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Morse MA, Crosby EJ, Halperin DM, Uronis HE, Hsu SD, Hurwitz HI, Rushing C, Bolch EK, Warren DA, Moyer AN, Lowe ME, Niedzwiecki D. Phase Ib/II study of Pembrolizumab with Lanreotide depot for advanced, progressive Gastroenteropancreatic neuroendocrine tumors (PLANET). J Neuroendocrinol 2025; 37:e13496. [PMID: 39933708 DOI: 10.1111/jne.13496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 11/28/2024] [Accepted: 01/25/2025] [Indexed: 02/13/2025]
Abstract
While performing a study of immune checkpoint blockade with the anti-PD-1 antibody pembrolizumab combined with the somatostatin analogue (SSA) lanreotide in patients with low- and intermediate-grade gastroenteropancreatic neuroendocrine tumors (GEP-NETs), we studied whether there were any immune correlates of response to the anti-PD-1 therapy that could guide future attempts to integrate immunotherapy into the treatment of NETs. Patients with grade 1 and 2 GEP-NETs who had progressed on a prior SSA received lanreotide 90 mg subcutaneously and pembrolizumab 200 mg intravenously every 3 weeks until progression or intolerable toxicity. Objective response rate (ORR) at any time in the study, clinical benefit rate (CBR, defined as stable disease or better), progression-free survival (PFS), and overall survival (OS) were measured. Changes in T cell subsets in peripheral blood before and during therapy were analyzed by multiparameter mass cytometry (CyTOF). Archived tissue samples were analyzed for PD-L1 expression and TIL infiltration. Twenty-two (22) patients (GI/pancreatic 14/8, median Ki67 7% [IQR 4, 10%], median 1.5 prior systemic therapies [range 1-4]) were enrolled. Among the GI-NETs, there was one partial response, the CBR was 50%, the median PFS was 8.5 months, and the median OS was 32.7 months. No responses were seen in pancreatic NETs, which had 0% CBR, a PFS of 2.7 months, and an OS of 23.9 months. Of the 16 analyzable tumors, 6 had detectable PD-L1 expression and 15 had detectable TILs. Neither TILs nor PD-L1 expression correlated with ORR or CBR. However, clinical benefit (SD or better) was associated with peripheral blood on-treatment effector memory T cell activation and progressive disease was associated with baseline peripheral blood regulatory T cell (Treg) activation. We conclude that immune checkpoint blockade had low activity in unselected patients with grade 1 and 2 GEP-NETs. Further study of strategies to reduce Treg activation or enhance effector memory activation during immunotherapy is warranted.
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Affiliation(s)
- Michael A Morse
- Division of Medical Oncology, Duke University Department of Medicine, Durham, North Carolina, USA
| | - Erika J Crosby
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Daniel M Halperin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Hope E Uronis
- Division of Medical Oncology, Duke University Department of Medicine, Durham, North Carolina, USA
| | - S David Hsu
- Division of Medical Oncology, Duke University Department of Medicine, Durham, North Carolina, USA
| | - Herbert I Hurwitz
- Division of Medical Oncology, Duke University Department of Medicine, Durham, North Carolina, USA
| | - Christel Rushing
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina, USA
| | - Emily K Bolch
- Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Dana A Warren
- Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Ashley N Moyer
- Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Melissa E Lowe
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina, USA
| | - Donna Niedzwiecki
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina, USA
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Muğlu H, Sünger E, Mıldanoğlu MM, Engin Delipoyraz E, Yücel MH, Özçelik H, Hamdard J, Açıkgöz Ö, Ölmez ÖF, Yıldız Ö, Bilici A. Clinicopathological Characteristics of Extrapulmonary Neuroendocrine Carcinomas: Treatment Responses and Survival Outcomes: Single-Center Experience. J Clin Med 2025; 14:2264. [PMID: 40217714 PMCID: PMC11989432 DOI: 10.3390/jcm14072264] [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: 03/06/2025] [Revised: 03/18/2025] [Accepted: 03/24/2025] [Indexed: 04/14/2025] Open
Abstract
Background/Objectives: Extrapulmonary neuroendocrine carcinomas (EP-NECs) are rare, aggressive malignancies with no standardized treatment approach. Although platinum-based chemotherapy is considered the first-line therapy, overall survival (OS) and progression-free survival (PFS) remain limited. This study aims to evaluate the clinical and pathological characteristics of EP-NEC patients, their treatment responses, and survival outcomes. Methods: This retrospective observational study included 29 EP-NEC patients diagnosed and followed between 2015 and 2024. Clinical and demographic data, tumor localization, disease stage, administered treatments, and survival outcomes were analyzed. Kaplan-Meier survival analysis was used to assess OS and PFS, with subgroup comparisons performed via the log-rank test. Results: The most common primary tumor sites were the pancreas (21%), prostate (17%), and cervix (14%). At diagnosis, 55.2% of patients had metastatic disease. First-line platinum-based chemotherapy achieved an objective response rate of 82.1%, with a median PFS of 8.16 months and a median OS of 14.16 months. Surgical intervention significantly improved survival (p = 0.020), while a high Ki-67 proliferation index (>80%) was associated with worse PFS (p = 0.032). Other factors, including smoking status and liver-directed therapies, had no significant impact on survival. Conclusions: EP-NECs present with a poor prognosis despite platinum-based chemotherapy achieving high response rates. Surgical resection improves survival outcomes, whereas high Ki-67 expression is associated with a worse prognosis. These findings highlight the need for further research into novel therapeutic strategies for EP-NECs.
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Affiliation(s)
- Harun Muğlu
- Department of Medical Oncology, Faculty of Medicine, Medipol University, Istanbul 34214, Türkiye; (E.S.); (M.M.M.); (E.E.D.); (M.H.Y.); (H.Ö.); (J.H.); (Ö.A.); (Ö.F.Ö.); (Ö.Y.); (A.B.)
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Fernandez-Cuesta L, Alcala N, Mathian E, Derks J, Thirlwell C, Dayton T, Marinoni I, Perren A, Walter T, Foll M. Basic science and translational implications of current knowledge on neuroendocrine tumors. J Clin Invest 2025; 135:e186702. [PMID: 40026252 PMCID: PMC11870734 DOI: 10.1172/jci186702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025] Open
Abstract
Neuroendocrine tumors (NETs) are a diverse group of malignancies that can occur in various organs, with a notable prevalence in the lungs and gastrointestinal tract, which are the focus of this Review. Although NETs are rare in individual organs, their incidence has increased over recent decades, highlighting the urgent need for current classification systems to evolve by incorporating recent advances in the understanding of NET biology. Several omics studies have revealed molecular subtypes, which, when integrated into existing classification frameworks, may provide more clinically relevant insights for patients with NETs. This Review examines recent progress in elucidating the biology of NETs, with a particular emphasis on the tumor microenvironment and cells of origin. The existence of different cells of origin, which may contribute to distinct molecular groups, along with profiles of immune infiltration - despite being generally low - could explain the emergence of more aggressive cases and the potential for metastatic progression. Given the molecular heterogeneity of NETs and the diversity of their microenvironments and different cells of origin, there is an urgent need to develop morphomolecular classification systems. Such systems would make it possible to better characterize tumor progression, identify new therapeutic targets, and, ultimately, guide the development of personalized therapies.
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Affiliation(s)
- Lynnette Fernandez-Cuesta
- Computational Cancer Genomics Team, Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Nicolas Alcala
- Computational Cancer Genomics Team, Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Emilie Mathian
- Computational Cancer Genomics Team, Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Jules Derks
- Department of Pulmonary Medicine, Erasmus MC Cancer institute, University Medical Center, Rotterdam, Netherlands
- GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands
| | | | - Talya Dayton
- European Molecular Biology Laboratory Barcelona, Tissue Biology and Disease Modeling, Barcelona, Spain
| | - Ilaria Marinoni
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Aurel Perren
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Thomas Walter
- Service d’Oncologie Médicale, Groupement Hospitalier Centre, Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France
| | - Matthieu Foll
- Computational Cancer Genomics Team, Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
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Fottner C, Apostolidis L, Krug S, Rinke A, Grün B, Michl P, Gress TM, Wagner DC, Roth W, Mettler E, Topsch J, Ruckes C, Galle PR, Weber MM. Activity and Safety of Avelumab in High-Grade Neuroendocrine Tumors and Poorly Differentiated Neuroendocrine Carcinomas Progressive after Chemotherapy (AveNEC Trial). Clin Cancer Res 2025; 31:860-867. [PMID: 39786465 DOI: 10.1158/1078-0432.ccr-24-2461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/08/2024] [Accepted: 12/23/2024] [Indexed: 01/12/2025]
Abstract
PURPOSE Neuroendocrine neoplasms grade 3 (NEN G3) are rare tumors with poor prognosis and no established second-line therapy. The role of immune checkpoint blockade in these aggressive tumors remains unclear. PATIENTS AND METHODS The phase II AveNEC study evaluated the effect of avelumab (AVE, 10 mg/kg i.v. every 2 weeks) in 60 patients with well-differentiated high-grade neuroendocrine tumors (N = 22) or poorly differentiated neuroendocrine carcinomas (N = 38) progressing after ≥1 prior chemotherapy (excluding Merkel cell carcinoma and small cell lung cancer). RESULTS The best overall response according to immune-related Response Evaluation Criteria in Solid Tumors (iRECIST) was partial response (PR) in three (5%) and stable disease (SD) in nine (15%) patients, with a disease control rate at 16 weeks of 15% (3 PRs; 6 SDs) and a median duration of response of 4.3 months. Six (10%) patients achieved SD or PR for >6 months and two for >1 year. Response rates were similar regardless of differentiation, Ki-67 expression, or primary localization. The median progression-free survival was 1.9 months, and the overall survival was 6.6 months. After a median follow-up of 3.6 years, only four (7%) patients were still alive; 1- and 2-year survival rates were 33% and 17%, respectively. Responders had a significantly longer overall survival of 30.2 months compared with 4.8 months in nonresponders. AVE was well tolerated, with few treatment-related grade 3/4 adverse events, and the quality of life remained stable during treatment. CONCLUSIONS In patients with progressive high-grade NEN G3, AVE was well tolerated and provided disease control with significant clinical benefit in 15% of heavily pretreated patients.
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MESH Headings
- Humans
- Male
- Female
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Middle Aged
- Aged
- Carcinoma, Neuroendocrine/drug therapy
- Carcinoma, Neuroendocrine/pathology
- Carcinoma, Neuroendocrine/mortality
- Neuroendocrine Tumors/drug therapy
- Neuroendocrine Tumors/pathology
- Neuroendocrine Tumors/mortality
- Adult
- Neoplasm Grading
- Aged, 80 and over
- Disease Progression
- Treatment Outcome
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Affiliation(s)
- Christian Fottner
- Unit of Endocrinology, I Medical Department, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Leonidas Apostolidis
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
| | - Sebastian Krug
- UKH-Universitätsklinikum Halle (Saale), Halle (Saale), Germany
| | - Anja Rinke
- Department of Gastroenterology, UKGM-Uniklinikum Giessen und Marburg-Standort Marburg, Marburg, Germany
| | - Barbara Grün
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
| | - Patrick Michl
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas M Gress
- Department of Gastroenterology, UKGM-Uniklinikum Giessen und Marburg-Standort Marburg, Marburg, Germany
| | - Daniel-Christoph Wagner
- Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Wilfried Roth
- Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Esther Mettler
- Unit of Endocrinology, I Medical Department, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Jana Topsch
- Interdisciplinary Centre for Clinical Trials, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Christian Ruckes
- Interdisciplinary Centre for Clinical Trials, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Peter R Galle
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Matthias M Weber
- Unit of Endocrinology, I Medical Department, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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Urman A, Schonman I, De Jesus-Acosta A. Evolving Immunotherapy Strategies in Gastrointestinal Neuroendocrine Neoplasms. Curr Treat Options Oncol 2025; 26:92-102. [PMID: 39843688 DOI: 10.1007/s11864-024-01283-4] [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] [Accepted: 12/02/2024] [Indexed: 01/24/2025]
Abstract
OPINION STATEMENT Treatment for neuroendocrine neoplasms (NENs) is tailored to the tumor's site of origin, grade, and differentiation. NENs are categorized into two main types: well-differentiated neuroendocrine tumors (NETs), which tend to grow more slowly and are less aggressive, and poorly differentiated neuroendocrine carcinomas (NECs), which are highly aggressive and harder to treat. Treatment options for NETs range from somatostatin analogues and mTOR inhibitors to peptide receptor radionuclide therapy (PRRT) with Lutetium-177 dotatate. In cases where the disease progresses more rapidly, cytotoxic chemotherapy may also be considered. In contrast, chemotherapy plays a central role in treating NECs, often following protocols similar to those used for small cell lung cancer. Exciting progress is being made in the development of new therapies for NENs. Inspired by the success of immunotherapy in other cancers, clinical trials have begun to explore its potential in NENs. Early findings suggest that immune checkpoint inhibitors (ICIs) may offer benefits, especially in patients with higher-grade NETs and NECs. However, because NENs have an immunologically "cold" tumor microenvironment-meaning they are less likely to trigger an immune response-new strategies are needed to boost ICI efficacy. To overcome this challenge, researchers are exploring innovative approaches, such as combining dual ICIs or pairing ICIs with other therapeutic agents to make the tumors more responsive to immune attack. Moreover, there is growing enthusiasm for cutting-edge therapies designed to enhance the immune system's ability to recognize and destroy cancer cells. These include bispecific T cell engagers, chimeric antigen receptor T cells, tumor-infiltrating lymphocytes, oncolytic viruses, and cancer vaccines. While their effectiveness in NENs is still being studied, these approaches hold considerable promise, offering new hope for patients with this challenging and complex cancer type.
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Affiliation(s)
- Arielle Urman
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Ian Schonman
- Johns Hopkins Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Ana De Jesus-Acosta
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
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Melhorn P, Raderer M, Kiesewetter B. Selecting systemic treatment for metastatic neuroendocrine tumors of the lung-current evidence and clinical implications. Cancer Treat Rev 2025; 133:102878. [PMID: 39787793 DOI: 10.1016/j.ctrv.2024.102878] [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: 09/20/2024] [Revised: 12/15/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
Neuroendocrine tumors (NET) of the lung are a slowly growing subtype of lung cancer that has a different treatment paradigm than aggressive and more common forms of lung neuroendocrine neoplasms (NEN) like small cell lung cancer (SCLC). Current guidelines for metastatic lung NET advocate a handful of treatment options, including somatostatin analogs (SSA), everolimus, temozolomide- or platin-based chemotherapy, and peptide receptor radionuclide therapy (PRRT). However, there is no clear treatment sequence, and the therapy of choice may depend on several factors such as tumor grade / growth rate, tumor burden / symptoms, disease progression status, and somatostatin receptor (SSTR) expression. In order to tailor treatment to each individual patient, the latest scientific findings and patient-specific clinical features must be considered together. This review critically evaluates the available evidence with regards to relevant patient characteristics, inclusion and exclusion criteria, and outcome metrics of clinical trials given the presumed natural disease course. Specific patient subgroups with an unmet therapeutic need are identified and discussed in the context of ongoing clinical trials.
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Affiliation(s)
- Philipp Melhorn
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria
| | - Markus Raderer
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria
| | - Barbara Kiesewetter
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria.
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Sen T, Dotsu Y, Corbett V, Puri S, Sen U, Boyle TA, Mack P, Hirsch F, Aljumaily R, Naqash AR, Sukrithan V, Karim NA. Pulmonary neuroendocrine neoplasms: the molecular landscape, therapeutic challenges, and diagnosis and management strategies. Lancet Oncol 2025; 26:e13-e33. [PMID: 39756451 DOI: 10.1016/s1470-2045(24)00374-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 05/20/2024] [Accepted: 06/25/2024] [Indexed: 01/07/2025]
Abstract
Lung neuroendocrine neoplasms are a group of diverse, heterogeneous tumours that range from well-differentiated, low-grade neuroendocrine tumours-such as typical and atypical carcinoids-to high-grade, poorly differentiated aggressive malignancies, such as large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). While the incidence of SCLC has decreased, the worldwide incidence of other pulmonary neuroendocrine neoplasms has been increasing over the past decades. In addition to the standard histopathological classification of lung neuroendocrine neoplasms, the introduction of molecular and sequencing techniques has led to new advances in understanding the biology of these diseases and might influence future classifications and staging that can subsequently improve management guidelines in the adjuvant or metastatic settings. Due to the rarity of neuroendocrine neoplasms, there is a paucity of prospective studies that focus on the lungs, especially in rare, well-differentiated carcinoids and LCNECs. In contrast with the success of targeted therapies in non-small-cell lung cancer (NSCLC), high-grade neuroendocrine carcinomas of the lung often only have a few specific targetable gene alterations. Optimal therapy for LCNECs is not well defined and treatment recommendations are based on extrapolating guidelines for the management of patients with SCLC and NSCLC. This Review explores the epidemiology, diagnosis, and staging of lung neuroendocrine neoplasms to date. In addition, we focus on the evolving molecular landscape and biomarkers, ranging from tumour phenotypes to functional imaging studies and novel molecular biomarkers. We outline the various clinical outcomes, challenges, the treatment landscape, ongoing clinical trials, and future directions.
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Affiliation(s)
- Triparna Sen
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Yosuke Dotsu
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Virginia Corbett
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sonam Puri
- Division of Clinical Oncology, The Huntsman Cancer Institute at The University of Utah, Salt Lake City, UT, USA
| | - Utsav Sen
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Phil Mack
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Fred Hirsch
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Raid Aljumaily
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
| | - Abdul Rafeh Naqash
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
| | - Vineeth Sukrithan
- Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
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Jiang J, Xu J, Ji S, Yu X, Chen J. Unraveling the mysteries of MGMT: Implications for neuroendocrine tumors. Biochim Biophys Acta Rev Cancer 2024; 1879:189184. [PMID: 39303858 DOI: 10.1016/j.bbcan.2024.189184] [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: 01/28/2024] [Revised: 07/15/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024]
Abstract
Neuroendocrine tumors (NETs) are a diverse group of tumors that arise from neuroendocrine cells and are commonly found in various organs. A considerable proportion of NET patients were diagnosed at an advanced or metastatic stage. Alkylating agents are the primary treatment for NET, and O6-methylguanine methyltransferase (MGMT) remains the first-line of defense against DNA damage caused by these agents. Clinical trials have indicated that MGMT promoter methylation or its low/lacked expression can predict a favorable outcome with Temozolomide in NETs. Its status could help select NET patients who can benefit from alkylating agents. Therefore, MGMT status serves as a biomarker to guide decisions on the efficacy of Temozolomide as a personalized treatment option. Additionally, delving into the regulatory mechanisms of MGMT status can lead to the development of MGMT-targeted therapies, benefiting individuals with high levels of MGMT expression. This review aims to explore the polymorphism of MGMT regulation and summarize its clinical implications in NETs, which would help establish the role of MGMT as a biomarker and its potential as a therapeutic target in NETs. Additionally, we explore the benefits of combining Temozolomide and immunotherapy in MGMT hypermethylated subgroups. Future studies can focus on optimizing Temozolomide administration to induce specific immunomodulatory changes.
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Affiliation(s)
- Jianyun Jiang
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Junfeng Xu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Shunrong Ji
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Xianjun Yu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Jie Chen
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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Fields BC, Ayabe RI, Seo YD, Maxwell JE, Halperin DM. Current Status of Immunotherapy in Management of Small Bowel Neuroendocrine Tumors. Curr Oncol Rep 2024; 26:1530-1542. [PMID: 39466478 PMCID: PMC11776107 DOI: 10.1007/s11912-024-01610-w] [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: 09/30/2024] [Indexed: 10/30/2024]
Abstract
PURPOSE OF REVIEW This study aims to present the current landscape of immunotherapy in the management of small bowel neuroendocrine tumors and identify ongoing and future targets for improved response. RECENT FINDINGS Somatostatin analogs and mTOR inhibitors remain cornerstones of non-surgical treatment, and applications of PRRT in SBNET are promising. Several efforts to replicate the success of immunotherapies in other solid tumors have been attempted in SBNET, with limited responses observed with current immune targets, such as PD-1/PD-L1 and CTLA-4. Epigenetic analyses have suggested a potential role for methylation and histone acetylation in SBNET tumorigenesis that warrant greater exploration. While the incidence of SBNET continues to increase, the number of effective therapies is few. Further elucidation of targetable components of the SBNET immune microenvironment with greater modulatory effects is necessary to improve outcomes in this growing patient population.
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Affiliation(s)
- Brittany C Fields
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Reed I Ayabe
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Y David Seo
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Jessica E Maxwell
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Daniel M Halperin
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
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García-Torralba E, Garcia-Lorenzo E, Doger B, Spada F, Lamarca A. Immunotherapy in Neuroendocrine Neoplasms: A Diamond to Cut. Cancers (Basel) 2024; 16:2530. [PMID: 39061170 PMCID: PMC11275146 DOI: 10.3390/cancers16142530] [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: 05/05/2024] [Revised: 07/08/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
A raise in the incidence of NENs is expected. Therefore, the identification of new therapeutic strategies, such as immunotherapy, remains crucial. To date, immune checkpoint inhibitors as monotherapy have shown modest activity in unselected NENs. Although immunotherapy combos (plus another immune agents or chemotherapy, among others) are potentially more active than single agents, this has not been uniformly confirmed, even in high-grade NENs. Other immunotherapeutic strategies under development include bispecific antibodies, targeting specific tumor antigens like DLL3, and cell therapy. Currently, no predictive immune biomarkers are available to guide clinical decisions. A comprehensive tumor molecular profiling approach needs to be developed for the selection of patients with NEN who could potentially benefit from immunotherapy. Ideally, clinical trials should incorporate this tumor molecular profiling to identify predictive biomarkers and improve efficacy. Achieving this goal requires an international collaborative effort.
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Affiliation(s)
- Esmeralda García-Torralba
- Department of Medical Oncology, Hospital Universitario Morales Meseguer, 30008 Murcia, Spain;
- Department of Medicine, Medical School, University of Murcia, 30001 Murcia, Spain
- IMIB-Arrixaca, 30120 Murcia, Spain
| | - Esther Garcia-Lorenzo
- START Madrid-FJD, Early Phase Clinical Trials Unit, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain
| | - Bernard Doger
- START Madrid-FJD, Early Phase Clinical Trials Unit, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain
| | - Francesca Spada
- European Institute of Oncology, European Institute of Oncology (IEO) IRCCS, 20141 Milan, Italy;
| | - Angela Lamarca
- Department of Oncology, OncoHealth Institute, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain
- Department of Medical Oncology, The Christie NHS Foundation, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
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11
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Zhong Y, Tian Y, Wang Y, Bai J, Long Q, Yan L, Gong Z, Gao W, Tang Q. Small Extracellular Vesicle piR-hsa-30937 Derived from Pancreatic Neuroendocrine Neoplasms Upregulates CD276 in Macrophages to Promote Immune Evasion. Cancer Immunol Res 2024; 12:840-853. [PMID: 38572963 PMCID: PMC11217728 DOI: 10.1158/2326-6066.cir-23-0825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/30/2024] [Accepted: 03/27/2024] [Indexed: 04/05/2024]
Abstract
The role of PIWI-interacting RNAs (piRNA) in small extracellular vesicles (sEV) derived from pancreatic neuroendocrine neoplasms (PNEN) in the tumor microenvironment (TME) remains unexplored. We used multiplex IHC to analyze the expression of CD68, CD276 (B7H3), and CD3 on PNEN. CD276+ tumor-associated macrophages (TAM) were more abundant in tumor tissues than nontumor tissues and negatively correlated with T-cell infiltration. Serum sEV piRNA sequencing was performed to identify piRNAs enriched in patients with PNEN. We then investigated the function and mechanism of sEV piR-hsa-30937 in the cross-talk between tumor cells and macrophages in the PNEN TME. PNEN-derived sEV piR-hsa-30937 targeted PTEN to activate the AKT pathway and drive CD276 expression. CD276+ macrophages inhibited T-cell proliferation and IFNγ production. piR-hsa-30937 knockdown and anti-CD276 treatment suppressed progression and metastasis in a preclinical model of PNEN by enhancing T-cell immunity. Thus, our data show that PNEN-derived sEV piR-hsa-30937 promotes CD276 expression in macrophages through the PTEN/AKT pathway and that CD276+ TAMs suppress T-cell antitumor immunity. sEV piR-hsa-30937 and CD276 are potential therapeutic targets for immunotherapy of PNEN.
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Affiliation(s)
- Yuan Zhong
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, P.R. China.
| | - Ye Tian
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, P.R. China.
| | - Yan Wang
- Department of Gastroenterology, The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Ili State, P.R. China.
| | - Jian’an Bai
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, P.R. China.
| | - Qin Long
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, P.R. China.
| | - Lijun Yan
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, P.R. China.
| | - Zhihui Gong
- Department of Gastroenterology, The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Ili State, P.R. China.
| | - Wei Gao
- Key Laboratory of Human Functional Genomics of Jiangsu Province, National Health Commission Key Laboratory of Antibody Techniques, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
| | - Qiyun Tang
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, P.R. China.
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12
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Angerilli V, Sabella G, Simbolo M, Lagano V, Centonze G, Gentili M, Mangogna A, Coppa J, Munari G, Businello G, Borga C, Schiavi F, Pusceddu S, Leporati R, Oldani S, Fassan M, Milione M. Comprehensive genomic and transcriptomic characterization of high-grade gastro-entero-pancreatic neoplasms. Br J Cancer 2024; 131:159-170. [PMID: 38729995 PMCID: PMC11231306 DOI: 10.1038/s41416-024-02705-8] [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: 11/14/2023] [Revised: 04/20/2024] [Accepted: 04/24/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND High-grade gastro-entero-pancreatic neoplasms (HG GEP-NENs) can be stratified according to their morphology and Ki-67 values into three prognostic classes: neuroendocrine tumors grade 3 (NETs G3), neuroendocrine carcinomas with Ki-67 < 55% (NECs <55) and NECs with Ki-67 ≥ 55% (NECs ≥55). METHODS We analyzed a cohort of 49 HG GEP-NENs by targeted Next-Generation Sequencing (TrueSight Oncology 500), RNA-seq, and immunohistochemistry for p53, Rb1, SSTR-2A, and PD-L1. RESULTS Frequent genomic alterations affected TP53 (26%), APC (20%), KRAS and MEN1 (both 11%) genes. NET G3 were enriched in MEN1 (p = 0.02) mutations, while both NECs groups were enriched in TP53 (p = 0.001), APC (p = 0.002) and KRAS (p = 0.02) mutations and tumors with TMB ≥ 10 muts/Mb (p = 0.01). No differentially expressed (DE) gene was found between NECs <55% and NECs ≥55%, while 1129 DE genes were identified between NET G3 and NECs. A slight enrichment of CD4+ and CD8+ T cells in NECs and of cancer-associated fibroblasts and macrophages (M2-like) in NET G3. Multivariate analysis identified histologic type and Rb1 loss as independent prognostic factors for overall survival. CONCLUSIONS This study showed that GEP-NET G3 and GEP-NECs exhibit clear genomic and transcriptomic differences, differently from GEP-NECs <55% and GEP-NECs ≥55%, and provided molecular findings with prognostic and potentially predictive value.
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Affiliation(s)
| | - Giovanna Sabella
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Michele Simbolo
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Vincenzo Lagano
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Centonze
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marco Gentili
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandro Mangogna
- Institute of Pathological Anatomy, Department of Medicine (DMED), University of Udine, Udine, Italy
| | - Jorgelina Coppa
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Giada Munari
- Department of Medicine (DIMED), University of Padua, Padua, Italy
| | | | - Chiara Borga
- Department of Medicine (DIMED), University of Padua, Padua, Italy
| | | | - Sara Pusceddu
- Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Rita Leporati
- Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Simone Oldani
- Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), University of Padua, Padua, Italy
- Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy
| | - Massimo Milione
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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13
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Lee DK, Park SR, Kim YH, Lee YG, Shin SJ, Ahn BC, Lee SS, Lim SM, Kim HR, Cho BC, Hong MH. A phase 2 study of spartalizumab (PDR001) among patients with recurrent or metastatic esophageal squamous cell carcinoma (KCSG HN18-17, K-MASTER project 12). Oncoimmunology 2024; 13:2371563. [PMID: 38919826 PMCID: PMC11197908 DOI: 10.1080/2162402x.2024.2371563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 06/19/2024] [Indexed: 06/27/2024] Open
Abstract
Spartalizumab (PDR001) is a humanized IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We conducted a single-arm, phase 2 trial to investigate the efficacy and safety of spartalizumab in patients with refractory esophageal squamous cell carcinoma (ESCC). Patients with histologically confirmed ESCC who experienced disease progression after platinum-based chemotherapy received 300 mg of intravenous spartalizumab every three weeks until disease progression or occurrence of unacceptable toxicity. The primary endpoint was centrally assessed objective response according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were closely monitored throughout the study. From March 2020 through April 2021, 44 patients with ESCC were enrolled. Of the 44 patients, the objective response rate was 20.5% (95% confidence interval: 8.5-32.4). With a median follow-up of 10.9 months, median progression-free survival and overall survival were 3.2 months and 11.2 months, respectively. In addition, the median duration of response was 24.7 months. The most common grade 3 or 4 adverse event was grade 3 dysphagia (eight [18%] patients). Biomarker analyses explored programmed cell death ligand 1 and CD20 as potential predictive markers for PD-1 blockade. Spartalizumab showed promising activity with a manageable safety profile, indicating its potential as a new treatment option for patients with refractory ESCC. Trial registration The trial was registered at ClinicalTrials.gov under the identifier NCT03785496.
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Affiliation(s)
- Dong Ki Lee
- Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
| | - Sook Ryun Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yeul Hong Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yun-Gyoo Lee
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Su-Jin Shin
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Beung-Chul Ahn
- Center for Lung Cancer, National Cancer Center, Goyang-si, South Korea
| | - Sung Sook Lee
- Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, South Korea
| | - Sun Min Lim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Ryun Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Byoung Chul Cho
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Min Hee Hong
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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14
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Corti F, Rossi RE, Cafaro P, Passarella G, Turla A, Pusceddu S, Coppa J, Oldani S, Guidi A, Longarini R, Cortinovis DL. Emerging Treatment Options for Neuroendocrine Neoplasms of Unknown Primary Origin: Current Evidence and Future Perspectives. Cancers (Basel) 2024; 16:2025. [PMID: 38893145 PMCID: PMC11171242 DOI: 10.3390/cancers16112025] [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: 04/25/2024] [Revised: 05/19/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9-22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting.
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Affiliation(s)
- Francesca Corti
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Roberta Elisa Rossi
- Gastroenterology and Endoscopy Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy;
| | - Pietro Cafaro
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Gaia Passarella
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Antonella Turla
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Sara Pusceddu
- Gastro-Entero-Pancreatic and Neuroendocrine Unit 1, Department of Medical Oncology, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (S.P.); (S.O.)
| | - Jorgelina Coppa
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy;
| | - Simone Oldani
- Gastro-Entero-Pancreatic and Neuroendocrine Unit 1, Department of Medical Oncology, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (S.P.); (S.O.)
| | - Alessandro Guidi
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Raffaella Longarini
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Diego Luigi Cortinovis
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
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15
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Rutherford M, Wheless M, Thomas K, Ramirez RA. Current and emerging strategies for the management of advanced/metastatic lung neuroendocrine tumors. Curr Probl Cancer 2024; 49:101061. [PMID: 38281845 DOI: 10.1016/j.currproblcancer.2024.101061] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/13/2023] [Accepted: 12/26/2023] [Indexed: 01/30/2024]
Abstract
Pulmonary neuroendocrine tumors represent a spectrum of disease ranging from typical carcinoid tumors to small cell lung cancers. The incidence of low-grade pulmonary NETs has been increasing, leading to improved awareness and the need for more treatment options for this rare cancer. Somatostatin analogs continue to be the backbone of therapy and may be followed or accompanied by targeted therapy, chemotherapy, and immune therapy. The recent addition of peptide receptor radionuclide therapy (PRRT) to the treatment armamentarium of NETs has led to the development of targeted alpha therapy to overcome PRRT resistance and minimize off-target adverse effects. Herein, we aim to highlight current treatment options for patients with advanced low grade pulmonary NETs along with emerging therapies, sequencing of therapies, upcoming clinical trials, and the importance of a multidisciplinary team to improve patient outcomes.
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Affiliation(s)
- Megan Rutherford
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Margaret Wheless
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Katharine Thomas
- Department of Medicine, Division of Hematology Oncology, Renown Medical Center Reno, NV, USA; Department of Medicine, University of Reno Nevada, Reno, NV, USA
| | - Robert A Ramirez
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
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16
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Al-Toubah T, Strosberg J, Hallanger-Johnson J, El-Haddad G. Targeted radionuclide therapy in endocrine-related cancers: advances in the last decade. Front Endocrinol (Lausanne) 2023; 14:1187870. [PMID: 38053729 PMCID: PMC10694449 DOI: 10.3389/fendo.2023.1187870] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 10/26/2023] [Indexed: 12/07/2023] Open
Abstract
Targeted radionuclide therapy plays an increasingly important role in managing endocrine-related tumors and significantly advances the therapeutic landscape for patients with these diseases. With increasing FDA-approved therapies and advances in the field, come an increased knowledge of the potential for long-term toxicities associated with these therapies and the field must develop new strategies to increase potency and efficacy while individualizing the selection of patients to those most likely to respond to treatment. Novel agents and modalities of therapy are also being explored. This review will discuss the current landscape and describe the avenues for growth in the field currently being explored.
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Affiliation(s)
- Taymeyah Al-Toubah
- Department of GI Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Jonathan Strosberg
- Department of GI Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Julie Hallanger-Johnson
- Department of Head and Neck - Endocrine Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Ghassan El-Haddad
- Department of Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Department of Nuclear Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
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17
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Granberg D, Juhlin CC, Falhammar H, Hedayati E. Lung Carcinoids: A Comprehensive Review for Clinicians. Cancers (Basel) 2023; 15:5440. [PMID: 38001701 PMCID: PMC10670505 DOI: 10.3390/cancers15225440] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Lung carcinoids are neuroendocrine tumors, categorized as typical or atypical carcinoids based on their histological appearance. While most of these tumors are slow-growing neoplasms, they still possess malignant potential. Many patients are diagnosed incidentally on chest X-rays or CT scans. Presenting symptoms include cough, hemoptysis, wheezing, dyspnea, and recurrent pneumonia. Endocrine symptoms, such as carcinoid syndrome or ectopic Cushing's syndrome, are rare. Surgery is the primary treatment and should be considered in all patients with localized disease, even when thoracic lymph node metastases are present. Patients with distant metastases may be treated with somatostatin analogues, chemotherapy, preferably temozolomide-based, mTOR inhibitors, or peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. Most patients have an excellent prognosis. Poor prognostic factors include atypical histology and lymph node metastases at diagnosis. Long-term follow-up is mandatory since metastases may occur late.
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Affiliation(s)
- Dan Granberg
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden;
- Department of Breast, Endocrine Tumors and Sarcomas, Karolinska University Hospital Solna, 17176 Stockholm, Sweden;
| | - Carl Christofer Juhlin
- Department of Oncology-Pathology, Karolinska Institutet, 17164 Stockholm, Sweden;
- Department of Pathology and Cancer Diagnostics, Karolinska University Hospital Solna, 17176 Stockholm, Sweden
| | - Henrik Falhammar
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden;
- Department of Endocrinology, Karolinska University Hospital Solna, 17176 Stockholm, Sweden
| | - Elham Hedayati
- Department of Breast, Endocrine Tumors and Sarcomas, Karolinska University Hospital Solna, 17176 Stockholm, Sweden;
- Department of Oncology-Pathology, Karolinska Institutet, 17164 Stockholm, Sweden;
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18
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Weaver JMJ, Hubner RA, Valle JW, McNamara MG. Selection of Chemotherapy in Advanced Poorly Differentiated Extra-Pulmonary Neuroendocrine Carcinoma. Cancers (Basel) 2023; 15:4951. [PMID: 37894318 PMCID: PMC10604995 DOI: 10.3390/cancers15204951] [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: 06/09/2023] [Revised: 10/02/2023] [Accepted: 10/02/2023] [Indexed: 10/29/2023] Open
Abstract
Extra-pulmonary poorly differentiated neuroendocrine carcinoma is rare, and evidence for treatment has been limited. In this article, the evidence behind the cytotoxic chemotherapy choices used for metastatic or unresectable EP-PD-NEC is reviewed. In the first-line setting, etoposide and platinum chemotherapy or irinotecan and platinum have been demonstrated to be equivalent in a large phase III trial. Questions remain regarding the optimal number of cycles, mode of delivery, and the precise definition of platinum resistance in this setting. In the second-line setting, FOLFIRI has emerged as an option, with randomized phase 2 trials demonstrating modest, but significant, response rates. Beyond this, data are extremely limited, and several regimens have been used. Heterogeneity in biological behaviour is a major barrier to optimal EP-PD-NEC management. Available data support the potential role of the Ki-67 index as a predictive biomarker for chemotherapy response. A more personalised approach to management in future studies will be essential, and comprehensive multi-omic approaches are required to understand tumour somatic genetic changes in relation to their effects on the surrounding microenvironment.
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Affiliation(s)
- Jamie M. J. Weaver
- The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK; (J.M.J.W.); (R.A.H.); (J.W.V.)
- Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester M20 4BX, UK
| | - Richard A. Hubner
- The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK; (J.M.J.W.); (R.A.H.); (J.W.V.)
| | - Juan W. Valle
- The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK; (J.M.J.W.); (R.A.H.); (J.W.V.)
- Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester M20 4BX, UK
| | - Mairead G. McNamara
- The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK; (J.M.J.W.); (R.A.H.); (J.W.V.)
- Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester M20 4BX, UK
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19
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Andreatos N, McGarrah PW, Sonbol MB, Starr JS, Capdevila J, Sorbye H, Halfdanarson TR. Managing Metastatic Extrapulmonary Neuroendocrine Carcinoma After First-Line Treatment. Curr Oncol Rep 2023; 25:1127-1139. [PMID: 37606874 DOI: 10.1007/s11912-023-01438-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2023] [Indexed: 08/23/2023]
Abstract
PURPOSE OF REVIEW Extrapulmonary neuroendocrine carcinoma (EP-NEC) is a rare, aggressive malignancy that can arise from any organ and frequently presents with distant metastases. Advanced disease has a poor prognosis with median overall survival (OS) rarely exceeding 1 year even with systemic therapy. The management paradigm of advanced/metastatic EP-NEC has been extrapolated from small cell lung cancer (SCLC) and commonly consists of 1st line therapy with etoposide and platinum (cisplatin or carboplatin), followed by alternative cytotoxic regimens at the time of progression. Only a minority of patients are able to receive 2nd line therapy, and cytotoxics derived from the SCLC paradigm such as topotecan or lurbinectedin have very limited activity. We aimed to evaluate emerging therapeutic options in the 2nd and later lines and survey potential future developments in this space. RECENT FINDINGS After a long period of stagnation in treatment options and outcomes, more promising regimens are gradually being utilized in the 2nd line setting including systemic therapy combinations such as FOLFIRI, FOLFOX, modified FOLFIRINOX, CAPTEM, and, more recently, novel checkpoint inhibitors such as nivolumab and ipilimumab. Simultaneously, advances in the understanding of disease biology are helping to refine patient selection and identify commonalities between NEC and their sites of origin which may eventually lead to additional targeted therapy options. While many questions remain, contemporary developments give grounds for optimism that improved outcomes for EP-NEC will soon be within reach.
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Affiliation(s)
- Nikolaos Andreatos
- Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Patrick W McGarrah
- Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | | | - Jason S Starr
- Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA
| | - Jaume Capdevila
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
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Kaur J, Vijayvergia N. Narrative Review of Immunotherapy in Gastroentero-Pancreatic Neuroendocrine Neoplasms. Curr Oncol 2023; 30:8653-8664. [PMID: 37754542 PMCID: PMC10527684 DOI: 10.3390/curroncol30090627] [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: 07/24/2023] [Revised: 09/06/2023] [Accepted: 09/19/2023] [Indexed: 09/28/2023] Open
Abstract
Gastroentero-pancreatic Neuroendocrine Neoplasms (GEP-NENs) are a diverse group of rare tumors that arise from neuroendocrine cells in the gastrointestinal tract and pancreas, and they can vary significantly in terms of clinical behavior and prognosis. Immunotherapy, particularly immune checkpoint inhibitors, has shown remarkable success in various malignancies by harnessing the body's immune system to target and eliminate cancer cells. Immune checkpoint inhibitor clinical studies in GEP-NENs have yielded promising outcomes, particularly in individuals with advanced and refractory disease. Objective responses and disease stabilization have been observed in some cases, even in those previously unresponsive to traditional treatments like chemotherapy or targeted therapies. However, it's important to note that the efficacy of immunotherapy in GEP-NENs can vary widely depending on tumor characteristics, the immune microenvironment, and patient factors. As such, identifying predictive biomarkers to select the most suitable patients for immunotherapy remains an ongoing challenge. Immunotherapy has considerable potential for treating GEP-NENs, but research is still in its early stages. Several combinations are being explored to enhance the effectiveness of immunotherapy and improve the outcomes of treatment, such as combining immunotherapy with other targeted therapies or chemotherapy.
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Affiliation(s)
| | - Namrata Vijayvergia
- Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA;
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21
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Ooki A, Osumi H, Fukuda K, Yamaguchi K. Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma. Cancer Metastasis Rev 2023; 42:1021-1054. [PMID: 37422534 PMCID: PMC10584733 DOI: 10.1007/s10555-023-10121-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 06/16/2023] [Indexed: 07/10/2023]
Abstract
Neuroendocrine neoplasms (NENs), which are characterized by neuroendocrine differentiation, can arise in various organs. NENs have been divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, each of which has a distinct etiology, molecular profile, and clinicopathological features. While the majority of NECs originate in the pulmonary organs, extrapulmonary NECs occur most predominantly in the gastro-entero-pancreatic (GEP) system. Although platinum-based chemotherapy is the main therapeutic option for recurrent or metastatic GEP-NEC patients, the clinical benefits are limited and associated with a poor prognosis, indicating the clinically urgent need for effective therapeutic agents. The clinical development of molecular-targeted therapies has been hampered due to the rarity of GEP-NECs and the paucity of knowledge on their biology. In this review, we summarize the biology, current treatments, and molecular profiles of GEP-NECs based on the findings of pivotal comprehensive molecular analyses; we also highlight potent therapeutic targets for future precision medicine based on the most recent results of clinical trials.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Koshiro Fukuda
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
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22
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Mosalem O, Sonbol MB, Halfdanarson TR, Starr JS. Tyrosine Kinase Inhibitors and Immunotherapy Updates in Neuroendocrine Neoplasms. Best Pract Res Clin Endocrinol Metab 2023; 37:101796. [PMID: 37414652 DOI: 10.1016/j.beem.2023.101796] [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] [Indexed: 07/08/2023]
Abstract
Neuroendocrine tumors (NETs) represent a heterogeneous group of malignancies that arise from neuroendocrine cells dispersed throughout the organs/tissues of the body. Treatment of advanced/metastatic disease varies depending on tumor origin and grade. Somatostatin analogs (SSA) have been the mainstay first-line treatment in the advanced/metastatic setting for tumor control and managing hormonal syndromes. Treatments beyond SSAs have expanded to include everolimus (mTOR inhibitor), tyrosine kinase inhibitors (TKI) (e.g., sunitinib), and peptide receptor radionuclide therapy (PRRT) with the choice of therapy to some extent dictated by the anatomic origin of the NETs. This review will focus on emerging systemic treatments for advanced/metastatic NETs, particularly TKIs, and immunotherapy.
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Affiliation(s)
- Osama Mosalem
- Division of Hematology and Oncology, Mayo Clinic Cancer Center, Jacksonville, FL, USA.
| | | | | | - Jason S Starr
- Division of Hematology and Oncology, Mayo Clinic Cancer Center, Jacksonville, FL, USA.
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23
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Raj N, Chan JA, Wang SJ, Aggarwal RR, Calabrese S, DeMore A, Fong L, Grabowsky J, Hope TA, Kolli KP, Mulvey CK, Munster PN, Perez K, Punn S, Reidy-Lagunes D, Von Fedak S, Zhang L, Bergsland EK. Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas. Br J Cancer 2023; 129:291-300. [PMID: 37208512 PMCID: PMC10338510 DOI: 10.1038/s41416-023-02298-8] [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: 11/14/2022] [Revised: 04/04/2023] [Accepted: 04/25/2023] [Indexed: 05/21/2023] Open
Abstract
BACKGROUND To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. METHODS Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. PRIMARY ENDPOINT objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. RESULTS Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. DISCUSSION Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov NCT03136055.
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Affiliation(s)
- Nitya Raj
- Memorial Sloan Kettering (MSK) Cancer Center, New York, NY, USA.
| | | | - Stephanie J Wang
- University of California San Francisco (UCSF), San Francisco, CA, USA
| | - Rahul R Aggarwal
- University of California San Francisco (UCSF), San Francisco, CA, USA
| | - Susan Calabrese
- University of California San Francisco (UCSF), San Francisco, CA, USA
| | - April DeMore
- Memorial Sloan Kettering (MSK) Cancer Center, New York, NY, USA
| | - Lawrence Fong
- University of California San Francisco (UCSF), San Francisco, CA, USA
| | | | - Thomas A Hope
- University of California San Francisco (UCSF), San Francisco, CA, USA
| | | | - Claire K Mulvey
- University of California San Francisco (UCSF), San Francisco, CA, USA
| | - Pamela N Munster
- University of California San Francisco (UCSF), San Francisco, CA, USA
| | | | - Sippy Punn
- Memorial Sloan Kettering (MSK) Cancer Center, New York, NY, USA
| | | | | | - Li Zhang
- University of California San Francisco (UCSF), San Francisco, CA, USA
| | - Emily K Bergsland
- University of California San Francisco (UCSF), San Francisco, CA, USA.
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24
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Pan WX, Zhang XM, Hao SL, Han W. Progress in immunotherapy for neuroendocrine neoplasm of the digestive system. World J Gastroenterol 2023; 29:4174-4185. [PMID: 37475845 PMCID: PMC10354576 DOI: 10.3748/wjg.v29.i26.4174] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/29/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are rare heterogeneous tumors that can develop in almost any organ, with the digestive organs, including the gastrointestinal tract and pancreas being the most commonly affected sites. Despite the fact that advances in initial therapies have progressed, there is presently no recognized effective treatment for advanced NEN. Immune checkpoint inhibitors (ICIs) have shown superior efficacy in treating several types of solid tumors. Despite their successful role in the treatment of partial NENs, such as small cell lung cancer, and Merkel cell carcinoma, the role of ICIs in most of the NENs remains limited. Nevertheless, due to their specific anti-tumor mechanisms and acceptable safety profile, ICIs are a promising avenue for further study in NENs therapy. Recent clinical trials have illustrated that combination therapy with ICI is more efficient than monotherapy, and multiple clinical trials are constantly ongoing to evaluate the efficacy and safety of these combination therapies. Therefore, the purpose of this review is to provide a comprehensive summary of the clinical progress of immunotherapy in NENs affecting the digestive system, with a specific emphasis on the application of programmed cell death protein 1/programmed death receptor ligand 1 inhibitor. Furthermore, this review has an exploration of the potential beneficiary population and the inherent value of utilizing immunotherapy in the management of NENs.
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Affiliation(s)
- Wei-Xuan Pan
- Department of General Surgery, Beijing Luhe Hospital, Capital Medical University, Beijing 101100, China
| | - Xin-Mu Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Shao-Long Hao
- Department of General Surgery, Beijing Luhe Hospital, Capital Medical University, Beijing 101100, China
| | - Wei Han
- Department of General Surgery, Beijing Luhe Hospital, Capital Medical University, Beijing 101100, China
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25
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Le BK, McGarrah P, Paciorek A, Mohamed A, Apolo AB, Chan DL, Reidy-Lagunes D, Hauser H, Rivero JD, Whitman J, Batty K, Zhang L, Raj N, Le T, Bergsland E, Halfdanarson TR. Urinary Neuroendocrine Neoplasms Treated in the "Modern Era": A Multicenter Retrospective Review. Clin Genitourin Cancer 2023; 21:403-414.e5. [PMID: 37031047 PMCID: PMC11296333 DOI: 10.1016/j.clgc.2023.02.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 02/15/2023] [Indexed: 03/19/2023]
Abstract
BACKGROUND Primary urinary neuroendocrine neoplasms (U-NENs) are extremely rare thus optimal treatment is unknown. Grading and treatment are typically extrapolated from other primary sites. Since 2010, the clinical landscape for NENs has changed substantially. We performed a retrospective review of U-NENs to assess treatment patterns and oncologic outcomes of patients treated in the recent era of NEN therapy. PATIENTS AND METHODS A multicenter retrospective review of patients diagnosed after 2005 and alive after 2010. Time to treatment failure (TTF) was used to evaluate progression and toxicity for systemic therapy. Tumors were categorized as having either well-differentiated neuroendocrine tumor (WDNET) or poorly differentiated neuroendocrine carcinoma (PDNEC) histology. RESULTS A total of 134 patients from 6 centers were included in our analysis, including 94 (70%) bladder, 32 (24%) kidney, 2 (1.5%) urethra and 4 other urinary primaries (3.0%). Poorly-differentiated neuroendocrine carcinoma was more common in bladder (92%) than non-bladder tumors (8%). Median Ki-67 available in bladder primary was 90% (n = 24), kidney 10% (n = 23), ureter 95% (n = 1), urethra 54% (n = 2), and others 90% (n = 3). Patients received a median of 2 therapies (range 0-10). Median time to death was not reached in locoregional WDNETs versus 8.2 years (95% CI, 3.5-noncalculable) in metastatic WDNETs (predominantly renal primary). Median time to death was 3.6 years (95% CI, 2.2-9.2) in locoregional PDNECs versus 1 year (95% CI, 0.8-1.3) in metastatic PDNECs (predominantly bladder primary). CONCLUSION This is the most extensive series examining treatment patterns in patients with U-NENs in the recent era of NEN therapy. The apparent inferior survival for bladder NENs is likely due to the preponderance of PDNECs in this group. As predicted, treatments for U-NENs mirrored that of other more common NENs. In our retrospective cohort, we observed that patients with WD-UNETs treated with peptide receptor radionuclide therapy (PRRT) and everolimus suggested potential activity for disease control in WD-UNETs. Prospective studies are needed to assess the activity of new oncology drugs in UNENs.
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Affiliation(s)
- Bryan Khuong Le
- Department of Medicine, University of California, San Francisco, CA
| | | | - Alan Paciorek
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA
| | - Amr Mohamed
- UH Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - Andrea B Apolo
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - David L Chan
- Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW 2065, Sydney, New South Wales, Australia
| | - Diane Reidy-Lagunes
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Haley Hauser
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Jaydira D Rivero
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Kathleen Batty
- Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW 2065, Sydney, New South Wales, Australia
| | - Li Zhang
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA
| | - Nitya Raj
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Tiffany Le
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Emily Bergsland
- Department of Medicine, University of California, San Francisco, CA.
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26
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Wheless M, Das S. Systemic Therapy for Pancreatic Neuroendocrine Tumors. Clin Colorectal Cancer 2023; 22:34-44. [PMID: 36114085 DOI: 10.1016/j.clcc.2022.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 07/21/2022] [Accepted: 08/02/2022] [Indexed: 11/03/2022]
Abstract
Patients with metastatic or advanced pancreatic neuroendocrine tumors (NETs) carry poorer prognoses relative to patients with other NETs due to bulkier and often, more proliferative baseline disease. Patients with these tumors also possess more approved treatment options relative to patients with other NETs, making therapeutic sequencing nuanced. As such, defining optimal therapeutic sequencing and developing more potent cytoreductive treatments for patients are significant areas of research need in the field. Herein this review, we discuss the current systemic therapy landscape, our approach to therapeutic sequencing in the clinic and ongoing studies seeking to define optimal sequencing of systemic therapies, and novel therapeutics in development, for patients with pancreatic NETs. We limit the scope of this latter topic to agents with preclinical or clinical rationale over the last 8 years to provide a contemporary view of the drug development landscape and focus primarily on new types of peptide receptor radionuclide therapy, anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors and anti-vascular endothelial growth receptor tyrosine kinase inhibitor plus immunotherapy combinations.
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Affiliation(s)
- Margaret Wheless
- Vanderbilt University Medical Center, Department of Medicine, Nashville, TN
| | - Satya Das
- Vanderbilt University Medical Center, Department of Medicine, Division of Hematology and Oncology, Nashville, TN.
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27
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Symons R, Daly D, Gandy R, Goldstein D, Aghmesheh M. Progress in the Treatment of Small Intestine Cancer. Curr Treat Options Oncol 2023; 24:241-261. [PMID: 36826686 DOI: 10.1007/s11864-023-01058-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2023] [Indexed: 02/25/2023]
Abstract
OPINION STATEMENT Small intestine cancer is rare, accounting for approximately 3% of all gastrointestinal malignancies. The most common histological subtypes include adenocarcinoma, neuroendocrine tumours (NETs) and gastrointestinal stromal tumours (GISTs). In localised disease, surgery remains the mainstay of treatment and the best approach to improve survival. Current treatment for small intestine adenocarcinoma (SIA) is extrapolated from small studies and data from colorectal cancer (CRC). There is limited evidence to guide therapy in the adjuvant setting. However, there are small phase II studies in the advanced setting providing evidence for the role of chemotherapy and immunotherapy. There is also limited evidence assessing the efficacy of targeted therapies. Small intestine NETs are rare, with evidence for somatostatin analogue therapy, particularly in the low to intermediate-grade well-differentiated tumours. Poorly differentiated NETs are generally managed with chemotherapy but have worse outcomes compared with well-differentiated NETs. The management of small intestine GISTs is largely targeting KIT mutations with imatinib. Recent trials have provided evidence for effective therapies in imatinib-resistant tumours and the potential role of immunotherapy. The aim of this article was to review the evidence for the current management and recent advances in the management of small intestine adenocarcinoma, NETs and GISTs.
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Affiliation(s)
- Rebecca Symons
- Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, High St, Randwick, Sydney, NSW, 2031, Australia
| | - Daniel Daly
- Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, High St, Randwick, Sydney, NSW, 2031, Australia.,University of New South Wales, Randwick, NSW, Australia
| | - Robert Gandy
- Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, High St, Randwick, Sydney, NSW, 2031, Australia.,University of New South Wales, Randwick, NSW, Australia
| | - David Goldstein
- Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, High St, Randwick, Sydney, NSW, 2031, Australia.,University of New South Wales, Randwick, NSW, Australia
| | - Morteza Aghmesheh
- Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, High St, Randwick, Sydney, NSW, 2031, Australia.
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28
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Emerging Immunotherapeutic and Diagnostic Modalities in Carcinoid Tumors. Molecules 2023; 28:molecules28052047. [PMID: 36903295 PMCID: PMC10004351 DOI: 10.3390/molecules28052047] [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: 10/28/2022] [Revised: 01/26/2023] [Accepted: 02/08/2023] [Indexed: 02/25/2023] Open
Abstract
Evasion of innate immunity represents a frequently employed method by which tumor cells survive and thrive. Previously, the development of immunotherapeutic agents capable of overcoming this evasion has realized pronounced clinical utility across a variety of cancer types. More recently, immunological strategies have been investigated as potentially viable therapeutic and diagnostic modalities in the management of carcinoid tumors. Classic treatment options for carcinoid tumors rely upon surgical resection or non-immune pharmacology. Though surgical intervention can be curative, tumor characteristics, such as size, location, and spread, heavily limit success. Non-immune pharmacologic treatments can be similarly limited, and many demonstrate problematic side effects. Immunotherapy may be able to overcome these limitations and further improve clinical outcomes. Similarly, emerging immunologic carcinoid biomarkers may improve diagnostic capabilities. Recent developments in immunotherapeutic and diagnostic modalities of carcinoid management are summarized here.
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29
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Popa Ilie IR, Georgescu CE. Immunotherapy in Gastroenteropancreatic Neuroendocrine Neoplasia. Neuroendocrinology 2023; 113:262-278. [PMID: 34348340 DOI: 10.1159/000518106] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/25/2021] [Indexed: 11/19/2022]
Abstract
The worldwide prevalence and incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) and of NENs, in general, have been increasing recently. While valuing the considerable progress made in the treatment strategies for GEP-NEN in recent years, patients with advanced, metastasized disease still have a poor prognosis, which calls for urgent novel therapies. The immune system plays a dual role: both host-protecting and "tumor-promoting." Hence, immunotherapy is potentially a powerful weapon to help NEN patients. However, although recent successes with checkpoint inhibitors have shown that enhancing antitumor immunity can be effective, the dynamic nature of the immunosuppressive tumor microenvironment presents significant hurdles to the broader application of these therapies. Studies led to their approval in NEN of the lung and Merkel cell carcinoma, whereas results in other settings have not been so encouraging. Oncolytic viruses can selectively infect and destroy cancer cells, acting as an in situ cancer vaccine. Moreover, they can remodel the tumor microenvironment toward a T cell-inflamed phenotype. Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to checkpoint inhibitors alone. Future efforts should focus on finding the best way to include immunotherapy in the GEP-NEN treatment scenario. In this context, this study aims at providing a comprehensive generalized review of the immune checkpoint blockade and the oncolytic virotherapy use in GEP-NENs that might improve GEP-NEN treatment strategies.
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Affiliation(s)
- Ioana Rada Popa Ilie
- Department of Endocrinology, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Carmen Emanuela Georgescu
- Department of Endocrinology, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
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30
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Greenberg J, Limberg J, Verma A, Kim D, Chen X, Lee YJ, Moore MD, Ullmann TM, Thiesmeyer JW, Loewenstein Z, Chen KJ, Egan CE, Stefanova D, Bareja R, Zarnegar R, Finnerty BM, Scognamiglio T, Du YCN, Elemento O, Fahey TJ, Min IM. Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration. JCI Insight 2022; 7:160130. [PMID: 36301668 PMCID: PMC9746918 DOI: 10.1172/jci.insight.160130] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 10/26/2022] [Indexed: 01/12/2023] Open
Abstract
Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. Therapeutic options are limited for the over 50% of patients who present with metastatic disease. We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy. The TMEs of localized and metastatic PNETs were investigated using an approach that combines RNA-Seq, cancer and T cell profiling, and pharmacologic perturbations. RNA-Seq analysis indicated that the primary tumors of metastatic PNETs showed significant activation of inflammatory and immune-related pathways. We determined that metastatic PNETs featured increased numbers of tumor-infiltrating T cells compared with localized tumors. T cells isolated from both localized and metastatic PNETs showed evidence of recruitment and antigen-dependent activation, suggestive of an immune-permissive microenvironment. A computational analysis suggested that vorinostat, a histone deacetylase inhibitor, may perturb the transcriptomic signature of metastatic PNETs. Treatment of PNET cell lines with vorinostat increased chemokine CCR5 expression by NF-κB activation. Vorinostat treatment of patient-derived metastatic PNET tissues augmented recruitment of autologous T cells, and this augmentation was substantiated in a mouse model of PNET. Pharmacologic induction of chemokine expression may represent a promising approach for enhancing the immunogenicity of metastatic PNET TMEs.
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Affiliation(s)
| | | | - Akanksha Verma
- Caryl and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, and
| | - David Kim
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Xiang Chen
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA
| | | | | | | | | | | | | | | | | | - Rohan Bareja
- Caryl and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, and
| | | | | | - Theresa Scognamiglio
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Yi-Chieh Nancy Du
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Olivier Elemento
- Caryl and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, and
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31
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Rösner E, Kaemmerer D, Sänger J, Lupp A. Evaluation of PD-L1 expression in a large set of gastroenteropancreatic neuroendocrine tumours and correlation with clinicopathological data. Transl Oncol 2022; 25:101526. [PMID: 36067541 PMCID: PMC9468575 DOI: 10.1016/j.tranon.2022.101526] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 08/15/2022] [Accepted: 08/24/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Targeting programmed death protein 1 (PD-1) or its ligand PD-L1 is a promising therapeutic approach for many types of cancer in which PD-L1 is overexpressed. However, data on PD-L1 expression levels in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are limited and contradictory. METHODS We evaluated PD-L1 expression in 457 archived, formalin-fixed, paraffin-embedded GEP-NEN samples from 175 patients by immunohistochemistry using the highly sensitive monoclonal anti-PD-L1 antibody 73-10. The immunostaining was semiquantitatively evaluated using a 12-point immunoreactivity score (IRS) taking both PD-L1-positive tumour cells and immune cells into account. Tumour samples with an IRS ≥ 3 were considered PD-L1-positive. Results were correlated with clinicopathological data and with the expression of several typical markers and receptors for neuroendocrine tumours. RESULTS Of the GEP-NEN samples, 73% were PD-L1-positive. The median IRS value across all samples was 4.0, corresponding to low expression. PD-L1 immunostaining was predominantly localised at the plasma membrane of the tumour cells. Positive correlations were observed between PD-L1 expression and tumour grading or Ki-67 index, between PD-L1 expression and the expression of chromogranin A, and between PD-L1 expression and the expression of each of the five somatostatin receptors. PD-L1 expression was lower in tumours with lymph node metastases at diagnosis than in those without regional metastasis and lower in high-stage than in earlier-stage tumours. No association was noted between PD-L1 expression and patient survival. CONCLUSIONS PD-L1 expression is common in GEP-NENs and increases with malignancy. Therefore, especially in high-grade GEP-NENs, targeting the PD-1/PD-L1 axis could be a promising additional therapeutic strategy.
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Affiliation(s)
- Erik Rösner
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Straße 1, Jena D-07747, Germany
| | - Daniel Kaemmerer
- Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany
| | - Jörg Sänger
- Laboratory of Pathology and Cytology Bad Berka, Bad Berka, Germany
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Straße 1, Jena D-07747, Germany.
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Pozas J, Alonso-Gordoa T, Román MS, Santoni M, Thirlwell C, Grande E, Molina-Cerrillo J. Novel therapeutic approaches in GEP-NETs based on genetic and epigenetic alterations. Biochim Biophys Acta Rev Cancer 2022; 1877:188804. [PMID: 36152904 DOI: 10.1016/j.bbcan.2022.188804] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/17/2022] [Accepted: 09/17/2022] [Indexed: 11/17/2022]
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous malignancies with distinct prognosis based on primary tumor localization, grade, stage and functionality. Surgery remains the only curative option in localized tumors, but systemic therapy is the mainstay of treatment for patients with advanced disease. For decades, the therapeutic landscape of GEP-NETs was limited to chemotherapy regimens with low response rates. The arrival of novel agents such as somatostatin analogues, peptide receptor radionuclide therapy, tyrosine kinase inhibitors or mTOR-targeted drugs, has changed the therapeutic paradigm of GEP-NETs. However, the efficacy of these agents is limited in time and there is scarce knowledge of optimal treatment sequencing. In recent years, massive parallel sequencing techniques have started to unravel the genomic intricacies of these tumors, allowing us to better understand the mechanisms of resistance to current treatments and to develop new targeted agents that will hopefully start an era for personalized treatment in NETs. In this review we aim to summarize the most relevant genomic aberrations and signaling pathways underlying GEP-NET tumorigenesis and potential therapeutic strategies derived from them.
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Affiliation(s)
- Javier Pozas
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medicine School, Alcalá University, Madrid, Spain
| | - Teresa Alonso-Gordoa
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medicine School, Alcalá University, Madrid, Spain
| | - Maria San Román
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medicine School, Alcalá University, Madrid, Spain
| | | | | | - Enrique Grande
- Medical Oncology Ddepartment. MD Anderson Cancer Center Madrid, 28033 Madrid, Spain
| | - Javier Molina-Cerrillo
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medicine School, Alcalá University, Madrid, Spain.
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Corbett V, Hallenbeck P, Rychahou P, Chauhan A. Evolving role of seneca valley virus and its biomarker TEM8/ANTXR1 in cancer therapeutics. Front Mol Biosci 2022; 9:930207. [PMID: 36090051 PMCID: PMC9458967 DOI: 10.3389/fmolb.2022.930207] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
Oncolytic viruses have made a significant inroad in cancer drug development. Numerous clinical trials are currently investigating oncolytic viruses both as single agents or in combination with various immunomodulators. Oncolytic viruses (OV) are an integral pillar of immuno-oncology and hold potential for not only delivering durable anti-tumor responses but also converting “cold” tumors to “hot” tumors. In this review we will discuss one such promising oncolytic virus called Seneca Valley Virus (SVV-001) and its therapeutic implications. SVV development has seen seismic evolution over the past decade and now boasts of being the only OV with a practically applicable biomarker for viral tropism. We discuss relevant preclinical and clinical data involving SVV and how bio-selecting for TEM8/ANTXR1, a negative tumor prognosticator can lead to first of its kind biomarker driven oncolytic viral cancer therapy.
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Affiliation(s)
- Virginia Corbett
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | | | - Piotr Rychahou
- Department of Surgery, Markey Cancer Center, University of Kentucky, Lexington, KY, United States
| | - Aman Chauhan
- Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- *Correspondence: Aman Chauhan,
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Hope TA, Pavel M, Bergsland EK. Neuroendocrine Tumors and Peptide Receptor Radionuclide Therapy: When Is the Right Time? J Clin Oncol 2022; 40:2818-2829. [PMID: 35649195 PMCID: PMC9390818 DOI: 10.1200/jco.22.00176] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/14/2022] [Accepted: 04/18/2022] [Indexed: 12/29/2022] Open
Abstract
Since its approval in 2018 by the US Food and Drug Administration, peptide receptor radionuclide therapy (PRRT) has become a mainstay in the treatment of neuroendocrine tumors. Lutetium-177-DOTATATE, the only approved agent, is indicated for the treatment of gastroenteropancreatic-neuroendocrine tumors. Although patient selection appears straightforward with somatostatin receptor-positron emission tomography, there is considerable complexity when deciding which patients to treat and when to start PRRT. Herein, we review the many factors that affect patient selection, focusing on the optimal patients to treat. Although significant effort has been expended to determine which patients benefit the most from PRRT, a validated predictive biomarker remains elusive. Although PRRT has been used for more than 2 decades in Europe and standards of care exist for safe treatment, there remain numerous questions regarding when PRRT should be used relative to other treatments. It is important to remember that multidisciplinary discussions are essential. Currently, there are a number of ongoing studies looking to assess the efficacy of PRRT compared with other treatment options and to optimize treatment through combination therapy, different dosing strategies, or use of different radionuclides and radioligands.
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Affiliation(s)
- Thomas A. Hope
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA
- Helen Diller Family Comprehensive Cancer Centre, University of California, San Francisco, San Francisco, CA
- Department of Radiology, San Francisco VA Medical Center, San Francisco, CA
| | - Marianne Pavel
- Department of Medicine 1, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Emily K. Bergsland
- Helen Diller Family Comprehensive Cancer Centre, University of California, San Francisco, San Francisco, CA
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
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Chan D, Rodriguez-Freixinos V, Doherty M, Wasson K, Iscoe N, Raskin W, Hallet J, Myrehaug S, Law C, Thawer A, Nguyen K, Singh S. Avelumab in unresectable/metastatic, progressive, grade 2–3 neuroendocrine neoplasms (NENs): Combined results from NET-001 and NET-002 trials. Eur J Cancer 2022; 169:74-81. [DOI: 10.1016/j.ejca.2022.03.029] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/07/2022] [Accepted: 03/18/2022] [Indexed: 11/30/2022]
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Xu S, Ye C, Chen R, Li Q, Ruan J. The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms. Cancers (Basel) 2022; 14:cancers14122911. [PMID: 35740577 PMCID: PMC9221445 DOI: 10.3390/cancers14122911] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/28/2022] [Accepted: 06/08/2022] [Indexed: 02/08/2023] Open
Abstract
Simple Summary The tumor microenvironment (TME) plays a role in promoting tumor progression. Elucidating the relationship between the TME and tumor cells will benefit current therapies. Therefore, this review summarizes the most recent relationship between the TME and tumor characteristics, discusses the differences in the TME at various sites along the digestive tract, and compares the TMEs of neuroendocrine tumors and neuroendocrine carcinomas. Microbial ecological changes in the TME were reviewed. The clinical application of the TME was summarized from bench to bedside. The TME can be used as a tumor drug target for diagnostic value, prognosis prediction, and efficacy evaluation, further revealing the potential of immune checkpoints combined with antiangiogenic drugs. The clinical application prospects of adoptive cell therapy and oncolytic viruses were described. The potential therapeutic approaches and strategies for gastrointestinal neuroendocrine neoplasms are considered. Abstract Gastroenteropancreatic neuroendocrine neoplasms feature high heterogeneity. Neuroendocrine tumor cells are closely associated with the tumor microenvironment. Tumor-infiltrating immune cells are mutually educated by each other and by tumor cells. Immune cells have dual protumorigenic and antitumorigenic effects. The immune environment is conducive to the invasion and metastasis of the tumor; in turn, tumor cells can change the immune environment. These cells also form cytokines, immune checkpoint systems, and tertiary lymphoid structures to participate in the process of mutual adaptation. Additionally, the fibroblasts, vascular structure, and microbiota exhibit interactions with tumor cells. From bench to bedside, clinical practice related to the tumor microenvironment is also regarded as promising. Targeting immune components and angiogenic regulatory molecules has been shown to be effective. The clinical efficacy of immune checkpoint inhibitors, adoptive cell therapy, and oncolytic viruses remains to be further discussed in clinical trials. Moreover, combination therapy is feasible for advanced high-grade tumors. The regulation of the tumor microenvironment based on multiple omics results can suggest innovative therapeutic strategies to prevent tumors from succeeding in immune escape and to support antitumoral effects.
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Affiliation(s)
- Shuaishuai Xu
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (S.X.); (C.Y.); (R.C.); (Q.L.)
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou 310000, China
| | - Chanqi Ye
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (S.X.); (C.Y.); (R.C.); (Q.L.)
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou 310000, China
| | - Ruyin Chen
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (S.X.); (C.Y.); (R.C.); (Q.L.)
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou 310000, China
| | - Qiong Li
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (S.X.); (C.Y.); (R.C.); (Q.L.)
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou 310000, China
| | - Jian Ruan
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (S.X.); (C.Y.); (R.C.); (Q.L.)
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou 310000, China
- Correspondence:
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Sun F, Grenert JP, Tan L, Van Ziffle J, Joseph NM, Mulvey CK, Bergsland E. Checkpoint Inhibitor Immunotherapy to Treat Temozolomide-Associated Hypermutation in Advanced Atypical Carcinoid Tumor of the Lung. JCO Precis Oncol 2022; 6:e2200009. [PMID: 35737914 PMCID: PMC9249272 DOI: 10.1200/po.22.00009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 04/06/2022] [Accepted: 05/04/2022] [Indexed: 01/23/2023] Open
Affiliation(s)
- Fangdi Sun
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - James P. Grenert
- Department of Pathology, University of California, San Francisco, San Francisco, CA
| | - Lisa Tan
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Jessica Van Ziffle
- Department of Pathology, University of California, San Francisco, San Francisco, CA
| | - Nancy M. Joseph
- Department of Pathology, University of California, San Francisco, San Francisco, CA
| | - Claire K. Mulvey
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Emily Bergsland
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
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Mandriani B, Pellè E, Mannavola F, Palazzo A, Marsano RM, Ingravallo G, Cazzato G, Ramello MC, Porta C, Strosberg J, Abate-Daga D, Cives M. Development of anti-somatostatin receptors CAR T cells for treatment of neuroendocrine tumors. J Immunother Cancer 2022; 10:e004854. [PMID: 35764366 PMCID: PMC9240886 DOI: 10.1136/jitc-2022-004854] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Neuroendocrine tumors (NETs) overexpress somatostatin receptors (SSTRs). METHODS We developed a second-generation, ligand-based, anti-SSTR chimeric antigen receptor (CAR) incorporating the somatostatin analog octreotide in its extracellular moiety. RESULTS Anti-SSTR CAR T cells exerted antitumor activity against SSTR+NET cell linesin vitro. The killing activity was highly specific, as demonstrated by the lack of CAR T cell reactivity against NET cells engineered to express mutated variants of SSTR2/5 by CRISPR/Cas9. When adoptively transferred in NSG mice, anti-SSTR CAR T cells induced significant antitumor activity against human NET xenografts. Although anti-SSTR CAR T cells could recognize the murine SSTRs as shown by their killing ability against murine NET cells, no obvious deleterious effects on SSTR-expressing organs such as the brain or the pancreas were observed in mice. CONCLUSIONS Taken together, our results establish anti-SSTR CAR T cells as a potential candidate for early phase clinical investigations in patients with NETs. More broadly, the demonstration that a known peptide drug can direct CAR T cell targeting may streamline the potential utility of multiple peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers.
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Affiliation(s)
- Barbara Mandriani
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Eleonora Pellè
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Francesco Mannavola
- Division of Medical Oncology, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Italy
| | - Antonio Palazzo
- Department of Biology, University of Bari "Aldo Moro", Bari, Italy
| | | | - Giuseppe Ingravallo
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Gerardo Cazzato
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Maria Cecilia Ramello
- Departments of Immunology and Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Camillo Porta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
- Division of Medical Oncology, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Italy
| | | | - Daniel Abate-Daga
- Departments of Immunology and Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida, USA
- Department of GI Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Mauro Cives
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
- Division of Medical Oncology, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Italy
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Kaliszewski K, Ludwig M, Greniuk M, Mikuła A, Zagórski K, Rudnicki J. Advances in the Diagnosis and Therapeutic Management of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs). Cancers (Basel) 2022; 14:2028. [PMID: 35454934 PMCID: PMC9030061 DOI: 10.3390/cancers14082028] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/10/2022] [Accepted: 04/14/2022] [Indexed: 02/07/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are an increasingly common cause of neoplastic diseases. One of the largest groups of NENs are neoplasms localized to the gastroenteropancreatic system, which are known as gastroenteropancreatic NENs (GEP-NENs). Because of nonspecific clinical symptoms, GEP-NEN patient diagnosis and, consequently, their treatment, might be difficult and delayed. This situation has forced researchers all over the world to continue progress in the diagnosis and treatment of patients with GEP-NENs. Our review is designed to present the latest reports on the laboratory diagnostic techniques, imaging tests and surgical and nonsurgical treatment strategies used for patients with these rare neoplasms. We paid particular attention to the nuclear approach, the use of which has been applied to GEP-NEN patient diagnosis, and to nonsurgical and radionuclide treatment strategies. Recent publications were reviewed in search of reports on new strategies for effective disease management. Attention was also paid to those studies still in progress, but with successful results. A total of 248 papers were analyzed, from which 141 papers most relevant to the aim of the study were selected. Using these papers, we highlight the progress in the development of diagnostic and treatment strategies for patients with GEP-NENs.
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Affiliation(s)
- Krzysztof Kaliszewski
- Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland; (M.L.); (M.G.); (A.M.); (K.Z.); (J.R.)
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Perez K, Chan J. Medical management of gastrointestinal neuroendocrine tumors. Curr Opin Endocrinol Diabetes Obes 2022; 29:219-224. [PMID: 35045527 DOI: 10.1097/med.0000000000000711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW To summarize the recent developments in the medical treatment of gastrointestinal neuroendocrine neoplasms. RECENT FINDINGS The medical management of gastrointestinal neuroendocrine tumors (GI-NETs) continues to evolve with advances in the management of symptoms related to hormone hypersecretion and therapeutic control of disease progression. Systemic therapy options include somatostatin analogs (SSAs), radiolabeled SSAs, molecularly targeted agents, and cytotoxic therapy. Recent progress has focused on new targeted therapies, the sequencing of therapy and the role of immunotherapy. SUMMARY This review will focus on treatment of GI-NETs and highlight new developments published over the last year.
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Affiliation(s)
- Kimberly Perez
- Harvard Medical School, Program in Carcinoid and Neuroendocrine Tumors, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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Inoue M, Kim M, Inoue T, Tait M, Byrne T, Nitschké M, Murer P, Cha H, Subramanian A, De Silva N, Chiaverotti T, McDonald DM. Oncolytic vaccinia virus injected intravenously sensitizes pancreatic neuroendocrine tumors and metastases to immune checkpoint blockade. Mol Ther Oncolytics 2022; 24:299-318. [PMID: 35118189 PMCID: PMC8783073 DOI: 10.1016/j.omto.2021.12.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 12/17/2021] [Indexed: 02/07/2023] Open
Abstract
This study determined the influence of intravenous (i.v.) oncolytic vaccinia virus mpJX-594 (mpJX) on antitumor activity of anti-programmed death receptor-1 antibody (aPD1) in functional and metastatic pancreatic neuroendocrine tumors (PanNETs). One i.v. dose of mpJX, engineered for mice with the same plasmid design as clinical virus Pexa-Vec, was administered alone or with repeated dosing of aPD1 (mpJX+aPD1) to two contrasting genetic models of PanNET: one developing benign insulin-secreting tumors (RIP1-Tag2;C57BL/6J mice) and the other developing liver metastases (RIP1-Tag2;AB6F1 mice). Experiments revealed that aPD1 had synergistic actions with mpJX on CD8+ T cell and natural killer (NK) cell influx, apoptosis, and suppression of proliferation in PanNETs. After mpJX+aPD1, the 53-fold increase in apoptosis (5 days) and 85% reduction in proliferation (20 days) exceeded the sum of mpJX and aPD1 given separately. mpJX+aPD1 also stabilized blood insulin and glucose in mice with functional PanNETs, regressed liver metastases in mice with aggressive PanNETs, and prolonged survival of both. The findings revealed that mpJX+aPD1 converted “cold” PanNETs into immunogenic tumors with widespread cytotoxic T cell influx, tumor cell killing, and suppression of proliferation. Reduction of tumor insulin secretion from functional PanNETs prolonged survival, and anti-metastatic actions on aggressive PanNETs reduced the metastatic burden to less than before treatment. The findings support the efficacy of the vaccinia virus with aPD1 for functional and metastatic PanNETs.
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Affiliation(s)
- Mitsuko Inoue
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Minah Kim
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Tomoyoshi Inoue
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Madeline Tait
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Thomas Byrne
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Maximilian Nitschké
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Patrizia Murer
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Howard Cha
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Aishwarya Subramanian
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Naomi De Silva
- SillaJen Biotherapeutics Inc., San Francisco, CA 94111, USA
| | | | - Donald M McDonald
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
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Abstract
PURPOSE OF REVIEW The field of neuroendocrine oncology has changed much since the time of Oberndorfer first described and coined the term carcinoid. The purpose of this review is to summarize recent findings and highlight clinically relevant updates in the management of NENs, particularly those that are practice changing. RECENT FINDINGS Neuroendocrine tumors (NETs) have replaced carcinoid tumor, for the most part. The classification of neuroendocrine neoplasms (NENs) improved, and the epidemiological understanding of this disease group also expanded with global collaborations and maturation of large tumor registries. Clarity in the utility of some NET biomarkers continues to be evolving. Knowledge of molecular drivers of tumorigenesis increases, and scientific/technological advancements lead the way to multiple drug approvals for the treatment of advanced NETs. The incidence and prevalence of NENs continue to increase, and patients are living longer. Better understanding of molecular drivers and further understanding of the role of immunotherapy in NENs will further elevate the level of care and transform care for all patients with NENs.
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Merola E, Michielan A, Rozzanigo U, Erini M, Sferrazza S, Marcucci S, Sartori C, Trentin C, de Pretis G, Chierichetti F. Therapeutic strategies for gastroenteropancreatic neuroendocrine neoplasms: State-of-the-art and future perspectives. World J Gastrointest Surg 2022; 14:78-106. [DOI: - merola e, michielan a, rozzanigo u, et al.therapeutic strategies for gastroenteropancreatic neuroendocrine neoplasms: state-of-the-art and future perspectives.world j gastrointestinal surgery, volume 14 number 2 february 27, 2022, doi: 10.4240/wjgs.v14.i2.78] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/16/2025] Open
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Merola E, Michielan A, Rozzanigo U, Erini M, Sferrazza S, Marcucci S, Sartori C, Trentin C, de Pretis G, Chierichetti F. Therapeutic strategies for gastroenteropancreatic neuroendocrine neoplasms: State-of-the-art and future perspectives. World J Gastrointest Surg 2022; 14:78-106. [PMID: 35317548 PMCID: PMC8908345 DOI: 10.4240/wjgs.v14.i2.78] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 10/18/2021] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have always been considered rare tumors, their incidence has risen over the past few decades. They represent a highly heterogeneous group of neoplasms with several prognostic factors, including disease stage, proliferative index (Ki67), and tumor differentiation. Most of these neoplasms express somatostatin receptors on the cell surface, a feature that has important implications in terms of prognosis, diagnosis, and therapy. Although International Guidelines propose algorithms aimed at guiding therapeutic strategies, GEP-NEN patients are still very different from one another, and the need for personalized treatment continues to increase. Radical surgery is always the best option when feasible; however, up to 80% of cases are metastatic upon diagnosis. Regarding medical treatments, as GEP-NENs are characterized by relatively long overall survival, multiple therapy lines are adopted during the lifetime of these patients, but the optimum sequence to be followed has never been clearly defined. Furthermore, although new molecular markers aimed at predicting the response to therapy, as well as prognostic scores, are currently being studied, their application is still far from being part of daily clinical practice. As they represent a complex disease, with therapeutic protocols that are not completely standardized, GEP-NENs require a multidisciplinary approach. This review will provide an overview of the available therapeutic options for GEP-NENs and attempts to clarify the possible approaches for the management of these patients and to discuss future perspectives in this field.
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Affiliation(s)
- Elettra Merola
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Andrea Michielan
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Umberto Rozzanigo
- Department of Radiology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Marco Erini
- Department of Nuclear Medicine, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Sandro Sferrazza
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Stefano Marcucci
- Department of Surgery, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Chiara Sartori
- Department of Pathology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Chiara Trentin
- Department of Medical Oncology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Giovanni de Pretis
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Franca Chierichetti
- Department of Nuclear Medicine, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
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Di Molfetta S, Feola T, Fanciulli G, Florio T, Colao A, Faggiano A, NIKE Group. Immune Checkpoint Blockade in Lung Carcinoids with Aggressive Behaviour: One More Arrow in Our Quiver? J Clin Med 2022; 11:jcm11041019. [PMID: 35207291 PMCID: PMC8876213 DOI: 10.3390/jcm11041019] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/09/2022] [Accepted: 02/13/2022] [Indexed: 02/05/2023] Open
Abstract
Lung carcinoids are well-differentiated and low-/intermediate-grade neuroendocrine neoplasms of the lung. Given their relative rarity, and the paucity of data available from prospective studies, no global consensus exists on the systemic treatment of these tumours. In recent years, immune checkpoint inhibitors have revolutionized cancer management and are under evaluation in patients with diverse types of neuroendocrine neoplasms. The aim of this narrative review is to analyse all available data for the use of approved immune checkpoint inhibitors in patients with lung carcinoids. We performed an extensive search for relevant data sources and found five published articles, one meeting abstract, and nine registered clinical trials indicating a growing interest of researchers in this field, and providing preliminary evidence of efficacy for combined nivolumab plus ipilimumab and durvalumab plus tremelimumab regimens in the treatment of advanced and/or metastatic lung carcinoids.
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Affiliation(s)
- Sergio Di Molfetta
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, 70124 Bari, Italy;
| | - Tiziana Feola
- Department of Experimental Medicine, “Sapienza” University of Rome, 00161 Rome, Italy;
- Neuroendocrinology, Neuromed Institute, Scientific Institute for Research, Hospitalization and Healthcare, 86077 Pozzilli, Italy
| | - Giuseppe Fanciulli
- NET Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari—Endocrine Unit, University Hospital of Sassari, 07100 Sassari, Italy
- Correspondence:
| | - Tullio Florio
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy;
- Scientific Institute for Research, Hospitalization and Healthcare Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Annamaria Colao
- Endocrinology Unit, Department of Clinical Medicine and Surgery, University Federico II, 80131 Naples, Italy;
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy;
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Park EJ, Park HJ, Kim KW, Suh CH, Yoo C, Chae YK, Tirumani SH, Ramaiya NH. Efficacy of Immune Checkpoint Inhibitors against Advanced or Metastatic Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 14:794. [PMID: 35159061 PMCID: PMC8833825 DOI: 10.3390/cancers14030794] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 01/28/2022] [Accepted: 02/01/2022] [Indexed: 02/04/2023] Open
Abstract
We performed a systematic review and meta-analysis of the treatment efficacy of immune checkpoint inhibitors (ICIs) in advanced/metastatic neuroendocrine neoplasms (NENs). MEDLINE and EMBASE were searched to identify studies that provide data on treatment response and/or survival outcomes of advanced/metastatic NEN patients treated with ICIs. The overall response rate (ORR) was pooled using a random-effects model. Meta-regression was performed to explore factors influencing the ORR. Individual patient data (IPD) meta-analysis of survival was performed using stratified Cox regression. Ten studies (464 patients) were included. The overall pooled ORR was 15.5% (95% confidence interval (CI), 9.5-24.3%), and it varied according to the primary site (thoracic, 24.7%; gastro-entero-pancreatic, 9.5%), tumor differentiation (poorly differentiated, 22.7%; well-differentiated, 10.4%), and drug regimen (combination, 25.3%; monotherapy, 10.1%). All these variables significantly influenced the ORR. Tumor differentiation was associated with both overall survival and progression-free survival (hazard ratio of poorly differentiated tumors, 4.2 (95% CI, 2.0-8.7) and 2.6 (95% CI, 1.6-4.4), respectively). Thus, the treatment efficacy of ICIs for advanced/metastatic NENs varied according to primary site, tumor differentiation, and drug regimen. Poorly differentiated NENs showed a better ORR than well-differentiated NENs but had a negative impact on survival.
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Affiliation(s)
- Eun-Joo Park
- Asan Medical Center, Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Seoul 05505, Korea; (E.-J.P.); (K.-W.K.); (C.-H.S.)
| | - Hyo-Jung Park
- Asan Medical Center, Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Seoul 05505, Korea; (E.-J.P.); (K.-W.K.); (C.-H.S.)
| | - Kyung-Won Kim
- Asan Medical Center, Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Seoul 05505, Korea; (E.-J.P.); (K.-W.K.); (C.-H.S.)
| | - Chong-Hyun Suh
- Asan Medical Center, Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Seoul 05505, Korea; (E.-J.P.); (K.-W.K.); (C.-H.S.)
| | - Changhoon Yoo
- Asan Medical Center, Department of Oncology, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Young-Kwang Chae
- Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Sree Harsha Tirumani
- University Hospitals Cleveland Medical Center, Department of Radiology, Case Western Reserve University, 11100 Euclid Ave., Cleveland, OH 44106, USA; (S.H.T.); (N.H.R.)
| | - Nikhil H. Ramaiya
- University Hospitals Cleveland Medical Center, Department of Radiology, Case Western Reserve University, 11100 Euclid Ave., Cleveland, OH 44106, USA; (S.H.T.); (N.H.R.)
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Prisciandaro M, Antista M, Raimondi A, Corti F, Morano F, Centonze G, Sabella G, Mangogna A, Randon G, Pagani F, Prinzi N, Niger M, Corallo S, Castiglioni di Caronno E, Massafra M, Bartolomeo MD, de Braud F, Milione M, Pusceddu S. Biomarker Landscape in Neuroendocrine Tumors With High-Grade Features: Current Knowledge and Future Perspective. Front Oncol 2022; 12:780716. [PMID: 35186729 PMCID: PMC8856722 DOI: 10.3389/fonc.2022.780716] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 01/10/2022] [Indexed: 11/26/2022] Open
Abstract
Neuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2–G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical–pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of KRAS, TP53, and RB1 is mainly reported, but also druggable alterations, including BRAF and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.
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Affiliation(s)
- Michele Prisciandaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- *Correspondence: Michele Prisciandaro,
| | - Maria Antista
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandra Raimondi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Corti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Morano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Centonze
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanna Sabella
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandro Mangogna
- Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy
| | - Giovanni Randon
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pagani
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Natalie Prinzi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Monica Niger
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Salvatore Corallo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Marco Massafra
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Massimo Milione
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Pusceddu
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Schöffski P, Tan DSW, Martín M, Ochoa-de-Olza M, Sarantopoulos J, Carvajal RD, Kyi C, Esaki T, Prawira A, Akerley W, De Braud F, Hui R, Zhang T, Soo RA, Maur M, Weickhardt A, Krauss J, Deschler-Baier B, Lau A, Samant TS, Longmire T, Chowdhury NR, Sabatos-Peyton CA, Patel N, Ramesh R, Hu T, Carion A, Gusenleitner D, Yerramilli-Rao P, Askoxylakis V, Kwak EL, Hong DS. Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies. J Immunother Cancer 2022; 10:e003776. [PMID: 35217575 PMCID: PMC8883259 DOI: 10.1136/jitc-2021-003776] [Citation(s) in RCA: 113] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/08/2022] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab. METHODS Eligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D). RESULTS In total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline. CONCLUSIONS Ieramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment. TRIAL REGISTRATION NUMBER NCT02460224.
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Affiliation(s)
- Patrick Schöffski
- Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
| | - Daniel S W Tan
- National Cancer Centre Singapore, Singapore
- Duke-NUS Medical School, Singapore
| | - Miguel Martín
- Hospital General Universitario Gregorio Maranon, Madrid, Spain
| | | | - John Sarantopoulos
- Institute for Drug Development, Mays Cancer Center at University of Texas Health San Antonio MD Anderson Cancer Center, San Antonio, Texas, USA
| | | | - Chrisann Kyi
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Taito Esaki
- National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Amy Prawira
- Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada
| | - Wallace Akerley
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | | | - Rina Hui
- Westmead Hospital and The University of Sydney, Sydney, New South Wales, Australia
| | - Tian Zhang
- University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Ross A Soo
- National University Cancer Institute, Singapore
| | - Michela Maur
- Oncologia Medica, AOU Policlinico di Modena, Modena, Emilia-Romagna, Italy
| | | | - Jürgen Krauss
- National Center for Tumor Diseases, Heidelberg, Germany
| | | | - Allen Lau
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | - Tanay S Samant
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | - Tyler Longmire
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | | | | | - Nidhi Patel
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | - Radha Ramesh
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | - Tiancen Hu
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | - Ana Carion
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | - Daniel Gusenleitner
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | | | | | - Eunice L Kwak
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | - David S Hong
- The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Xu JX, Wu DH, Ying LW, Hu HG. Immunotherapies for well-differentiated grade 3 gastroenteropancreatic neuroendocrine tumors: A new category in the World Health Organization classification. World J Gastroenterol 2021; 27:8123-8137. [PMID: 35068858 PMCID: PMC8704278 DOI: 10.3748/wjg.v27.i47.8123] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/28/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
According to the 2019 World Health Organization (WHO) classification, well-differentiated grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are a new category of cancer of the digestive system. G3 GEP-NET research and treatment are not as robust as those of lower grade (G1/2) NETs and poorly differentiated neuroendocrine carcinomas (NECs). Previously, the management of high-grade NETs was mainly based on NEC therapies, as high-grade NETs were classified as NECs under the previous WHO classification. Despite this, G3 GEP-NETs are significantly less responsive to platinum-based chemotherapy regimens than NECs, due to their distinct molecular pathogenesis and course of pathological grade transition. Patients with advanced G3 GEP-NETs, who have progressed or are intolerant to chemotherapy regimens such as capecitabine plus temozolomide, have limited treatment choices. Immunotherapy has helped patients with a variety of cancers attain long-term survival through the use of immune checkpoint inhibitors. Immunotherapies, either alone or in combination with other therapies, do not have a clear function in the treatment of G3 GEP-NETs. Currently, the majority of immunotherapy studies, both prospective and retrospective, do not reliably differentiate G3 GEP-NETs from NECs. By contrast, a significant number of studies include non-GEP neuroendocrine neoplasms (NENs). Therefore, there is an urgent need to summarize and evaluate these data to provide more effective therapeutic approaches for patients with this rare tumor. The purpose of this mini-review was to screen and summarize information on G3 GEP-NETs from all studies on NENs immunotherapy.
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Affiliation(s)
- Jun-Xi Xu
- Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - De-Hao Wu
- Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Li-Wei Ying
- Department of Orthopedic, Taizhou Hospital, Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Han-Guang Hu
- Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
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50
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[Progress of Immune Checkpoint Inhibitors
in the Treatment of Advanced Pulmonary Neuroendocrine Tumors]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 24:784-789. [PMID: 34802210 PMCID: PMC8607289 DOI: 10.3779/j.issn.1009-3419.2021.102.42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Pulmonary neuroendocrine tumors (PNETs) are a kind of epithelial tumors originating from pulmonary neuroendocrine cells, accounting for about 20% of primary lung tumors, including typical carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma. The morphologic and clinical characteristics of these four types of PNETs are relatively highly heterogeneous. Immune checkpoint inhibitors (ICIs) have been shown robust antitumor activity in a variety of solid tumors. Treatment regimens of advanced PNETs have developed greatly in the past decade, but ICIs are still in their infancy in the field of PNETs. This review focuses on the landscape of current clinical trials and research as well as the situation of ICIs-related biomarkers in PNETs.
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