin Enfermedad , Femenino , Fiebre/inducido químicamente , Cefalea/inducido químicamente , Humanos , Cinesinas/inmunología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Pronóstico , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Vacunas de Subunidad/efectos adversos , Vacunas de Subunidad/inmunología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/inmunología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/inmunologíaRESUMEN
BACKGROUND: In advanced biliary tract carcinoma (BTC), the prognosis is very poor, and the overall survival is less than 1 year. This study aimed to determine the effect of neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), C-reactive protein (CRP)/albumin ratio (CAR), and prognostic nutritional index (PNI) on the survival of BTC patients treated with gemcitabine/oxaliplatin (GEMOX) regimen. METHODS: Data of 53 patients with advanced BTC were evaluated retrospectively. Association between inflammatory markers and 6-month PFS and 12-month OS were compared by the log-rank test. The optimal cutoff values were determined by a receiver operating characteristic (ROC) curve analysis. NLR, dNLR, CAR, and PNI were grouped based on cutoff points 1.95, 1.15, 0.57, and 33, respectively. Univariate and multivariate analyses were used to assess their prognostic values for survival. RESULTS: Lower dNLR (< 1.15) was prognostic for higher 6-month PFS and 12-month OS rates, while lower NLR (< 1.95) was prognostic for higher 6-month PFS rates only. CAR and PNI did not have statistically significant effects on survival. CONCLUSIONS: Pretreatment dNLR and NLR values in advanced BTC can be used as predictive markers for survival in patients undergoing the GEMOX regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/mortalidad , Biomarcadores de Tumor/sangre , Carcinoma/mortalidad , Desoxicitidina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Biliar/sangre , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/inmunología , Biomarcadores de Tumor/inmunología , Carcinoma/sangre , Carcinoma/tratamiento farmacológico , Carcinoma/inmunología , Desoxicitidina/uso terapéutico , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Inflamación/inmunología , Recuento de Linfocitos , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Evaluación Nutricional , Compuestos Organoplatinos/uso terapéutico , Pronóstico , Supervivencia sin Progresión , Medición de Riesgo/métodosRESUMEN
BACKGROUND: Chemotherapy is a standard regimen for advanced or relapsed biliary tract cancer (BTC) with a 5-year overall survival (OS) rate of approximately 5% and a median OS of less than a year. Targeted therapies and immunotherapy aimed at providing more personalized treatments for BTCs have been tested. The objective of this study was to evaluate the effects of targeted therapy and immunotherapy on advanced BTC patients. METHODS: Twenty-four advanced/relapsed BTC patients were enrolled and examined with next-generation sequencing (NGS). Eight of them received NGS-guided targeted or immunotherapy, and the other 16 patients underwent routine chemotherapy. Comparison analysis of OS and objective response rate (ORR) was performed. RESULTS: IDH1, BRCA2, MAP2K1, and BRAF (V600E) were the major actionable genes mutated in this cohort. Patients who received NGS-guided therapy exhibited higher OS (not achieved vs. 6.5 months, p < 0.001) and ORR (87.5% vs. 25%, p < 0.001) than those without targetable mutations and who received first-line chemotherapy. BTCs harboring mutations in IDH1, ATM/BRCA2, or MAP2K1/BRAF (V600E) received treatment with dasatinib, olaparib, or trametinib, respectively. Three of the patients had high tumor mutation burden (TMB-H) and were treated with immune-checkpoint inhibitors and chemotherapy. All these patients achieved complete response or partial response. CONCLUSIONS: NGS-guided targeted therapy and immunotherapy are promising personalized therapies for advanced or relapsed BTCs. TMB is a useful biomarker for predicting immunotherapy efficacy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/terapia , Biomarcadores de Tumor/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Inmunoterapia/métodos , Terapia Molecular Dirigida/métodos , Recurrencia Local de Neoplasia/terapia , Adulto , Anciano , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/inmunología , Neoplasias del Sistema Biliar/patología , Terapia Combinada , Dasatinib/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Pronóstico , Estudios Prospectivos , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Tasa de SupervivenciaRESUMEN
OBJECTIVE: CAR T cell therapy is an innovative approach to treat cancers in the modern era. It utilizes the application of chimeric antigen receptors targeted against specific antigens expressed by the tumor cells. Although its efficacy is established in hematological malignancies, the safety and efficacy of this therapy in solid tumors, especially pancreaticobiliary cancers, is a highly investigated aspect. A focused review of clinical data was conducted to examine the outcomes of this therapy in pancreaticobiliary cancers. METHODS: A comprehensive literature search was done on Medline and Embase databases through April 24, 2020 for studies that evaluated the outcomes of CAR T cell therapy in pancreaticobiliary cancers. RESULTS: There were six phase 1 trials, while one was phase 1/2. Some of these trials were specifically done for pancreaticobiliary cancers, while others included patients of various solid organ cancers, including pancreatic and biliary tract cancers. The target antigens for therapy in these trials included mesothelin, CD133, prostate stem cell antigen, claudin 18.2, epidermal growth factor receptor, and human epidermal growth factor receptor 2. CAR T cell therapy has shown very few grade 3 and 4 side effects. Most of the adverse events are associated with cytokine release syndrome. CONCLUSION: CAR T cell therapy has a manageable safety profile based on phase 1 studies, and efficacy assessments are currently ongoing in dose expansion and phase 2 studies.
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Neoplasias del Sistema Biliar/terapia , Inmunoterapia Adoptiva/efectos adversos , Neoplasias Pancreáticas/terapia , Receptores Quiméricos de Antígenos/inmunología , Antígenos de Neoplasias/inmunología , Neoplasias del Sistema Biliar/inmunología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Humanos , Inmunoterapia Adoptiva/métodos , Neoplasias Pancreáticas/inmunología , Resultado del TratamientoRESUMEN
Introduction: Cancers of the biliary tract (BTC) are aggressive malignancies with limited treatment options and an overall dismal prognosis. In recent years, two concepts, namely precision oncology and immune oncology (IO) have profoundly influenced and, in some cancers, even revolutionized tumor treatments. While positive data from randomized trials have led to the incorporation of targeted concepts for genetically select BTC patients, IO is not yet implemented in clinical practice.Areas covered: We discuss published results from completed, as well as from ongoing studies on IO in BTC, based on a literature search on Pubmed and information provided by clinicaltrials.gov in October 2020. Apart from monotherapy, we outline IO-based combination approaches and highlight pivotal studies whose results will likely influence the future development of relevant concepts in BTC.Expert opinion: Despite partially positive signals, IO thus far disappointed in unselected BTC populations and should currently not be considered as a preferred systemic treatment in patients with microsatellite stable disease outside of clinical trials. In the coming years, a better understanding of the molecular mechanisms underlying resistance to checkpoint inhibition, and the identification of positive predictive biomarkers will be important for the successful integration of IO into treatment concepts for BTC patients.
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Antineoplásicos Inmunológicos/administración & dosificación , Neoplasias del Sistema Biliar/tratamiento farmacológico , Inmunoterapia/métodos , Neoplasias del Sistema Biliar/inmunología , Biomarcadores de Tumor/metabolismo , Humanos , Terapia Molecular Dirigida , Selección de Paciente , Medicina de Precisión , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Introduction: Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies comprising intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer. Although recent years have witnessed the emergence of novel treatment targets, medical therapy remains a compelling challenge in these hepatobiliary malignancies. In order to provide more effective treatment options, immune checkpoint inhibitors (ICIs) are currently under investigation in advanced BTC, with controversial results reported so far.Areas covered: This review provides an overview regarding current scenario of ICIs and immune-based combinations in advanced BTC, where several novel treatments are currently being developed, some of which have suggested interesting efficacy in recent clinical trials. In addition, we provide a report of ongoing Phase I to III clinical trials assessing ICIs and new immunotherapeutic strategies for advanced BTC.Expert opinion: Although immunotherapy has revolutionized the treatment landscape of several hematological and solid tumors, the role of ICIs and immune-based combinations in advanced BTC is still unclear. Despite ICI monotherapy has reported limited efficacy in this setting, the durable responses observed in sporadic cases suggest that testing patients for MMR, MSI, TMB, and PD-L1 expression is warranted. Results of currently ongoing trials are highly awaited.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/diagnóstico , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/inmunología , Biomarcadores/análisis , Biomarcadores de Tumor/análisis , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Factores Inmunológicos/uso terapéutico , Inmunoterapia , Terapia Molecular DirigidaRESUMEN
The transcription factor E74-like factor 3 (ELF3) is inactivated in a range of cancers, including biliary tract cancer (BTC). Here, we investigated the tumor-suppressive role of ELF3 in bile duct cells by identifying several previously unknown direct target genes of ELF3 that appear to be implicated in biliary duct carcinogenesis. ELF3 directly repressed ZEB2, a key regulator of epithelial-mesenchymal transition, and upregulated the expression of CGN, an integral element in lumen formation. Loss of ELF3 led to decreased cell-cell junctions and enhanced cell motility. ALOX5 and CXCL16 were also identified as additional direct targets of ELF3; their corresponding proteins 5-lipoxygenase and CXCL16 play a role in the immune response. Conditioned medium from cells overexpressing ELF3 significantly enhanced the migration of natural killer cells and CD8+ T cells toward the conditioned medium. Gene expression profiling for BTC expressing high levels of ELF3 revealed significant enrichment of the ELF3-related genes. In a BTC xenograft model, activation of ELF3 increased expression of ELF3-related genes, enhanced the tubular structure of the tumors, and led to a loss of vimentin. Overall, our results indicate that ELF3 is a key regulator of both epithelial integrity and immune responses in BTC. SIGNIFICANCE: Thease finding shows that ELF3 regulates epithelial integrity and host immune responses and functions as a tumor suppressor in biliary tract cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/2/489/F1.large.jpg.
Asunto(s)
Neoplasias del Sistema Biliar/patología , Biomarcadores de Tumor/metabolismo , Linfocitos T CD8-positivos/inmunología , Proteínas de Unión al ADN/metabolismo , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-ets/metabolismo , Factores de Transcripción/metabolismo , Anciano , Animales , Apoptosis , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/inmunología , Neoplasias del Sistema Biliar/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Movimiento Celular , Proliferación Celular , Proteínas de Unión al ADN/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Pronóstico , Proteínas Proto-Oncogénicas c-ets/genética , Factores de Transcripción/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND/AIM: This study evaluated the prognostic significance of preoperative neutrophil-to-lymphocyte ratio (NLR) and CD8+ tumor-infiltrating lymphocytes (TILs), and whether preoperative NLR was associated with CD8+ TILs in biliary tract cancers (BTCs). PATIENTS AND METHODS: A total of 154 patients with BTCs who underwent surgery were enrolled in this study. We obtained neutrophil and lymphocyte counts, and calculated NLR from preoperative peripheral blood samples. CD8+ TILs were identified by immunohistochemical staining. RESULTS: The overall survival (OS) and recurrence-free survival (RFS) of patients with high NLR were shorter than those with low NLR. The OS and RFS of patients with high CD8+ TILs were longer than those with low CD8+ TILs. Preoperative NLR and CD8+ TILs were negatively correlated. CONCLUSION: NLR and CD8+ TILs were associated with OS and RFS in BTCs. NLR can predict CD8+ TILs infiltrating the cancer microenvironment.
Asunto(s)
Neoplasias del Sistema Biliar/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos/inmunología , Neutrófilos/inmunología , Anciano , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Patients with biliary tract cancer (BTC) have poor prognosis with few treatment options. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor (TGF)-ßRII receptor (a TGF-ß 'trap') fused to a human IgG1 antibody blocking programmed death ligand 1 (PD-L1), has shown clinical efficacy in multiple solid tumors. METHODS: In this phase I, open-label trial expansion cohort, Asian patients with BTC whose disease progressed after first-line chemotherapy received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint is safety/tolerability, while the secondary endpoints include best overall response per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: As of August 24, 2018, 30 patients have received bintrafusp alfa for a median of 8.9 (IQR 5.7-32.1) weeks; 3 patients remained on treatment for >59.7 weeks. Nineteen (63%) patients experienced treatment-related adverse events (TRAEs), most commonly rash (17%), maculopapular rash and fever (13% each), and increased lipase (10%). Eleven (37%) patients had grade ≥3 TRAEs; three patients had grade 5 events (septic shock due to bacteremia, n=1; interstitial lung disease (reported term: interstitial pneumonitis), n=2). The objective response rate was 20% (95% CI 8 to 39) per independent review committee (IRC), with five of six responses ongoing (12.5+ to 14.5+ months) at data cut-off. Two additional patients with durable stable disease had a partial response per investigator. Median progression-free survival assessed by IRC and overall survival were 2.5 months (95% CI 1.3 to 5.6) and 12.7 months (95% CI 6.7 to 15.7), respectively. Clinical activity was observed irrespective of PD-L1 expression and microsatellite instability-high status. CONCLUSIONS: Bintrafusp alfa had clinical activity in Asian patients with pretreated BTC, with durable responses. Based on these results, bintrafusp alfa is under further investigation in patients with BTC (NCT03833661 and NCT04066491). TRIAL REGISTRATION NUMBER: NCT02699515.
Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Neoplasias del Sistema Biliar/tratamiento farmacológico , Inmunoconjugados/efectos adversos , Proteínas Recombinantes de Fusión/efectos adversos , Adulto , Anciano , Antineoplásicos Inmunológicos/administración & dosificación , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Neoplasias del Sistema Biliar/inmunología , Neoplasias del Sistema Biliar/mortalidad , Femenino , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/genética , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/metabolismo , Adulto JovenRESUMEN
Biliary tract cancers (BTC) comprise a group of rare and heterogeneous poor-prognosis tumours with the incidence of intrahepatic cholangiocarcinoma increasing over recent years. Combination chemotherapy with gemcitabine and cisplatin is the established first-line treatment for advanced BTC with a significant but modest survival advantage over monotherapy. There remains no accepted standard treatment in the second-line setting, although recent results from a randomised study have shown a survival benefit with 5-fluorouracil and oxaliplatin chemotherapy. Historically, clinical trials investigating targeted therapies in unselected BTC have failed to demonstrate significant clinical benefit. More recently, advancement in molecular exploration of BTC has shed light on the complex biological heterogeneity within these tumours and has also identified actionable genomic aberrations, such as fibroblast growth factor receptor 2 (FGFR2) gene fusions, isocitrate dehydrogenase (IDH) and BRAF mutations, which offer promise with the anticipation of increased responses and durable clinical benefit in selected patients. Several targeted drugs have now entered clinical development with some encouraging results being seen. Here we review the current and rapidly evolving therapeutic landscape of advanced BTC, including targeted therapies and immunotherapy. We also discuss how recent efforts and successes in BTC are overcoming the obstacles typically associated with precision medicine in rare cancers. Ultimately, the management of advanced BTC is likely to become molecularly selected in the near future with the hope of finally improving the bleak prognosis of patients with this disease.