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BACKGROUND: Biliary tract cancers (BTCs) comprise a heterogeneous group of aggressive malignancies with unfavorable prognoses. The benefit of chemotherapy seems to have reached a bottleneck and, therefore, new effective therapeutic strategies for advanced BTCs are needed. Molecularly targeted therapies in selected patients are rapidly changing the situation. However, the low frequency of specific driver alterations in BTCs limits their wide application. Recently, immunotherapeutic approaches are also under active investigation in BTCs, but the role of immunotherapy in BTCs remains controversial. DATA SOURCES: PubMed, Web of Science, and meeting resources were searched for relevant articles published from January 2017 to May 2022. The search aimed to identify current and emerging immunotherapeutic approaches for BTCs. Information on clinical trials was obtained from https://clinicaltrials.gov/ and http://www.chictr.org.cn/. RESULTS: Immunotherapy in BTC patients is currently under investigation, and most of the investigations focused on the application of immune checkpoint inhibitors (ICIs). However, only a subgroup of BTCs with microsatellite-instability high (MSI-H)/DNA mismatch repair-deficient (dMMR) or tumor mutational burden-high (TMB-H) benefit from monotherapy of ICIs, and limited activity was observed in the second or subsequent settings. Nevertheless, promising results come from studies of ICIs in combination with other therapeutic approaches, including chemotherapy, in advanced BTCs, with a moderate toxicity profile. Recent studies demonstrated that compared to GEMCIS alone, durvalumab plus GEMCIS significantly improved patient survival (TOPAZ-1 trial) and that ICIs-combined chemoimmunotherapy is poised to become a new frontline therapy option, regardless of TMB and MMR/MSI status. Adoptive cell therapy and peptide- or dendritic-based cancer vaccines are other immunotherapeutic options that are being studied in BTCs. Numerous biomarkers have been investigated to define their predictive role in response to ICIs, but no predictive biomarker has been validated, except MSI-H/dMMR. CONCLUSIONS: The role of immunotherapy in BTCs is currently under investigation and the results of ongoing studies are eagerly anticipated. Several studies have demonstrated the safety and efficacy of ICIs in combination with chemotherapy in treatment-naive patients, such as the phase III TOPAZ-1 trial, which will change the standard care of first-line chemotherapy for advanced BTCs. However, further research is needed to understand the best combination with immunotherapy and to discover more predictive biomarkers to guide clinical practice.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Vacunas contra el Cáncer , Neoplasias del Sistema Biliar/terapia , Vacunas contra el Cáncer/efectos adversos , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia/métodos , Inestabilidad de MicrosatélitesRESUMEN
INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) is characterized by a dismal prognosis with limited therapeutic alternatives. To explore phosphatase and tension homolog (PTEN) as a biomarker for proteasome inhibition inâICC, we conducted a phase II trial to assess the second-line efficacy of bortezomib in PTEN-deficient advanced ICC patients. METHODS: A total of 130 patients with advanced ICC in our centre were screened by PTEN immunohistochemical staining between 1 July 2017, and 31 December 2021, and 16 patients were ultimately enrolled and treated with single-agent bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. RESULTS: The median follow-up was 6.55 months (95% confidence interval [CI]: 0.7-19.9 months). Among the 16 enrolled patients, the ORR was 18.75% (3/16) and the disease control rate was 43.75% (7/16). The median progress-free survival was 2.95 months (95% CI: 2.1-5.1 months) and the median overall survival (mOS) was 7.2 months (95% CI: 0.7-21.6 months) in the intent-to-treat-patients. Treatment-related adverse events of any grade were reported in 16 patients, with thrombopenia being the most common toxicity. Patients with PTEN staining scores of 0 were more likely to benefit from bortezomib than those with staining scores > 0. CONCLUSIONS: Bortezomib yielded an encouraging objective response and a favourable OS as a second-line agent in PTEN-deficient ICC patients. Our findings suggest bortezomib as a promising therapeutic option for patients with PTEN-deficient ICC. HIGHLIGHTS: There is a limited strategy for the second-line option of intrahepatic cholangiocarcinoma (ICC). This investigator-initiated phase 2 study evaluated bortezomib in ICC patients with phosphatase and tension homology deficiency. The overall response rate was 18.75% and the overall survival was 7.2 months in the intent-to-treat cohort. These results justify further developing bortezomib in ICC patients with PTEN deficiency.
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Neoplasias de los Conductos Biliares , Bortezomib , Colangiocarcinoma , Fosfohidrolasa PTEN , Humanos , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Bortezomib/uso terapéutico , Bortezomib/farmacología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Adulto , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
Gemcitabine is a nucleoside analog that has been successfully used in the treatment of multiple cancers. However, intrinsic or acquired resistance reduces the chemotherapeutic potential of gemcitabine. Here, we revealed a previously unappreciated mechanism by which phosphatase and tensin homolog (PTEN), one of the most frequently mutated genes in human cancers, dominates the decision-making process that is central to the regulation of gemcitabine efficacy in cholangiocarcinoma (CCA). By investigating a gemcitabine-treated CCA cohort, we found that PTEN deficiency was correlated with the improved efficacy of gemcitabine-based chemotherapy. Using cell-based drug sensitivity assays, cell line-derived xenograft, and patient-derived xenograft models, we further confirmed that PTEN deficiency or genetic-engineering down-regulation of PTEN facilitated gemcitabine efficacy both in vitro and in vivo. Mechanistically, PTEN directly binds to and dephosphorylates the C terminus of the catalytic subunit of protein phosphatase 2A (PP2Ac) to increase its enzymatic activity, which further dephosphorylates deoxycytidine kinase (DCK) at Ser74 to diminish gemcitabine efficacy. Therefore, PTEN deficiency and high phosphorylation of DCK predict a better response to gemcitabine-based chemotherapy in CCA. We speculate that the combination of PP2A inhibitor and gemcitabine in PTEN-positive tumors could avoid the resistance of gemcitabine, which would benefit a large population of patients with cancer receiving gemcitabine or other nucleoside analogs.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Fosforilación , Gemcitabina , Nucleósidos , Conductos Biliares Intrahepáticos , Fosfohidrolasa PTENRESUMEN
The prognosis of biliary tract cancer (BTC) remains unsatisfactory. This single-arm, phase II clinical trial (ChiCTR2000036652) investigated the efficacy, safety, and predictive biomarkers of sintilimab plus gemcitabine and cisplatin as the first-line treatment for patients with advanced BTCs. The primary endpoint was overall survival (OS). Secondary endpoints included toxicities, progression-free survival (PFS), and objective response rate (ORR); multi-omics biomarkers were assessed as exploratory objective. Thirty patients were enrolled and received treatment, the median OS and PFS were 15.9 months and 5.1 months, the ORR was 36.7%. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Predefined biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations or loss-of-function mutations in chromatin remodeling genes presented better tumor response and survival outcomes. Furthermore, transcriptome analysis revealed a markedly longer PFS and tumor response were associated with higher expression of a 3-gene effector T cell signature or an 18-gene inflamed T cell signature. Sintilimab plus gemcitabine and cisplatin meets pre-specified endpoints and displays acceptable safety profile, multiomics potential predictive biomarkers are identified and warrant further verification.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Cisplatino/uso terapéutico , Desoxicitidina/uso terapéutico , GemcitabinaRESUMEN
Background: Immune checkpoint inhibitor (ICI)-combined chemotherapy in advanced intrahepatic cholangiocarcinoma has been proved to have more efficacy in a series of clinical trials. However, whether the tumor microenvironment (TME) plays a vital role in immune-combined therapy has not been rigorously evaluated. Methods: Firstly, we assayed the immunogenic properties of GEM-based chemotherapy. Then, 12 ICC patients treated with PD-1 inhibitor (sintilimab) combined with gemcitabine and cisplatin (GemCis) from a phase 2 clinical trial (ChiCTR2000036652) were included and their immune-related gene expression profiles were analyzed using RNA from baseline tumor samples. Immune-related signature correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in an ICC cohort with 26 patients. Multiplexed immunofluorescence (mIF) and flow cytometry (FCM) analysis were performed to evaluate the immune-related molecules with therapeutic outcomes. Results: GEM-based chemotherapy induced immunogenic cell death of cholangiocarcinoma cells, together with increased CD274 expression. In an ICC cohort, we found that upregulation of immune-checkpoint molecules and immune response-related pathways were significantly related to better clinical outcome. On the contrary, baseline immune-cell proportions in tumor tissues did not show any correlation with clinical benefit between responders and non-responders. Immune-related signature (including six genes) correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in a small ICC cohort with 26 patients. Conclusion: Immune-related RNA signature predicts the outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma, which could be tested as a biomarker for immune-chemotherapy in the future.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos/metabolismo , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Cisplatino/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , ARN , Microambiente TumoralRESUMEN
Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chromosome ten (PTEN) deficiency promotes protein synthesis and proteasome subunit expression and proteolytic activity, creating a dependency on the proteasome for cancer cell growth and survival. Thus, targeting the proteasome machinery with the inhibitor bortezomib inhibited the proliferation and survival of CCA cells lacking functional PTEN. Therapeutic evaluation of PDXs, autochthonous mouse models, and patients confirmed this dependency on the proteasome. Mechanistically, we found that PTEN promoted the nuclear translocation of FOXO1, resulting in the increased expression of BACH1 and MAFF BACH1 and MAFF are transcriptional regulators that recognize the antioxidant response element, which is present in genes encoding proteasome subunits. PTEN induced the accumulation and nuclear translocation of these proteins, which directly repressed the transcription of genes encoding proteasome subunits. We revealed that the PTEN-proteasome axis is a potential target for therapy in PTEN-deficient CCA and other PTEN-deficient cancers.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Animales , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos , Bortezomib/farmacología , Bortezomib/uso terapéutico , Línea Celular Tumoral , Colangiocarcinoma/tratamiento farmacológico , Humanos , Ratones , Fosfohidrolasa PTEN/genética , Complejo de la Endopetidasa ProteasomalRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of dose-reduced intravenous busulfan, cyclophosphamide and etoposide (BCV) as conditioning for autologous stem cell transplantation (ASCT) in multiple myeloma (MM). METHODS: From September 2007 to September 2010, thirty-two ASCT-eligible patients with MM received high dose melphalan (HDM) as conditioning in our center. Median age was 53.5 (30-63) years. From October 2010 to October 2012, thirty-eight patients conditioned by BCV regimen (intravenous busulfan, total doses 9.6 mg/kg), whose median age was 54(35-64) years. RESULTS: There were no statistical differences in clinical characteristics between the two groups, including myeloma isotype, Durie-Salmon staging, international staging system(ISS), and patients received the first line, second line or more than third line therapy. The median time to neutrophil and platelet engraftment were 10.5 vs 11 days (P=0.057) and 11 vs 12 days (P=0.100) in the BCV and HDM groups, respectively. The toxicity of two conditioning regimens had no significant difference. None of hepatic veno-occlusive disease and early transplant related mortality was observed. Although overall response rates showed no significant difference between two groups (P>0.05), the CR rates increased from 44.74% pre-ASCT to 63.18% post-ASCT in the BCV group, while 37.50% to 59.38% in the HDM group. During the median follow-up of 16 months (range 2-27) in BCV group, ten patients (26.32%) developed progressive disease and PFS at 12 months were 71.37%. CONCLUSIONS: In this study, the dose-reduced intravenous busulfan, cyclophosphamide and etoposide (BCV) conditioning was demonstrated an effective and safety regimen for ASCT-eligible patients with MM. However, the long term observation is needed.
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Busulfano/uso terapéutico , Ciclofosfamida/uso terapéutico , Etopósido/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/terapia , Acondicionamiento Pretrasplante , Adulto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Trasplante Autólogo , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of bortezomib retreatment in 76 patients with relapsed/refractory multiple myeloma (MM), who previously responded to bortezomib. METHODS: Retrospective analysis of 76 MM patients, who had achieved at least a partial response (PR) on initial bortezomib therapy in our hospital from May 2006 to August 2011, received bortezomib retreatment when they relapsed or progressed. RESULTS: The overall response rate (ORR) was 60.5%, among them 6.5% patients achieved CR, 5.8% patients achieved very good partial response (VGPR), 38.2% patients achieved PR. Then we further stratified all patients into 3 groups according to the response of initial bortezomib therapy, including CR group, VGPR group and PR group. After bortezomib retreatment, the ORR of the 3 groups was 84.6%, 73.1% and 43.2%, respectively. According to the response of bortezomib retreatment, the patients were divided into 2 groups: group 1 who at least achieved PR, group 2 who showed no response. The median progression-free survival (PFS) after bortezomib retreatment for group 1 and 2 was 7(1-39) and 5(1-14) months, respectively (P>0.05), while the median overall survival (OS) after bortezomib retreatment was 16(2-64) and 8(1-28) months, respectively (P<0.05). Adverse events (AE) were identified in 88% patients during bortezomib retreatment, including neutropenia, diarrhea and thrombocytopenia, only 9.2%(7 patients) reached â ¢-â £ grade of AE. Severe peripheral neuropathy occurred in only one patient. CONCLUSION: Bortezomib retreatment regimen is demonstrated a higher response rate in patients who achieved deeper response in initial treatment, with no more adverse events.