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Sun Z, Liu C, Yao Y, Gao C, Li H, Wang L, Li Y, Sun C. Therapeutic potential of triple-negative breast cancer immune checkpoint blockers: A 21-year bibliometric analysis. Medicine (Baltimore) 2025; 104:e41739. [PMID: 40068043 PMCID: PMC11903016 DOI: 10.1097/md.0000000000041739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is an aggressive metastatic subtype of BC that frequently develops chemoresistance. Immune checkpoint blockers (ICB) have led to breakthroughs in TNBC treatment. This study aimed to explore research trends and public interest in ICB interventions for TNBC. METHODS We searched the Web of Science Core Collection (WoSCC) database for publications related to ICB for TNBC from 2003 to 2024. VOSviewer, CiteSpace, and R package "bibliometrix" were used to analyze the characteristics of ICB publications in TNBC from a quantitative and qualitative perspective and to visualize the results to comprehensively present the research trends in this field. RESULTS After removing duplicates, 2698 publications were included. The New England Journal of Medicine may be the leading and influential in the field of ICB in TNBC according to data on the total number of publications, number of citations, and impact factors. Its article entitled "Atezolizumab and Nab-Paclitaxel in Advanced TNBC" is 1 of the most cited articles. Keyword analysis showed that current research hotspots in this field are tumor microenvironment, complete pathological response, neoadjuvant chemotherapy, and PARP inhibitors. Future research hotspots may include the PD-L1 inhibitor durvalumab and antibody-drug conjugates (ADC). CONCLUSIONS This study revealed that ICB therapy for TNBC is a rapidly evolving and high-profile topic. Future research should focus on the optimal selection of different targets for ICB in combination with neoadjuvant chemotherapy, ADC, and poly ADP-ribose polymerase inhibitors to treat TNBC.
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Affiliation(s)
- Zhongli Sun
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
- Department of Traditional Chinese Medicine, Chongqing Three Gorges Medical College, Chongqing, China
| | - Cun Liu
- Department of Traditional Chinese Medicine, Weifang Medical University, Weifang, China
| | - Yan Yao
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chundi Gao
- Department of Traditional Chinese Medicine, Weifang Medical University, Weifang, China
| | - Huayao Li
- Department of Traditional Chinese Medicine, Weifang Medical University, Weifang, China
| | - Longyun Wang
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China
| | - Ye Li
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China
| | - Changgang Sun
- Department of Traditional Chinese Medicine, Weifang Medical University, Weifang, China
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China,
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Baretti M, Shekhar S, Sahai V, Shu D, Howe K, Gunchick V, Assarzadegan N, Kartalia E, Zhu Q, Hallab E, Sheth-Shah A, Kondo A, Azad NS, Yarchoan M. Deep immune profiling of intrahepatic cholangiocarcinoma with CODEX multiplexed imaging. Hepatol Commun 2025; 9:e0632. [PMID: 39969434 PMCID: PMC11841852 DOI: 10.1097/hc9.0000000000000632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 11/05/2024] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (iCCA) may be genomically subclassified by the presence of potentially actionable molecular aberrations, of which pathogenic alterations in isocitrate dehydrogenase (IDH)1 and fibroblast growth factor receptor (FGFR)2 are the most frequently observed. The impact of these molecular alterations on the tumor immune microenvironment remains incompletely understood. METHODS We performed a high-parameter spatial immune phenotyping of iCCA samples with pathogenic FGFR2 or IDH1 alterations and FGFR2/IDH1 wild-type controls at the single-cell level using CO-Detection by indEXing. RESULTS A total of 24 tumors were examined. Tumors with FGFR2 alterations were characterized by fewer CD8+ T cells and "M2-like" macrophages but higher levels of polymorphonuclear myeloid-derived suppressor cells as compared to FGFR2 wild-type tumors. Spatial relationships between polymorphonuclear myeloid-derived suppressor cells and multiple other cell types in the tumor microenvironment (including tumor cells, CD4+, and CD8+ T cells) were enriched in tumors with FGFR2 alterations. Tumors with IDH1 mutations had a trend toward more fibroblasts and were characterized by a closer proximity of tumor cells to CD4+ T cells, and between macrophages and multiple structural tumor microenvironment components as compared to other subtypes. CONCLUSIONS iCCAs with pathogenic FGFR2 fusions/rearrangements and IDH1 mutations have distinct immunophenotypes. Tailoring immunotherapeutic approaches to specific molecular subsets could improve treatment outcomes across the divergent molecularly defined iCCA subtypes.
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Affiliation(s)
- Marina Baretti
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Soumya Shekhar
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Vaibhav Sahai
- Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Rogel Cancer Center, Ann Arbor, Michigan, USA
| | - Daniel Shu
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Kathryn Howe
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Valerie Gunchick
- Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Rogel Cancer Center, Ann Arbor, Michigan, USA
| | - Naziheh Assarzadegan
- Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Rogel Cancer Center, Ann Arbor, Michigan, USA
| | - Emma Kartalia
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Qingfeng Zhu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Elsa Hallab
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | | | - Aya Kondo
- Enable Medicine, Menlo Park, California, USA
| | - Nilofer S. Azad
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Mark Yarchoan
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
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Kim Y, Song J, Kim N, Sim T. Recent progress in emerging molecular targeted therapies for intrahepatic cholangiocarcinoma. RSC Med Chem 2025:d4md00881b. [PMID: 39925737 PMCID: PMC11800140 DOI: 10.1039/d4md00881b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/11/2025] [Indexed: 02/11/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a diverse group of epithelial malignant tumors arising from the biliary tract, characterized by high molecular heterogeneity. It is classified into intrahepatic (iCCA) and extrahepatic CCA (eCCA) based on the location of the primary tumor. CCA accounts for approximately 15% of all primary liver cancers, with iCCA comprising 10-20% of all CCAs. iCCA is especially known for its characteristic aggressiveness and refractoriness, leading to poor prognosis. Despite the increasing global incidence and mortality rates, surgery remains the only available standard treatment approach for a subset (25%) of patients with early-stage, resectable iCCA. The paucity of effective systemic medical therapies restricts therapeutic options for patients with advanced or metastatic iCCA. In the past decade, advances in the understanding of the molecular complexity of these tumors have provided fruitful insights for the identification of promising new druggable targets and the development of feasible therapeutic strategies that may improve treatment outcomes for patients with iCCA. In this review, we aim to highlight critical up-to-date studies and medicinal chemistry aspects, focusing on novel targeted approaches utilizing promising candidates for molecular targeted therapy in iCCA. These candidates include aberrations in isocitrate dehydrogenase (IDH) 1/2, fibroblast growth factor receptor (FGFR), B-Raf proto-oncogene (BRAF), neurotrophic tyrosine receptor kinase (NTRK), human epidermal growth factor receptor 2 (HER2), and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1). Furthermore, this review provides an overview of potential inhibitors aimed at overcoming acquired drug resistance in these actionable targets for iCCA.
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Affiliation(s)
- Younghoon Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University 145 Anam-ro, Seongbuk-gu Seoul 02841 Korea
- Department of Biomedical Sciences, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea +822 2228 0797
- Clinical Candidate Discovery & Development Institute, Yonsei University College of Medicine Seoul Korea
| | - Jaewon Song
- Graduate School of Clinical Drug Discovery & Development, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea
| | - Namkyoung Kim
- Department of Biomedical Sciences, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea +822 2228 0797
| | - Taebo Sim
- KU-KIST Graduate School of Converging Science and Technology, Korea University 145 Anam-ro, Seongbuk-gu Seoul 02841 Korea
- Department of Biomedical Sciences, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea +822 2228 0797
- Clinical Candidate Discovery & Development Institute, Yonsei University College of Medicine Seoul Korea
- Graduate School of Clinical Drug Discovery & Development, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea
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Zhan T, Betge J, Schulte N, Dreikhausen L, Hirth M, Li M, Weidner P, Leipertz A, Teufel A, Ebert MP. Digestive cancers: mechanisms, therapeutics and management. Signal Transduct Target Ther 2025; 10:24. [PMID: 39809756 PMCID: PMC11733248 DOI: 10.1038/s41392-024-02097-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 10/20/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025] Open
Abstract
Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.
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Affiliation(s)
- Tianzuo Zhan
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johannes Betge
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Schulte
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena Dreikhausen
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Michael Hirth
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Moying Li
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philip Weidner
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Antonia Leipertz
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
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Dai B, Jiang J, Yu X, Zhan H, Hu Z. Efficacy and safety of nivolumab plus ipilimumab in gastrointestinal cancers: a systematic review and meta-analysis. Front Oncol 2025; 14:1515992. [PMID: 39839773 PMCID: PMC11746121 DOI: 10.3389/fonc.2024.1515992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 12/16/2024] [Indexed: 01/23/2025] Open
Abstract
Introduction Gastrointestinal (GI) cancers represent a significant global health burden, and the need for more effective treatment options is exceptionally pressing. The present meta-analysis aimed to explore the efficacy and safety of the combination of nivolumab and ipilimumab in treating GI cancers. Methods A systematic search of four databases (PubMed, Embase, Web of Science, and Cochrane Library) was conducted for articles on the treatment of GI cancers with nivolumab combined with ipilimumab, published from 2014 up to 30 August 2024. The inclusion criteria were designed according to the principles of Participants, Intervention, Control, Outcomes, and Study (PICOS). The control group was chemotherapy or nivolumab monotherapy or nivolumab in combination with other drugs. We extracted data from 10 randomized controlled trials and utilized a random effects model to assess the objective response rate (ORR), median progression-free survival (mPFS), median overall survival (mOS), median duration of response (mDOR), and treatment-related adverse events (TRAEs). The data analysis was conducted using Review Manager version 5.4 and Stata version 12.0. Results Overall, the combination of nivolumab and ipilimumab demonstrated superior outcomes, including a higher ORR (OR = 1.69, P = 0.01), prolonged mOS (MD = 1.74, P = 0.04) and extended mDOR (MD = 5.64, P < 0.00001) compared to the control group. Subgroup analysis demonstrated that the ORR (OR = 1.75, P = 0.02) and mOS (MD = 5.02, P = 0.003) were significantly improved in patients with esophageal cancer. Notably, the ORR in patients with biliary cancer was significantly lower (OR = 0.11, P = 0.04). Additionally, the ORR was significantly higher in the NIVO1 + IPI3group (OR = 2.82, P = 0.01) and NIVO3 + IPI1 group (OR = 1.62, P = 0.01). Regarding safety, there was no statistically significant difference between the combination regimen and the control group in terms of any grade (OR = 0.72, P = 0.26) or grade 3-4 TRAEs (OR = 1.36, P = 0.14). Conclusions Nivolumab in combination with ipilimumab demonstrated significant efficacy in GI cancers (especially esophageal cancer) without causing more adverse reactions. However, its efficacy in biliary cancer still needs to be further proven. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42024590994.
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Affiliation(s)
- Bowen Dai
- Southwest Medical University, Luzhou, China
| | | | - Xiaoyu Yu
- Southwest Medical University, Luzhou, China
| | | | - Zhengchuan Hu
- Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
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Santoso A, Levink I, Pihlak R, Chau I. The Immune Landscape and Its Potential for Immunotherapy in Advanced Biliary Tract Cancer. Curr Oncol 2024; 32:24. [PMID: 39851940 PMCID: PMC11763487 DOI: 10.3390/curroncol32010024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/19/2024] [Accepted: 12/25/2024] [Indexed: 01/26/2025] Open
Abstract
Biliary tract cancers (BTC) are a highly heterogeneous group of cancers at the genomic, epigenetic and molecular levels. The vast majority of patients initially present at an advanced (unresectable) disease stage due to a lack of symptoms and an aggressive tumour biology. Chemotherapy has been the mainstay of treatment in patients with advanced BTC but the survival outcomes and prognosis remain poor. The addition of immune checkpoint inhibitors (ICI) to chemotherapy have shown only a marginal benefit over chemotherapy alone due to the complex tumour immune microenvironment of these cancers. This review appraises our current understanding of the immune landscape of advanced BTC, including emerging transcriptome-based classifications, highlighting the mechanisms of immune evasion and resistance to ICI and their therapeutic implications. It describes the shifting treatment paradigm from traditional chemotherapy to immunotherapy combinations as well as the potential biomarkers for predicting response to ICI.
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Affiliation(s)
- Andry Santoso
- Gastrointestinal Unit, The Royal Marsden Hospital, London SW3 6JJ, UK; (A.S.); (I.L.)
| | - Iris Levink
- Gastrointestinal Unit, The Royal Marsden Hospital, London SW3 6JJ, UK; (A.S.); (I.L.)
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, 3015 GD Rotterdam, The Netherlands
| | - Rille Pihlak
- University Hospitals Sussex NHS Foundation Trust, Brighton BN1 9RW, UK;
| | - Ian Chau
- Gastrointestinal Unit, The Royal Marsden Hospital, London SW3 6JJ, UK; (A.S.); (I.L.)
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Sahai V, Griffith KA, Lin BS, Soares HP, Chandana SR, Crysler O, Kumar-Sinha C, Enzler T, Dippman D, Gunchick V, Zalupski MM. BilT03: Phase 1b/2 multicenter trial of nivolumab with 5-fluorouracil and liposomal irinotecan for previously treated advanced biliary tract cancer. MED 2024:100547. [PMID: 39701097 DOI: 10.1016/j.medj.2024.10.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/24/2024] [Accepted: 10/31/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND Second-line chemotherapy with 5-fluorouracil/leucovorin (5FULV) and liposomal irinotecan improves survival in advanced biliary tract cancer (BTC). In this phase 1b/2 trial, we investigated the combination of 5FULV and liposomal irinotecan with nivolumab following progression on first-line chemotherapy for advanced BTC. METHODS Patients received 2,400 mg/m2 5-fluorouracil, leucovorin (dose level: 0:400 or -1:200 mg/m2), 70 mg/m2 liposomal irinotecan, and 240 mg nivolumab every 2 weeks (ClinicalTrials.gov: NCT03785873). The phase 1b and 2 primary objectives included recommended phase 2 dose (RP2D) and median progression-free survival (PFS; null and alternative hypotheses of 2.9 and 5.0 months) with a two-sided alpha of 0.05 and >80% power. Secondary objectives were safety, objective response rate (ORR), and overall survival (OS). FINDINGS Of 30 patients with a median age of 63.5 years, 18 (60%) were men, 25 (83%) were White, 16 (53%) had an ECOG performance status of 0, and 19 (63.3%) had intrahepatic cholangiocarcinoma. In phase 1b, the RP2D was dose level 0 after a dose-limiting toxicity event of enterocolitis (n = 1). Median PFS was 4.1 months (95% confidence interval [CI], 1.9-9.9). The ORR was 16.7% (5 partial responses) per irRECIST, the median OS was 7.4 months (95% CI, 5.7-15.9), and the 24-month survival rate was 23.3%. The most common grade ≥3 treatment-related adverse events were diarrhea (5; 16.7%), fatigue (4; 13.3%), and neutropenia (3; 10%). CONCLUSIONS Treatment was well tolerated, but the primary endpoint was not met. The median OS was similar to prior trials with this drug combination, but the 24-month survival rate was higher than expected. FUNDING This work was funded by Ipsen Biopharmaceuticals, Bristol-Myers Squibb (CA209-8LF), and the University of Michigan Rogel Cancer Center (P30CA046592).
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Affiliation(s)
- Vaibhav Sahai
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
| | - Kent A Griffith
- Center for Cancer Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Bruce S Lin
- Virginia Mason Medical Center, Seattle, WA, USA
| | - Heloisa P Soares
- Huntsman Cancer Institute and Hospital, University of Utah, Salt Lake City, UT, USA
| | | | - Oxana Crysler
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Chandan Kumar-Sinha
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Thomas Enzler
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | | | - Valerie Gunchick
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Mark M Zalupski
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
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Laface C, Fina E, Ricci AD, Guven DC, Ambrogio F, De Summa S, Vitale E, Massafra R, Brunetti O, Rizzo A. Immunobiology of biliary tract cancer and recent clinical findings in approved and upcoming immune checkpoint inhibitors. Expert Opin Biol Ther 2024; 24:1363-1374. [PMID: 39545466 DOI: 10.1080/14712598.2024.2431088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/14/2024] [Accepted: 11/14/2024] [Indexed: 11/17/2024]
Abstract
INTRODUCTION Recently, immunotherapy has offered new hope for treating biliary tract cancer (BTC). However, several issues are to be considered, including the lack of validated predictive biomarkers that could help to identify patient groups which are most likely to benefit from such therapeutic approaches. AREAS COVERED In the current article, we will provide an overview of recent results and ongoing and future research directions of immunotherapy in BTC, with a special focus on recently published, practice-changing data, and ongoing active and recruiting clinical trials. EXPERT OPINION At this moment, dozens of clinical trials in phases I to III are evaluating the role of cancer immunotherapy in this setting, with the hope of adding more therapeutic options for BTC patients. Future research must focus on the development of novel agents and combinations, but the validation of biomarkers remains an urgent need. As more research results emerge, novel combinatorial strategies are destined to further transform the treatment paradigm for this heterogeneous and aggressive tumor type.
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Affiliation(s)
- Carmelo Laface
- Azienda Sanitaria Provinciale, Reggio Calabria (RC), Italy
| | - Emanuela Fina
- Thoracic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angela Dalia Ricci
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS "S. de Bellis" Research Hospital, Castellana Grotte, Italy
| | - Deniz Can Guven
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
- Medical Oncology Clinic, Elazig City Hospital, Health Sciences University, Elazig, Turkey
| | - Francesca Ambrogio
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, Bari, Italy
| | - Simona De Summa
- Molecular Diagnostics and Pharmacogenetics Unit, IRCCS Istituto Tumori, "Giovanni Paolo II", Bari, Italy
| | - Elsa Vitale
- Scientific Directorate, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Raffaella Massafra
- Scientific Directorate, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Oronzo Brunetti
- S.S.D. C.O.r.O. Bed Management Presa in Carico, TDM, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Alessandro Rizzo
- S.S.D. C.O.r.O. Bed Management Presa in Carico, TDM, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
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Li R, Chen X, Wang B, Ai B, Min F, Cao D, Zhou J, Yan T. Comparison of treatment models for single primary advanced gallbladder cancer. Front Immunol 2024; 15:1500091. [PMID: 39606221 PMCID: PMC11599203 DOI: 10.3389/fimmu.2024.1500091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 10/21/2024] [Indexed: 11/29/2024] Open
Abstract
Purpose Treatment for advanced gallbladder cancer (GBC) remains controversial, with various recommendations regarding the choice and combination of surgery and adjuvant therapy. The present article is targeting for the exploration of optimal treatment models for advanced GBC. Methods AJCC (American Joint Committee on Cancer, 8th edition) stage III and stage IV GBC, were defined as advanced GBC. Patients with advanced GBC were identified using the Surveillance, Epidemiology, and End Results (SEER) database and departmental cohort. Because of the most representative, only gallbladder adenocarcinoma (GBAC) patients were selected. Based on their surgical status (No, Non-radical and Radical surgery), chemotherapy status (Chemotherapy, No chemotherapy), and radiotherapy status (Radiotherapy, No radiotherapy), treatment models were categorized. For the purposes of evaluating the treatment outcomes of various treatment models and determining the risk element for cancer-specific survival (CSS), Cox regression analysis was applied. Kaplan-Meier curves were used before and after adjusting for covariates, with log-rank tests used to analyze discrepancies between curves. Immunotherapy was analyzed using clinical data from departmental cohort. Finally, to compensate for the limitations of the database, a review examines the progress in treatment models for advanced GBC. Results 5,154 patients aged over 18 years with solitary primary advanced GBC were identified from the SEER database. In advanced GBC patients, the treatment model has emerged as a significant prognostic factor. "Radical surgery + Chemotherapy + Radiotherapy" models maximally improved the CSS of advanced GBC before and after adjusting for covariates, while "No surgery + No chemotherapy + No radiotherapy" model had the lowest CSS. The present conclusions were supported even after subgroup analysis by AJCC stage. The efficacy of immunotherapy was demonstrated in the departmental cohort analysis. Additionally, this article provides a comprehensive overview of recent advancements in various emerging treatment strategies. Conclusion Even when optimal treatment model cannot be pursued, providing comprehensive combinations of treatments to advanced GBC patients whenever possible is always beneficial for their survival.
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Affiliation(s)
- Rongxuan Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiao Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bingchen Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bolun Ai
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fangdi Min
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dayong Cao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianguo Zhou
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tao Yan
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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10
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Chang HJ, Ke CH, Wang YS. Case report: Combinations of immune checkpoint inhibitor, chemotherapy, and hyperthermia therapy avoid lymphatic recurrence in cholangiocarcinoma. Front Oncol 2024; 14:1421340. [PMID: 39512770 PMCID: PMC11540691 DOI: 10.3389/fonc.2024.1421340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024] Open
Abstract
Cholangiocarcinoma is a malignancy known for its aggressiveness and limited treatment options. The malignant tumor behaviors include intrahepatic recurrence, regional lymph node (LN) metastasis, peritoneal carcinomatosis, and lung metastasis. Herein, we reported a case of lymphatic recurrence in an intrahepatic cholangiocarcinoma patient after surgery, adjuvant concurrent chemoradiotherapy (CCRT), who experienced a remarkable response to a combination therapy. However, the patient failed to undergo radiotherapy or other invasive local therapy and therefore received Opdivo (nivolumab) in combination with chemotherapy (FOLFOX) and modulated electro-hyperthermia. Notably, after these medical interventions, this patient had a complete response (CR) to treatments, in which no lymph node metastasis occurred, and a significantly decreased tumor marker, CA 19-9, level was found. This case highlights the potential of multiple anti-tumor therapies, including immune checkpoint inhibitors, chemotherapy, and hyperthermia, in managing challenging cholangiocarcinoma cases.
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Affiliation(s)
- Heng-Jui Chang
- Department of Radiation Oncology, Wesing Surgery Hospital, Kaohsiung, Taiwan
| | - Chiao-Hsu Ke
- Department of Chemical Engineering and Biotechnology, Institute of Chemical Engineering, National Taipei University of Technology, Taipei, Taiwan
| | - Yu-Shan Wang
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
- Uni-Pharma Co-Ltd., Taipei, Taiwan
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11
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Zhang G, Li J, Li G, Zhang J, Yang Z, Yang L, Jiang S, Wang J. Strategies for treating the cold tumors of cholangiocarcinoma: core concepts and future directions. Clin Exp Med 2024; 24:193. [PMID: 39141161 PMCID: PMC11324771 DOI: 10.1007/s10238-024-01460-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 07/31/2024] [Indexed: 08/15/2024]
Abstract
Cholangiocarcinoma (CCA) is a rare type of digestive tract cancer originating from the epithelial cells of the liver and biliary tract. Current treatment modalities for CCA, such as chemotherapy and radiation therapy, have demonstrated limited efficacy in enhancing survival rates. Despite the revolutionary potential of immunotherapy in cancer management, its application in CCA remains restricted due to the minimal infiltration of immune cells in these tumors, rendering them cold and unresponsive to immune checkpoint inhibitors (ICIs). Cancer cells within cold tumors deploy various mechanisms for evading immune attack, thus impeding clinical management. Recently, combination immunotherapy has become increasingly essential to comprehend the mechanisms underlying cold tumors to enhance a deficient antitumor immune response. Therefore, a thorough understanding of the knowledge on the combination immunotherapy of cold CCA is imperative to leverage the benefits of immunotherapy in treating patients. Moreover, gut microbiota plays an essential role in the immunotherapeutic responses in CCA. In this review, we summarize the current concepts of immunotherapy in CCA and clarify the intricate dynamics within the tumor immune microenvironment (TIME) of CCA. We also delve into the evasion mechanisms employed by CCA tumors against the anti-tumor immune responses. The context of combination immunotherapies in igniting cold tumors of CCA and the critical function of gut microbiota in prompting immune responses have also been annotated. Furthermore, we have proposed future directions in the realm of CCA immunotherapy, aiming to improve the clinical prognosis of CCA patients.
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Affiliation(s)
- GuanBo Zhang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - JinSong Li
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Gang Li
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Jie Zhang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Zhi Yang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Lin Yang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - ShiJie Jiang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - JiaXing Wang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China.
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12
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Yue S, Zhang Y, Zhang W. Recent Advances in Immunotherapy for Advanced Biliary Tract Cancer. Curr Treat Options Oncol 2024; 25:1089-1111. [PMID: 39066855 PMCID: PMC11329538 DOI: 10.1007/s11864-024-01243-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2024] [Indexed: 07/30/2024]
Abstract
OPINION STATEMENT Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies that arise from the epithelium of the biliary tract. Most patients present with locally advanced or metastatic disease at the time of diagnosis. For patients with unresectable BTC, the survival advantage provided by systemic chemotherapy was limited. Over the last decade, immunotherapy has significantly improved the therapeutic landscape of solid tumors. There is an increasing number of studies evaluating the application of immunotherapy in BTC, including immune checkpoint inhibitors (ICIs), cancer vaccines and adoptive cell therapy. The limited response to ICIs monotherapy in unselected patients prompted investigators to explore different combination therapy strategies. Early clinical trials of therapeutic cancer vaccination and adoptive cell therapy have shown encouraging clinical results. However, there still has been a long way to go via validation of therapeutic efficacy and exploration of strategies to increase the efficacy. Identifying biomarkers that predict the response to immunotherapy will allow a more accurate selection of candidates. This review will provide an up-to-date overview of the current clinical data on the role of immunotherapy, summarize the promising biomarkers predictive of the response to ICIs and discuss the perspective for future research direction of immunotherapy in advanced BTC.
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Affiliation(s)
- Shiwei Yue
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China
| | - Yunpu Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China
| | - Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China.
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China.
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13
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Ni L, Xu J, Li Q, Ge X, Wang F, Deng X, Miao L. Focusing on the Immune Cells: Recent Advances in Immunotherapy for Biliary Tract Cancer. Cancer Manag Res 2024; 16:941-963. [PMID: 39099760 PMCID: PMC11296367 DOI: 10.2147/cmar.s474348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 07/17/2024] [Indexed: 08/06/2024] Open
Abstract
Biliary tract cancer (BTC) represents a challenging malignancy characterized by aggressive behavior, high relapse rates, and poor prognosis. In recent years, immunotherapy has revolutionized the treatment landscape for various cancers, but its efficacy in BTC remains limited. This article provides a comprehensive overview of the advances in preclinical and clinical studies of immunotherapy for BTC. We explore the potential of immune checkpoint inhibitors in reshaping the management of BTC. Despite disappointing results thus far, ongoing clinical trials are investigating the combination of immunotherapy with other treatment modalities. Furthermore, research on the tumor microenvironment has unveiled novel targets for immunotherapeutic interventions. By understanding the current state of immunotherapy in BTC and highlighting future directions, this article aims to fuel further exploration and ultimately improve patient outcomes in this challenging disease.
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Affiliation(s)
- Luohang Ni
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Jianing Xu
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Quanpeng Li
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Xianxiu Ge
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Fei Wang
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Xueting Deng
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Lin Miao
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
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14
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Marin JJG, Macias RIR, Asensio M, Romero MR, Temprano AG, Pereira OR, Jimenez S, Mauriz JL, Di Giacomo S, Avila MA, Efferth T, Briz O. Strategies to enhance the response of liver cancer to pharmacological treatments. Am J Physiol Cell Physiol 2024; 327:C11-C33. [PMID: 38708523 DOI: 10.1152/ajpcell.00176.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 05/07/2024]
Abstract
In contrast to other types of cancers, there is no available efficient pharmacological treatment to improve the outcomes of patients suffering from major primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma. This dismal situation is partly due to the existence in these tumors of many different and synergistic mechanisms of resistance, accounting for the lack of response of these patients, not only to classical chemotherapy but also to more modern pharmacological agents based on the inhibition of tyrosine kinase receptors (TKIs) and the stimulation of the immune response against the tumor using immune checkpoint inhibitors (ICIs). This review summarizes the efforts to develop strategies to overcome this severe limitation, including searching for novel drugs derived from synthetic, semisynthetic, or natural products with vectorial properties against therapeutic targets to increase drug uptake or reduce drug export from cancer cells. Besides, immunotherapy is a promising line of research that is already starting to be implemented in clinical practice. Although less successful than in other cancers, the foreseen future for this strategy in treating liver cancers is considerable. Similarly, the pharmacological inhibition of epigenetic targets is highly promising. Many novel "epidrugs," able to act on "writer," "reader," and "eraser" epigenetic players, are currently being evaluated in preclinical and clinical studies. Finally, gene therapy is a broad field of research in the fight against liver cancer chemoresistance, based on the impressive advances recently achieved in gene manipulation. In sum, although the present is still dismal, there is reason for hope in the non-too-distant future.
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Affiliation(s)
- Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Alvaro G Temprano
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Olívia R Pereira
- Centro de Investigação de Montanha (CIMO), Laboratório Associado para a Sustentabilidade e Tecnologia em Regiões de Montanha (SusTEC), Instituto Politécnico de Bragança, Bragança, Portugal
- Research Centre for Active Living and Wellbeing (LiveWell), Instituto Politécnico de Bragança, Bragança, Portugal
| | - Silvia Jimenez
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Servicio de Farmacia Hospitalaria, Hospital de Salamanca, Salamanca, Spain
| | - Jose L Mauriz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Institute of Biomedicine (IBIOMED), University of Leon, Leon, Spain
| | - Silvia Di Giacomo
- Department of Food Safety, Nutrition and Veterinary Public Health, National Institute of Health, Rome, Italy
| | - Matias A Avila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Hepatology Laboratory, Solid Tumors Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Instituto de Investigaciones Sanitarias de Navarra (IdisNA), Pamplona, Spain
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
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15
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Demir T, Moloney C, Mahalingam D. Emerging targeted therapies and strategies to overcome resistance in biliary tract cancers. Crit Rev Oncol Hematol 2024; 199:104388. [PMID: 38754771 DOI: 10.1016/j.critrevonc.2024.104388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/14/2024] [Accepted: 05/06/2024] [Indexed: 05/18/2024] Open
Abstract
In the last decade, targeted therapies have shown rapid advancement in biliary tract cancer (BTC). Today, many targeted agents are available and under investigation for patients with BTC. More recently, immune checkpoint inhibitors (ICI) such as durvalumab and pembrolizumab in combination with gemcitabine plus cisplatin (gem/cis) have resulted in improved overall survival and progression-free survival in the first-line setting. However, the efficacy benefit of these novel therapeutics is often short-lived, with literature outlining concerns about both primary and secondary resistance to these agents. Investigators also need to consider toxicity profiles that can emerge using this strategy. There have been efforts to reduce evolving resistance through combinatory approaches, both pre-clinically and in early clinical settings. This review summarizes the emerging targeted therapies in BTC, evolving biomarkers of resistance, strategies to overcome them, and an analysis of ongoing clinical trials of patients with advanced BTC.
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Affiliation(s)
- Tarik Demir
- Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine1, Chicago, IL 60611, USA.
| | - Carolyn Moloney
- Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine1, Chicago, IL 60611, USA
| | - Devalingam Mahalingam
- Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine1, Chicago, IL 60611, USA
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16
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Chen F, Sheng J, Li X, Gao Z, Zhao S, Hu L, Chen M, Fei J, Song Z. Unveiling the promise of PD1/PD-L1: A new dawn in immunotherapy for cholangiocarcinoma. Biomed Pharmacother 2024; 175:116659. [PMID: 38692063 DOI: 10.1016/j.biopha.2024.116659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 05/03/2024] Open
Abstract
Cholangiocarcinoma (CCA), a rare yet notably aggressive cancer, has experienced a surge in incidence in recent years. Presently, surgical resection remains the most effective curative strategy for CCA. Nevertheless, a majority of patients with CCA are ineligible for surgical removal at the time of diagnosis. For advanced stages of CCA, the combination of gemcitabine and cisplatin is established as the standard chemotherapy regimen. Despite this, treatment efficacy is often hindered by the development of resistance. In recent times, immune checkpoint inhibitors, particularly those that block programmed death 1 and its ligand (PD1/PD-L1), have emerged as promising strategies against a variety of cancers and are being increasingly integrated into the therapeutic landscape of CCA. A growing body of research supports that the use of PD1/PD-L1 monoclonal antibodies in conjunction with chemotherapy may significantly improve patient outcomes. This article seeks to meticulously review the latest studies on PD1/PD-L1 involvement in CCA, delving into their expression profiles, prognostic significance, contribution to oncogenic processes, and their potential clinical utility.
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Affiliation(s)
- Fei Chen
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Jian Sheng
- Department of Research and Teaching, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xiaoping Li
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Zhaofeng Gao
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Siqi Zhao
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Lingyu Hu
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Minjie Chen
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
| | - Jianguo Fei
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
| | - Zhengwei Song
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
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17
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Storandt MH, Jin Z, Mahipal A. Evaluating the Therapeutic Potential of Durvalumab in Adults with Locally Advanced or Metastatic Biliary Tract Cancer: Evidence to Date. Onco Targets Ther 2024; 17:383-394. [PMID: 38774819 PMCID: PMC11107832 DOI: 10.2147/ott.s391707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 05/06/2024] [Indexed: 05/24/2024] Open
Abstract
Advanced biliary tract cancers (BTCs) have historically been managed with chemotherapy but, in recent years, this treatment paradigm has begun to shift with the introduction of immune checkpoint inhibitors in addition to standard of care chemotherapy. The tumor microenvironment of BTC may be enriched with regulatory T lymphocytes and immune checkpoint expression in some patients. Durvalumab, an anti-programmed death ligand-1 (PD-L1) antibody, in combination with gemcitabine and cisplatin, has now received United States Food and Drug Administration approval for treatment of advanced BTC. Regulatory approval was based on the Phase III, randomized TOPAZ-1 trial that demonstrated survival benefit with addition of durvalumab to gemcitabine plus cisplatin compared to chemotherapy alone. The combination of chemotherapy and immunotherapy was well tolerated, and a subset of patients were able to achieve a durable response, with a 2-year overall survival rate of 23.6%. However, limitations remain in identifying which patients are most likely to benefit from immune checkpoint inhibition. Future study should aim to identify biomarkers predictive of substantial benefit, as well as the role of immune checkpoint inhibition in combination with targeted therapies and radiotherapy in the management of advanced BTC.
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Affiliation(s)
| | - Zhaohui Jin
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Amit Mahipal
- Department of Medical Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA
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18
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Larson AC, Doty KR, Solheim JC. The double life of a chemotherapy drug: Immunomodulatory functions of gemcitabine in cancer. Cancer Med 2024; 13:e7287. [PMID: 38770637 PMCID: PMC11106691 DOI: 10.1002/cam4.7287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 04/19/2024] [Accepted: 04/28/2024] [Indexed: 05/22/2024] Open
Abstract
Although the development of immunotherapies has been revolutionary in the treatment of several cancers, many cancer types remain unresponsive to immune-based treatment and are largely managed by chemotherapy drugs. However, chemotherapeutics are not infallible and are frequently rendered ineffective as resistance develops from prolonged exposure. Recent investigations have indicated that some chemotherapy drugs have additional functions beyond their normative cytotoxic capacity and are in fact immune-modifying agents. Of the pharmaceuticals with identified immune-editing properties, gemcitabine is well-studied and of interest to clinicians and scientists alike. Gemcitabine is a chemotherapy drug approved for the treatment of multiple cancers, including breast, lung, pancreatic, and ovarian. Because of its broad applications, relatively low toxicity profile, and history as a favorable combinatory partner, there is promise in the recharacterization of gemcitabine in the context of the immune system. Such efforts may allow the identification of suitable immunotherapeutic combinations, wherein gemcitabine can be used as a priming agent to improve immunotherapy efficacy in traditionally insensitive cancers. This review looks to highlight documented immunomodulatory abilities of one of the most well-known chemotherapy agents, gemcitabine, relating to its influence on cells and proteins of the immune system.
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Affiliation(s)
- Alaina C. Larson
- Eppley Institute for Research in Cancer & Allied DiseasesUniversity of Nebraska Medical CenterOmahaNebraskaUSA
- Fred & Pamela Buffett Cancer CenterUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Kenadie R. Doty
- Eppley Institute for Research in Cancer & Allied DiseasesUniversity of Nebraska Medical CenterOmahaNebraskaUSA
- Fred & Pamela Buffett Cancer CenterUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Joyce C. Solheim
- Eppley Institute for Research in Cancer & Allied DiseasesUniversity of Nebraska Medical CenterOmahaNebraskaUSA
- Fred & Pamela Buffett Cancer CenterUniversity of Nebraska Medical CenterOmahaNebraskaUSA
- Department of Biochemistry & Molecular BiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
- Department of Pathology, Microbiology, & ImmunologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
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19
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Werner W, Kuzminskaya M, Lurje I, Tacke F, Hammerich L. Overcoming Resistance to Immune Checkpoint Blockade in Liver Cancer with Combination Therapy: Stronger Together? Semin Liver Dis 2024; 44:159-179. [PMID: 38806159 PMCID: PMC11245330 DOI: 10.1055/a-2334-8311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/30/2024]
Abstract
Primary liver cancer, represented mainly by hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA), is one of the most common and deadliest tumors worldwide. While surgical resection or liver transplantation are the best option in early disease stages, these tumors often present in advanced stages and systemic treatment is required to improve survival time. The emergence of immune checkpoint inhibitor (ICI) therapy has had a positive impact especially on the treatment of advanced cancers, thereby establishing immunotherapy as part of first-line treatment in HCC and CCA. Nevertheless, low response rates reflect on the usually cold or immunosuppressed tumor microenvironment of primary liver cancer. In this review, we aim to summarize mechanisms of resistance leading to tumor immune escape with a special focus on the composition of tumor microenvironment in both HCC and CCA, also reflecting on recent important developments in ICI combination therapy. Furthermore, we discuss how combination of ICIs with established primary liver cancer treatments (e.g. multikinase inhibitors and chemotherapy) as well as more complex combinations with state-of-the-art therapeutic concepts may reshape the tumor microenvironment, leading to higher response rates and long-lasting antitumor immunity for primary liver cancer patients.
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Affiliation(s)
- Wiebke Werner
- Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Maria Kuzminskaya
- Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Isabella Lurje
- Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Linda Hammerich
- Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
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20
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Heumann P, Albert A, Gülow K, Tümen D, Müller M, Kandulski A. Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma. Cancers (Basel) 2024; 16:1690. [PMID: 38730642 PMCID: PMC11083102 DOI: 10.3390/cancers16091690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/17/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor.
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Affiliation(s)
- Philipp Heumann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
| | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
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21
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Goetze T, Gonzalez-Carmona MA, Kochen L, Agaoglu NB, Al-Batran SE, Habibzada T, Pons M, Brunner M, Ettrich TJ, Köhne CH, Roderburg C, Modest D. ADJUBIL: phase II study of adjuvant immunotherapy with STRIDE regimen with/without capecitabine in biliary tract cancers. Future Oncol 2024; 20:307-315. [PMID: 38410920 DOI: 10.2217/fon-2023-0961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2024] Open
Abstract
Biliary tract cancer is a highly heterogeneous group of gastrointestinal cancers, and the only curative treatment is surgery, which is only applicable at early stages of the malignancy. ADJUBIL, a phase II trial (NCT05239169), aims to evaluate immunotherapy with durvalumab and tremelimumab with or without capecitabine in adjuvant situations for biliary tract cancers. A total of 40 prospective patients will be randomly assigned following surgery, consisting of a two-arm feasibility pilot part with a pick-the-winner design with durvalumab and tremelimumab in combination with or without capecitabine.
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Affiliation(s)
- Thorsten Goetze
- Krankenhaus Nordwest, University Cancer Center Frankfurt, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
- Frankfurter Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
| | | | - Lisa Kochen
- Frankfurter Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
| | - Nihat Bugra Agaoglu
- Frankfurter Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
| | - Salah-Eddin Al-Batran
- Krankenhaus Nordwest, University Cancer Center Frankfurt, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
- Frankfurter Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
| | - Timorshah Habibzada
- Krankenhaus Nordwest, University Cancer Center Frankfurt, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
| | - Miriam Pons
- Frankfurter Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
| | - Marius Brunner
- Universitätsklinikum Göttingen, Robert Koch Straße 40, 37075 Göttingen, Germany
| | - Thomas J Ettrich
- Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | - Claus-Henning Köhne
- Department of Gynaekology,Klinikum Oldenburg AöR, Rahel-Straus-Straße 10, 26133 Oldenburg, Germany
| | | | - Dominik Modest
- Department of Hematology, Oncology, and Cancer Immunology (CVK)Charité Berlin, Augustenburger Platz 1 Ostring 1, 13353 Berlin, Germany
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22
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Speckart J, Rasmusen V, Talib Z, GnanaDev DA, Rahnemai-Azar AA. Emerging Therapies in Management of Cholangiocarcinoma. Cancers (Basel) 2024; 16:613. [PMID: 38339363 PMCID: PMC10854763 DOI: 10.3390/cancers16030613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/12/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
Cholangiocarcinoma is a heterogeneous group of biliary tract cancers that has a poor prognosis and globally increasing incidence and mortality. While surgical resection remains the only curative option for the treatment of cholangiocarcinoma, the majority of cancers are unresectable at the time of diagnosis. Additionally, the prognosis of cholangiocarcinoma remains poor even with the current first-line systemic therapy regimens, highlighting the difficulty of treating locally advanced, metastatic, or unresectable cholangiocarcinoma. Through recent developments, targetable oncogenic driver mutations have been identified in the pathogenesis of cholangiocarcinoma, leading to the utilization of molecular targeted therapeutics. In this review, we comprehensively discuss the latest molecular therapeutics for the treatment of cholangiocarcinoma, including emerging immunotherapies, highlighting promising developments and strategies.
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Affiliation(s)
- Jessica Speckart
- School of Medicine, California University of Science and Medicine, Colton, CA 92324, USA; (J.S.); (V.R.)
| | - Veronica Rasmusen
- School of Medicine, California University of Science and Medicine, Colton, CA 92324, USA; (J.S.); (V.R.)
| | - Zohray Talib
- Department of Medicine, Arrowhead Regional Medical Center, California University of Science and Medicine, Colton, CA 92324, USA;
| | - Dev A. GnanaDev
- Department of Surgery, Arrowhead Regional Medical Center, Colton, CA 92324, USA
| | - Amir A. Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA
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23
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Yang S, Zou R, Dai Y, Hu Y, Li F, Hu H. Tumor immune microenvironment and the current immunotherapy of cholangiocarcinoma (Review). Int J Oncol 2023; 63:137. [PMID: 37888583 PMCID: PMC10631767 DOI: 10.3892/ijo.2023.5585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 10/12/2023] [Indexed: 10/28/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy originating from the epithelial system of the bile ducts, and its incidence in recent years is steadily increasing. The immune microenvironment of CCA is characterized by diversity and complexity, with a substantial presence of cancer‑associated fibroblasts and immune cell infiltration, which plays a key role in regulating the distinctive biological behavior of cholangiocarcinoma, including tumor growth, angiogenesis, lymphangiogenesis, invasion and metastasis. Despite the notable success of immunotherapy in the treatment of solid tumors in recent years, patients with CCA have responded poorly to immune checkpoint inhibitor therapy. The interaction of tumor cells with cellular components of the immune microenvironment can regulate the activity and function of immune cells and form an immunosuppressive microenvironment, which may cause ineffective immunotherapy. Therefore, the components of the tumor immune microenvironment appear to be novel targets for immune therapies. Combination therapy focusing on immune checkpoint inhibitors is a promising and valuable first‑line or translational treatment approach for intractable biliary tract malignancies. The present review discusses the compositional characteristics and regulatory factors of the CCA immune microenvironment and the possible immune escape mechanisms. In addition, a summary of the advances in immunotherapy for CCA is also provided. It is hoped that the present review may function as a valuable reference for the development of novel immunotherapeutic strategies for CCA.
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Affiliation(s)
- Siqi Yang
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ruiqi Zou
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yushi Dai
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yafei Hu
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Fuyu Li
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Haijie Hu
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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24
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He WZ, Huang YH, Hu WM, Wang F, Xu YX, Yi JH, Xue J, Yang YZ, Chao XY, Lin HB, Guo GF, Yun JP, Xia LP. Response to programmed cell death protein 1 antibody in patients with Epstein-Barr virus-associated intrahepatic cholangiocarcinoma. Eur J Cancer 2023; 194:113337. [PMID: 37862797 DOI: 10.1016/j.ejca.2023.113337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/29/2023] [Accepted: 09/04/2023] [Indexed: 10/22/2023]
Abstract
AIM Epstein-Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) has a distinct genomic profile and increased CD3+ and CD8+ T cells infiltration. However, the efficacy of immunotherapy in EBVaICC remains largely unknown. This study aimed to assess the efficacy of programmed cell death protein 1 (PD-1) antibody therapy in EBVaICC. METHODS Patients with metastatic biliary tract cancer (BTC) diagnosed at Sun Yat-sen University Cancer Center from January 2016 to December 2021 were identified. In situ hybridisation was performed to detect EBV. Overall survival (OS) and progression-free survival (PFS) were measured. RESULTS A total of 698 patients with metastatic BTC were identified, of whom 39 (5.6%) had EBVaICC. Among the 136 patients who were not administered PD-1 antibody, the OS was similar between patients with EBVaICC and EBV-negative ICC (median OS 12.5 versus 9.5 months, respectively; P = 0.692). For the 205 patients who were administered PD-1 antibody, patients with EBVaICC had significantly longer OS than patients with EBV-negative ICC (median OS 24.9 versus 11.9 months, respectively; P = 0.004). Seventeen patients with EBVaICC were administered PD-1 antibody. Eight patients (47%) achieved a partial response, and 17 patients achieved disease control. The median PFS was 17.5 months. CONCLUSIONS This study identified a clinically actionable subset of patients with EBVaICC with a promising response to the PD-1 antibody.
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Affiliation(s)
- Wen-Zhuo He
- VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Yu-Hua Huang
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Wan-Ming Hu
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Fang Wang
- Department of Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, PR China
| | - Yu-Xia Xu
- Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Jia-Hong Yi
- VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Ju Xue
- VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Yuan-Zhong Yang
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Xiao-Ying Chao
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, PR China; Zhongshan Institute for Drug Discovery, SIMM, Chinese Academy of Sciences, Zhongshan, Guangdong, China
| | - Han-Bin Lin
- Zhongshan Institute for Drug Discovery, SIMM, Chinese Academy of Sciences, Zhongshan, Guangdong, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
| | - Gui-Fang Guo
- VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China.
| | - Jing-Ping Yun
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China.
| | - Liang-Ping Xia
- VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China.
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25
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Zhang Z, Wang X, Li H, Sun H, Chen J, Lin H. Case Report: Camrelizumab combined with gemcitabine and oxaliplatin in the treatment of advanced intrahepatic cholangiocarcinoma: a case report and literature review. Front Immunol 2023; 14:1230261. [PMID: 37671157 PMCID: PMC10475830 DOI: 10.3389/fimmu.2023.1230261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 08/08/2023] [Indexed: 09/07/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is one of the most common invasive malignant tumors, with a 5-year survival rate of less than 5%. Currently, radical surgical resection is the preferred treatment for ICC. However, most patients are only diagnosed at an advanced stage and are therefore not eligible for surgery. Herein, we present a case of advanced ICC in which radical surgery was not possible due to tumor invasion of the second porta hepatis and right hepatic artery. Six treatment cycles with a gemcitabine and oxaliplatin (GEMOX) regimen combined with camrelizumab immunotherapy achieved a partial response and successful tumor conversion, as tumor invasion of the second porta hepatis and right hepatic artery was no longer evident. The patient subsequently underwent successful radical surgical resection, including hepatectomy, caudate lobe resection, and cholecystectomy combined with lymph node dissection. Cases of patients with advanced ICC undergoing surgical resection after combined immunotherapy and chemotherapy are rare. The GEMOX regimen combined with camrelizumab demonstrated favorable antitumor efficacy and safety, suggesting that it might be a potential feasible and safe conversion therapy strategy for patients with advanced ICC.
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Affiliation(s)
- Zhongyan Zhang
- Department of Hepatobiliary Surgery, Weifang People’s Hospital, Weifang, China
| | - Xin Wang
- Department of Hepatobiliary Surgery, Weifang People’s Hospital, Weifang, China
| | - Hehe Li
- Department of Geriatrics, Weifang People’s Hospital, Weifang, China
| | - Huimin Sun
- Department of Pathology, Weifang People’s Hospital, Weifang, China
| | - Jianhong Chen
- Department of Hepatobiliary Surgery, Weifang People’s Hospital, Weifang, China
| | - Hongfeng Lin
- Department of Hepatobiliary Surgery, Weifang People’s Hospital, Weifang, China
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26
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Kawamura E, Matsubara T, Kawada N. New Era of Immune-Based Therapy in Intrahepatic Cholangiocarcinoma. Cancers (Basel) 2023; 15:3993. [PMID: 37568808 PMCID: PMC10417782 DOI: 10.3390/cancers15153993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/31/2023] [Accepted: 08/04/2023] [Indexed: 08/13/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (CC) accounts for approximately 20% of all biliary tract cancer (BTC) cases and 10-15% of all primary liver cancer cases. Many patients are diagnosed with unresectable BTC, and, even among patients with resectable BTC, the 5-year survival rate is approximately 20%. The BTC incidence rate is high in Southeast and East Asia and has increased worldwide in recent years. Since 2010, cytotoxic chemotherapy, particularly combination gemcitabine + cisplatin (ABC-02 trial), has been the first-line therapy for patients with BTC. In 2022, a multicenter, double-blind, randomized phase 3 trial (TOPAZ-1 trial) examined the addition of programmed death-ligand 1 immunotherapy (durvalumab) to combination gemcitabine + cisplatin for BTC treatment, resulting in significantly improved survival without notable additional toxicity. As a result of this trial, this three-drug combination has become the new standard first-line therapy, leading to notable advances in BTC management for the first time since 2010. The molecular profiling of BTC has continued to drive the development of new targeted therapies for use when first-line therapies fail. Typically, second-line therapy decisions are based on identified genomic alterations in tumor tissue. Mutations in fibroblast growth factor receptor 1/2/3, isocitrate dehydrogenase 1/2, and neurotrophic tyrosine receptor kinase A/B/C are relatively frequent in intrahepatic CC, and precision medicines are available that can target associated pathways. In this review, we suggest strategies for systemic pharmacotherapy with a focus on intrahepatic CC, in addition to presenting the results and safety outcomes of clinical trials evaluating immune checkpoint inhibitor therapies in BTC.
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Affiliation(s)
- Etsushi Kawamura
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
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27
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Lo JH, Agarwal R, Goff LW, Heumann TR. Immunotherapy in Biliary Tract Cancers: Current Standard-of-Care and Emerging Strategies. Cancers (Basel) 2023; 15:3312. [PMID: 37444422 PMCID: PMC10340362 DOI: 10.3390/cancers15133312] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade, immunotherapy has had a profound impact on the management of many solid tumor types, particularly in using immune checkpoint inhibition to enable a tumor-directed T cell response. Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of biomarker-based tumor-agnostic indications for immunotherapy. However, immunotherapy in conjunction with chemotherapy, molecularly targeted therapies, and/or anti-angiogenic therapies has gained traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific immunotherapy approval, establishing the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of pembrolizumab with gemcitabine and cisplatin in the same setting, adding further evidence for the addition of immune checkpoint inhibition to the standard chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted therapeutics for the subset of BTCs harboring alterations in IDH1, FGFR2, MAP kinase signaling, HER2, and beyond, and there has been great interest in investigating combinations of these agents with immunotherapy. Emerging immunotherapy strategies beyond immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive cell therapy, and cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of immunotherapy in BTC management in the near future.
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Affiliation(s)
| | | | | | - Thatcher R. Heumann
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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28
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Leowattana W, Leowattana T, Leowattana P. Paradigm shift of chemotherapy and systemic treatment for biliary tract cancer. World J Gastrointest Oncol 2023; 15:959-972. [PMID: 37389105 PMCID: PMC10302992 DOI: 10.4251/wjgo.v15.i6.959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/14/2023] [Accepted: 05/05/2023] [Indexed: 06/14/2023] Open
Abstract
Biliary tract cancers (BTC) are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens. For more than a decade, the combination of gemcitabine and cis-platin has served as the first-line standard treatment. There are few choices for second-line chemo-therapy. Targeted treatment with fibroblast growth factor receptor 2 inhibitors, neurotrophic tyrosine receptor kinase inhibitors, and isocitrate dehydrogenase 1 inhibitors has had important results. Immune checkpoint inhibitors (ICI) such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients. The TOPAZ-1 trial's outcome is encouraging, and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options. Newer targets and agents for existing goals are being studied, which may represent a paradigm shift in BTC management. Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications, the new category of drugs may occupy a significant role in BTC therapies.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Wattana 10110, Bangkok, Thailand
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
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29
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Manthopoulou E, Ramai D, Dhar J, Samanta J, Ioannou A, Lusina E, Sacco R, Facciorusso A. Cholangiocarcinoma in the Era of Immunotherapy. Vaccines (Basel) 2023; 11:1062. [PMID: 37376451 DOI: 10.3390/vaccines11061062] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/27/2023] [Accepted: 06/03/2023] [Indexed: 06/29/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a rare malignancy of the gastrointestinal tract, with aggressive behavior, and portends a poor prognosis. Traditionally, it is classified according to its site of involvement as intrahepatic, perihilar, and distal cholangiocarcinoma. A host of genetic and epigenetic factors have been involved in its pathogenesis. Chemotherapy has remained the standard first-line treatment over the last decade, with a disappointing median overall survival of 11 months for locally advanced and metastatic CCA. The advent of immunotherapy has revolutionized the treatment of many pancreaticobiliary malignancies, offering durable responses with a safe therapeutic profile. To date, there have been no significant advances in the management of CCA. Novel immunotherapeutic methods, such as cancer vaccines, adoptive cell therapy, and combinations of immune checkpoint inhibitors with other agents, are currently under investigation and may improve prognosis with overall survival. Efforts to find robust biomarkers for response to treatment along with multiple clinical trials are also ongoing in this regard. In this review, we present an overview of the current advances and the future perspectives of immunotherapy in the management of CCA.
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Affiliation(s)
- Eleni Manthopoulou
- Department of Gastroenterology, St. Savvas Oncology Hospital of Athens, 11522 Athens, Greece
| | - Daryl Ramai
- Gastroenterology and Hepatology, University of Utah Health, Salt Lake City, UT 801385, USA
| | - Jahnvi Dhar
- Department of Gastroenterology, Sohana Multi-Speciality Hospital, Mohali 140308, India
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Jayanta Samanta
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Alexandros Ioannou
- Department of Gastroenterology, Alexandra General Hospital, Lourou 4-2, 11528 Athens, Greece
| | - Ekaterina Lusina
- Therapeutic Unit, Gastroenterology Department, Chaika Clinics, Lesnaya Street 9, 125196 Moscow, Russia
| | - Rodolfo Sacco
- Department Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy
| | - Antonio Facciorusso
- Department Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy
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30
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Yamaki H, Kono M, Wakisaka R, Komatsuda H, Kumai T, Hayashi R, Sato R, Nagato T, Ohkuri T, Kosaka A, Ohara K, Kishibe K, Takahara M, Hayashi T, Kobayashi H, Katada A. Brachyury-targeted immunotherapy combined with gemcitabine against head and neck cancer. Cancer Immunol Immunother 2023:10.1007/s00262-023-03460-0. [PMID: 37173455 DOI: 10.1007/s00262-023-03460-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023]
Abstract
Brachyury is a transcription factor belonging to the T-box gene family and is involved in the posterior formation of the mesoderm and differentiation of chordates. As the overexpression of Brachyury is a poor prognostic factor in a variety of cancers, the establishment of Brachyury-targeted therapy would be beneficial for the treatment of aggressive tumors. Because transcription factors are difficult to treat with a therapeutic antibody, peptide vaccines are a feasible approach for targeting Brachyury. In this study, we identified Brachyury-derived epitopes that elicit antigen-specific and tumor-reactive CD4+ T cells that directly kill tumors. T cells recognizing Brachyury epitopes were present in patients with head and neck squamous cell carcinoma. Next, we focused on gemcitabine (GEM) as an immunoadjuvant to augment the efficacy of antitumor responses by T cells. Interestingly, GEM upregulated HLA class I and HLA-DR expression in tumor, followed by the upregulation of anti-tumor T cell responses. As tumoral PD-L1 expression was also augmented by GEM, PD-1/PD-L1 blockade and GEM synergistically enhanced the tumor-reactivity of Brachyury-reactive T cells. The synergy between the PD-1/PD-L1 blockade and GEM was also confirmed in a mouse model of head and neck squamous cell carcinoma. These results suggest that the combined treatment of Brachyury peptide with GEM and immune checkpoint blockade could be a promising immunotherapy against head and neck cancer.
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Affiliation(s)
- Hidekiyo Yamaki
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Michihisa Kono
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Risa Wakisaka
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Hiroki Komatsuda
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Takumi Kumai
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
- Department of Innovative Head and Neck Cancer Research and Treatment, Asahikawa Medical University, Asahikawa, Japan.
| | - Ryusuke Hayashi
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Ryosuke Sato
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Toshihiro Nagato
- Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Takayuki Ohkuri
- Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Akemi Kosaka
- Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Kenzo Ohara
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Kan Kishibe
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Miki Takahara
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
- Department of Innovative Head and Neck Cancer Research and Treatment, Asahikawa Medical University, Asahikawa, Japan
| | - Tatsuya Hayashi
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Hiroya Kobayashi
- Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Akihiro Katada
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
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31
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Serrano Uson Junior PL, Bekaii-Saab T. Moving beyond single-agent checkpoint inhibition in biliary tract cancers: what is the next frontier? Immunotherapy 2023; 15:531-540. [PMID: 37096922 DOI: 10.2217/imt-2022-0201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023] Open
Abstract
Background: Immunotherapy has been shown to improve outcomes for patients with cancer. Biliary tract cancers are a group of lethal diseases, and immunotherapy is an exciting new strategy to treat patients in advanced stages. Role of immunotherapy in biliary cancers: Durvalumab, an anti-PD-L1 antibody, is a new immunotherapy option for patients with advanced biliary cancers. In a randomized phase III trial, the combination of durvalumab and chemotherapy improved disease outcomes, including overall survival, in patients with advanced biliary cancers regardless of PD-L1 expression. Future perspective: Promising new combinations with new and potent antibodies or antiangiogenics are under development. Combinations with new immunotherapy agents targeting CTLA-4 or OX40 can enhance T-cell activation and improve outcomes compared with single anti-PD-1/PD-L1 agents. Furthermore, ctDNA is being used as an alternative to tissue genomic analysis and can be used to identify actionable targets. In this review, we will discuss the most important studies involving immunotherapy in biliary cancers as well as future perspectives in the field.
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32
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Beri N. Immune checkpoint inhibitors in cholangiocarcinoma. Immunotherapy 2023; 15:541-551. [PMID: 37096964 DOI: 10.2217/imt-2022-0288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023] Open
Abstract
Cholangiocarcinoma is an epithelial malignancy originating in the biliary tracts and frequently recurs even with surgical resection. Unresectable disease has a 5-year overall survival of less than 10%. Given this poor prognosis, additional therapies are urgently needed. Chemotherapy has been the mainstay of treatment for many years. However, with the incorporation of immunotherapy into the treatment of other malignancies, there has been a great deal of interest in immunotherapy for biliary cancers. Recently, durvalumab was approved in combination with gemcitabine and cisplatin for the treatment of unresectable cholangiocarcinoma in the first-line setting. However, predicting which patients may respond to immunotherapy remains a challenge due to the lack of a reliable biomarker.
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Affiliation(s)
- Nina Beri
- Perlmutter Cancer Center, New York University Medical Center, New York, NY 10016, USA
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33
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Sahai V, Zalupski MM. Reply to "Is there a role for combined anti-PD-1/CTLA-4 checkpoint blockade in the management of advanced biliary tract cancers?". Cancer 2023; 129:1131-1132. [PMID: 36692955 DOI: 10.1002/cncr.34659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Vaibhav Sahai
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Mark M Zalupski
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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34
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Klein O, Kee D, Nagrial A, Markman B, Underhill C, Michael M, Behren A, Palmer J, Tebbutt NC, Carlino MS, Cebon J. Is there a role for combined anti-PD-1/CTLA-4 checkpoint blockade in the management of advanced biliary tract cancers? Cancer 2023; 129:1129-1130. [PMID: 36692958 DOI: 10.1002/cncr.34660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Oliver Klein
- Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia.,Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
| | - Damien Kee
- Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia.,Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Adnan Nagrial
- Blacktown Hospital, Blacktown, New South Wales, Australia.,University of Sydney, Sydney, New South Wales, Australia
| | - Ben Markman
- Department of Medical Oncology, Alfred Health, Prahran, Victoria, Australia.,Monash University, Melbourne, Victoria, Australia
| | - Craig Underhill
- Albury-Wodonga Regional Cancer Centre, Albury-Wodonga, New South Wales, Australia
| | - Michael Michael
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Andreas Behren
- Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Jodie Palmer
- Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Niall C Tebbutt
- Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia.,University of Melbourne, Melbourne, Victoria, Australia
| | - Matteo S Carlino
- Blacktown Hospital, Blacktown, New South Wales, Australia.,University of Sydney, Sydney, New South Wales, Australia
| | - Jonathan Cebon
- Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia.,Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
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35
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Skouteris N, Papageorgiou G, Fioretzaki R, Charalampakis N, Schizas D, Kykalos S, Tolia M. Immune checkpoint inhibitors and combinations with other agents in cholangiocarcinoma. Immunotherapy 2023; 15:487-502. [PMID: 36876442 DOI: 10.2217/imt-2022-0225] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023] Open
Abstract
Cholangiocarcinoma consists of a heterogeneous group of malignancies with generally poor prognoses. Immunotherapy has emerged in the treatment landscape of many tumors, offering survival benefits, but data regarding the use of immunotherapy for cholangiocarcinoma remain vague. In this review, the authors analyze differences in the tumor microenvironment and various immune escape mechanisms and discuss available immunotherapy combinations with other agents among completed and ongoing clinical trials, such as chemotherapy, targeted agents, antiangiogenic drugs, local ablative therapies, cancer vaccines, adoptive cell therapy and PARP and TGF-β inhibitors. Ongoing research to identify appropriate biomarkers is warranted.
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Affiliation(s)
- Nikolaos Skouteris
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Georgios Papageorgiou
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Rodanthi Fioretzaki
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Nikolaos Charalampakis
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | - Stylianos Kykalos
- Second Propedeutic Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | - Maria Tolia
- Department of Radiation Oncology, University Hospital of Crete, Voutes, Heraklion, Crete, 71110, Greece
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Wang L, Huang K, Zhang Y, Wu YF, Yue ZD, Fan ZH, Liu FQ, Li YW, Dong J. Short-term efficacy assessment of transarterial chemoembolization combined with radioactive iodine therapy in primary hepatocellular carcinoma. World J Gastrointest Surg 2023; 15:105-113. [PMID: 36741065 PMCID: PMC9896495 DOI: 10.4240/wjgs.v15.i1.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/30/2022] [Accepted: 12/21/2022] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Transarterial chemoembolization (TACE) is an effective treatment for primary hepatocellular carcinoma (PHC). Radioactive iodine therapy has been used in the treatment of advanced PHC, especially in patients with portal vein tumor thrombosis. However, data on the therapeutic effect of TACE combined with radioactive iodine therapy in PHC are scarce.
AIM To investigate the clinical efficacy of TACE combined with radioactive iodine implantation therapy in advanced PHC via perfusion computed tomography (CT).
METHODS For this study, 98 advanced PHC patients were recruited and divided randomly into the study and control groups. Patients in the study group were treated with TACE combined radioactive iodine implantation therapy. Patients in the control group were treated with only TACE. The tumor lesion length, clinical effect, serum alpha-fetoprotein (AFP) and CT perfusion parameters were compared before and after therapy, and statistical analysis was performed.
RESULTS There was no significant difference in tumor length and serum AFP between the study and control groups (P > 0.05) before treatment. However, the tumor length and serum AFP in the study group were lower than those in the control group 1 mo and 3 mo after therapy. After 3 mo of treatment, the complete and partial remission rate of the study group was 93.88%, which was significantly higher than the control group (77.55%) (P < 0.05). Before treatment, there were no significant differences between the two groups on the perfusion CT variables, including the lesion blood volume, permeability surface, blood flow, hepatic artery flow and mean transit time (P > 0.05). After 3 mo of treatment, all perfusion CT variables were lower in the study group compared to the control group (P < 0.05). The survival time of patients in the study group was 22 mo compared to 18 mo in the control group, which was significantly different [log rank (Mantel-Cox) = 4.318, P = 0.038].
CONCLUSION TACE combined with radioactive iodine implantation in the treatment of advanced PHC can inhibit the formation of blood vessels in tumor tissue and reduce the perfusion level of tumor lesions, thereby improving the clinical efficacy and prolonging the survival time of patients.
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Affiliation(s)
- Lei Wang
- Department of Interventional Radiology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Kun Huang
- Department of Radiology, Chinese Medical University Affiliated First Hospital, Shenyang 110001, Liaoning Province, China
| | - Yu Zhang
- Department of Interventional Radiology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Yi-Fan Wu
- Department of Interventional Radiology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Zhen-Dong Yue
- Department of Interventional Radiology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Zhen-Hua Fan
- Department of Interventional Radiology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Fu-Quan Liu
- Department of Interventional Radiology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Yong-Wu Li
- Department of Nuclear Medicine, The Fifth Center of People’s Liberation Army General Hospital, Beijing 100071, China
| | - Jian Dong
- Department of Radiology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
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Zhang W, Luo C, Zhang ZY, Zhang BX, Chen XP. Conversion therapy for advanced intrahepatic cholangiocarcinoma with lenvatinib and pembrolizumab combined with gemcitabine plus cisplatin: A case report and literature review. Front Immunol 2023; 13:1079342. [PMID: 36700218 PMCID: PMC9868150 DOI: 10.3389/fimmu.2022.1079342] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/20/2022] [Indexed: 01/11/2023] Open
Abstract
Background Intrahepatic cholangiocarcinoma (ICC) is a highly malignant biliary tumor. Patients with unresectable and advanced ICC have a poor prognosis with current gemcitabine-based chemotherapy. Combination therapy strategies based on immunotherapy have achieved promising results in various tumor types. Case presentation We reported a patient with unresectable ICC who received lenvatinib and pembrolizumab in combination with gemcitabine plus cisplatin (GP) chemotherapy and subsequently underwent radical liver resection. A 46-year-old male with a history of chronic hepatitis B and hypertension was diagnosed with ICC. Multiple liver tumors with ring-like enhancement were detected on abdominal contrast-enhanced CT and MRI. Enlarged lymph nodes were found in the hilar and retroperitoneal areas. The tumor was clinically staged as T2N1M0 (stage IIIB). Lenvatinib and pembrolizumab in combination with GP chemotherapy were adopted as first-line treatments for the patient. After six cycles of scheduled treatment, the diameter of the largest liver lesion and the number of liver lesions were markedly reduced. The level of the tumor marker CA19-9 decreased to a normal range. A partial response according to the mRECIST criteria was achieved without severe toxicities. Non-anatomical liver resection (segment 4b, 5,6 + segment 7 + segment 8), cholecystectomy and hilar lymph node dissection were performed one month after stopping combination therapy. Pathological examination confirmed a diagnosis of moderate-to-poorly differentiated ICC with lymph node metastasis. The patient has survived 15 months following resection of the tumors, with no evidence of local recurrence or distant metastasis. Conclusion Lenvatinib and anti-PD1 antibody pembrolizumab in combination with GP chemotherapy provided promising antitumor efficacy with reasonable tolerability, which may be a potentially feasible and safe conversion therapy strategy for patients with initially unresectable and advanced ICC.
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Vatankhah F, Salimi N, Khalaji A, Baradaran B. Immune checkpoints and their promising prospect in cholangiocarcinoma treatment in combination with other therapeutic approaches. Int Immunopharmacol 2023; 114:109526. [PMID: 36481527 DOI: 10.1016/j.intimp.2022.109526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/21/2022] [Accepted: 11/27/2022] [Indexed: 12/12/2022]
Abstract
Cholangiocarcinoma (CCA) is one of the malignant tumors that has shown rapid development in incidence and mortality in recent years. Like other types of cancer, patients with CCA experience alterations in the expression of immune checkpoints, indicating the importance of immune checkpoint inhibitors in treating CCA. The results of TCGA analysis in this study revealed a marginal difference in the expression of important immune checkpoints, Programmed cell death 1 (PD-1) and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and their ligands in CCA samples compared to normal ones. This issue showed the importance of combination therapy in this cancer. This review considers CCA treatment and covers several therapeutic modalities or combined treatment strategies. We also cover the most recent developments in the field and outline the important areas of immune checkpoint molecules as prognostic variables and therapeutic targets in CCA.
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Affiliation(s)
- Fatemeh Vatankhah
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Salimi
- School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
| | - Amirreza Khalaji
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Ruff SM, Shannon AH, Pawlik TM. Advances in Targeted Immunotherapy for Hepatobiliary Cancers. Int J Mol Sci 2022; 23:13961. [PMID: 36430440 PMCID: PMC9698563 DOI: 10.3390/ijms232213961] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer of the hepatobiliary system can be divided into primary liver cancer and biliary tract cancer (BTC), which includes hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder cancer (GBC). These aggressive cancers often present at an advanced stage or among patients with poorly preserved liver function. The primary treatment for HCC and BTC when diagnosed early is surgical resection, but given the high rate of recurrence and often advanced stage at diagnosis, many patients will require systemic therapy. Unfortunately, even with systemic therapy, long-term survival is poor. The immune system plays an important role in preventing cancer progression. The unique immune environment of the liver and subsequent alterations to the immune microenvironment by tumor cells to create a favorable microenvironment plays a key role in the progression of HCC and BTC. Due to the paucity of effective systemic therapies and distinctive immune environment of the liver, research and clinical trials are investigating the use of immunotherapy in HCC and BTC. This review will focus on current immunotherapies and emerging data for the treatment of HCC and BTC.
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Affiliation(s)
| | | | - Timothy M. Pawlik
- Department of Surgery, Division of Surgical Oncology, Wexner Medical Center, The James Comprehensive Cancer Center, The Ohio State University, 395 W. 12th Ave., Suite 670, Columbus, OH 43210, USA
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