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Wang Q, Yu M, Zhang S. The characteristics of the tumor immune microenvironment in colorectal cancer with different MSI status and current therapeutic strategies. Front Immunol 2025; 15:1440830. [PMID: 39877377 PMCID: PMC11772360 DOI: 10.3389/fimmu.2024.1440830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 12/16/2024] [Indexed: 01/31/2025] Open
Abstract
Colorectal cancer (CRC) remains a significant cause of cancer-related mortality worldwide. Despite advancements in surgery, chemotherapy, and radiotherapy, the effectiveness of these conventional treatments is limited, particularly in advanced cases. Therefore, transition to novel treatment is urgently needed. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has shown promise in improving outcomes for CRC patients. Notably, patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) tumors often benefit from ICIs, while the majority of CRC cases, which exhibit proficient mismatch repair (pMMR) or microsatellite-stable (MSS) status, generally show resistance to this approach. It is assumed that the MSI phenotype cause some changes in the tumor microenvironment (TME), thus triggering antitumor immunity and leading to response to immunotherapy. Understanding these differences in the TME relative to MSI status is essential for developing more effective therapeutic strategies. This review provides an overview of the TME components in CRC and explores current approaches aimed at enhancing ICI efficacy in MSS CRC.
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Affiliation(s)
- Qingzhe Wang
- Department of Targeting Therapy and Immunology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Min Yu
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shuang Zhang
- Department of Targeting Therapy and Immunology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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2
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Schiele P, Kolling S, Rosnev S, Junkuhn C, Walter AL, von Einem JC, Stintzing S, Schöning W, Sauer IM, Modest DP, Heinrich K, Weiss L, Heinemann V, Bullinger L, Frentsch M, Na IK. Flow Cytometric Assessment of FcγRIIIa-V158F Polymorphisms and NK Cell Mediated ADCC Revealed Reduced NK Cell Functionality in Colorectal Cancer Patients. Cells 2024; 14:32. [PMID: 39791733 PMCID: PMC11720420 DOI: 10.3390/cells14010032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 12/17/2024] [Accepted: 12/24/2024] [Indexed: 01/12/2025] Open
Abstract
Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells is a key mechanism in anti-cancer therapies with monoclonal antibodies, including cetuximab (EGFR-targeting) and avelumab (PDL1-targeting). Fc gamma receptor IIIa (FcγRIIIa) polymorphisms impact ADCC, yet their clinical relevance in NK cell functionality remains debated. We developed two complementary flow cytometry assays: one to predict the FcγRIIIa-V158F polymorphism using a machine learning model, and a 15-color flow cytometry panel to assess antibody-induced NK cell functionality and cancer-immune cell interactions. Samples were collected from healthy donors and metastatic colorectal cancer (mCRC) patients from the FIRE-6-Avelumab phase II study. The machine learning model accurately predicted the FcγRIIIa-V158F polymorphism in 94% of samples. FF homozygous patients showed diminished cetuximab-mediated ADCC compared to VF or VV carriers. In mCRC patients, NK cell dysfunctions were evident as impaired ADCC, decreased CD16 downregulation, and reduced CD137/CD107a induction. Elevated PD1+ NK cell levels, reduced lysis of PDL1-expressing CRC cells and improved NK cell activation in combination with the PDL1-targeting avelumab indicate that the PD1-PDL1 axis contributes to impaired cetuximab-induced NK cell function. Together, these optimized assays effectively identify NK cell dysfunctions in mCRC patients and offer potential for broader application in evaluating NK cell functionality across cancers and therapeutic settings.
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MESH Headings
- Humans
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/immunology
- Colorectal Neoplasms/pathology
- Colorectal Neoplasms/drug therapy
- Receptors, IgG/metabolism
- Receptors, IgG/genetics
- Antibody-Dependent Cell Cytotoxicity
- Flow Cytometry/methods
- Cetuximab/pharmacology
- Cetuximab/therapeutic use
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Female
- Male
- Polymorphism, Genetic
- Middle Aged
- Cell Line, Tumor
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Affiliation(s)
- Phillip Schiele
- BIH Center for Regenerative Therapies (BCRT), Therapy-Induced Remodeling in Immuno-Oncology, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
| | - Stefan Kolling
- BIH Center for Regenerative Therapies (BCRT), Therapy-Induced Remodeling in Immuno-Oncology, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
- BIH Biomedical Innovation Academy, BIH Charité Junior Digital Clinician Scientist Program, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 10178 Berlin, Germany
- BSIO Berlin School of Integrative Oncology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10178 Berlin, Germany
| | - Stanislav Rosnev
- Department of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
| | - Charlotte Junkuhn
- BIH Center for Regenerative Therapies (BCRT), Therapy-Induced Remodeling in Immuno-Oncology, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
- BSIO Berlin School of Integrative Oncology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10178 Berlin, Germany
| | - Anna Luzie Walter
- BIH Center for Regenerative Therapies (BCRT), Therapy-Induced Remodeling in Immuno-Oncology, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
- BSIO Berlin School of Integrative Oncology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10178 Berlin, Germany
- Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité—Universitätsmedizin, 10117 Berlin, Germany
| | - Jobst Christian von Einem
- Department of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
- MVZ Onkologie Tiergarten, 10559 Berlin, Germany
| | - Sebastian Stintzing
- Department of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 10117 Berlin, Germany
| | - Igor Maximilian Sauer
- Department of Surgery, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
| | - Dominik Paul Modest
- Department of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
- German Cancer Consortium (DKTK), 10115 Berlin, Germany
| | - Kathrin Heinrich
- Department of Medicine III, Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
| | - Lena Weiss
- Department of Hematology/Oncology and Comprehensive Cancer Center, University Hospital, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
| | - Volker Heinemann
- Department of Hematology/Oncology and Comprehensive Cancer Center, University Hospital, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
| | - Lars Bullinger
- Department of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
| | - Marco Frentsch
- BIH Center for Regenerative Therapies (BCRT), Therapy-Induced Remodeling in Immuno-Oncology, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
| | - Il-Kang Na
- BIH Center for Regenerative Therapies (BCRT), Therapy-Induced Remodeling in Immuno-Oncology, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 13353 Berlin, Germany
- BSIO Berlin School of Integrative Oncology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10178 Berlin, Germany
- German Cancer Consortium (DKTK), 10115 Berlin, Germany
- ECRC Experimental and Clinical Research Center, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 10178 Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
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Khushalani NI, Ott PA, Ferris RL, Cascone T, Schadendorf D, Le DT, Sharma MR, Barlesi F, Sharfman W, Luke JJ, Melero I, Lathers D, Neely J, Suryawanshi S, Sanyal A, Holloway JL, Suryawanshi R, Ely S, Segal NH. Final results of urelumab, an anti-CD137 agonist monoclonal antibody, in combination with cetuximab or nivolumab in patients with advanced solid tumors. J Immunother Cancer 2024; 12:e007364. [PMID: 38458639 PMCID: PMC10921538 DOI: 10.1136/jitc-2023-007364] [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: 01/15/2024] [Indexed: 03/10/2024] Open
Abstract
BACKGROUND Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors. METHODS CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments. RESULTS CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab. CONCLUSIONS Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer. TRIAL REGISTRATION NUMBERS NCT02110082; NCT02253992.
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Affiliation(s)
- Nikhil I Khushalani
- Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Patrick A Ott
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Robert L Ferris
- Hillman Cancer Center, University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania, USA
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Tina Cascone
- University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Dirk Schadendorf
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, University Hospital Essen, Essen, Germany
| | - Dung T Le
- Johns Hopkins University, Baltimore, Maryland, USA
| | | | - Fabrice Barlesi
- Aix-Marseille University, Marseille, France
- Hopital de la Timone, Marseille, France
| | | | - Jason J Luke
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ignacio Melero
- CIBERONC, and Clinica Universidad de Navarra, Pamplona, Spain
| | - Deanne Lathers
- Bristol Meyers Squibb Lawrenceville, Lawrenceville, New Jersey, USA
| | - Jaclyn Neely
- Bristol Meyers Squibb Lawrenceville, Lawrenceville, New Jersey, USA
| | | | | | - James L Holloway
- Bristol Meyers Squibb Lawrenceville, Lawrenceville, New Jersey, USA
| | | | - Scott Ely
- Bristol Meyers Squibb Lawrenceville, Lawrenceville, New Jersey, USA
| | - Neil H Segal
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Cornell Medical College, New York, NY, USA
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4
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Burcher KM, Bloomer CH, Gavrila E, Kalada JM, Chang MJ, Gebeyehu RR, Song AH, Khoury LM, Lycan TW, Kinney R, D’Agostino R, Bunch PM, Shukla K, Triozzi P, Furdui CM, Zhang W, Porosnicu M. Study protocol: phase II study to evaluate the effect of cetuximab monotherapy after immunotherapy with PD-1 inhibitors in patients with head and neck squamous cell cancer. Ther Adv Med Oncol 2024; 16:17588359231217959. [PMID: 38249330 PMCID: PMC10799583 DOI: 10.1177/17588359231217959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 11/15/2023] [Indexed: 01/23/2024] Open
Abstract
Background Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%. Objectives We hypothesize that cetuximab monotherapy following an immune checkpoint inhibitor (ICI) will lead to increased efficacy due to a potential synergistic effect on the antitumor immune response, as a result of activation effects of both treatments on innate and adaptative immune responses. To the authors' knowledge, this is the only ongoing prospective clinical study that evaluates the combination of cetuximab and ICIs administered sequentially. Methods and analysis In this non-randomized, open-label, phase II trial, 30 patients with R/M HNSCC who have previously failed or could not tolerate a PD-1 inhibitor as a single agent or in combination with chemotherapy will subsequently be treated with cetuximab monotherapy. Outcomes of interest include overall response rate, duration of response, progression-free survival, overall survival, and treatment toxicity, as well as treatment outcome measured by a patient-reported outcome questionnaire. Saliva and blood will be collected for correlative studies to investigate the immune response status at the end of therapy with an ICI and the effect of cetuximab on the antitumor immune response. The results will be correlated with the response to cetuximab and the time window between the last administration of an ICI and the loading dose of cetuximab. The clinical study is actively recruiting. Ethics This study was approved by the Wake Forest Comprehensive Cancer Center Institutional Review Board: IRB00065239. Clinical trial registration This study is registered on ClinicalTrials.gov: NCT04375384.
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Affiliation(s)
- Kimberly M. Burcher
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Chance H. Bloomer
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Elena Gavrila
- Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - John M. Kalada
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Mark J. Chang
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Rediet R. Gebeyehu
- Section on Hematology and Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Alexander H. Song
- Section on Hematology and Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Lara M. Khoury
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Thomas W. Lycan
- Section on Hematology and Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Rebecca Kinney
- Section on Hematology and Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Ralph D’Agostino
- Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Paul M. Bunch
- Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Kirtikar Shukla
- Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Pierre Triozzi
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Cristina M. Furdui
- Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Wei Zhang
- Center for Cancer Genomics and Precision Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Mercedes Porosnicu
- Section on Hematology and Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
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Jiang YJ, Guo NT, Xia XP, Ji Y, Huo JG. Immunotherapy strategies and traditional Chinese medicine treatment for microsatellite stable metastatic colorectal cancer. Shijie Huaren Xiaohua Zazhi 2023; 31:1007-1013. [DOI: 10.11569/wcjd.v31.i24.1007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 11/24/2023] [Accepted: 12/20/2023] [Indexed: 12/28/2023] Open
Abstract
The incidence and mortality of colorectal cancer (CRC) have increased year by year. In addition to traditional radiotherapy, chemotherapy, and targeted therapy, immunotherapy also brings hope to more patients with metastatic colorectal cancer (mCRC). However, these treatments are limited to patients with high microsatellite instability, and about 95% of mCRC patients with microsatellite stability (MSS) can not benefit from them. How to enhance the response of MSS mCRC patients to immunotherapy is the focus of current research. In recent years, it has been found that immunotherapy strategies are expected to improve the clinical efficacy for such patients, and the research reports of TCM combined with immunotherapy are increasing day by day. Therefore, this article aims to review the immunotherapy and traditional Chinese medicine treatment for MSS colorectal cancer.
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Affiliation(s)
- Yu-Jing Jiang
- The Third Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, China
| | - Nai-Ting Guo
- The Third Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, China
| | - Xue-Ping Xia
- The Third Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, China
| | - Yi Ji
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, China
| | - Jie-Ge Huo
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, China
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Matteucci L, Bittoni A, Gallo G, Ridolfi L, Passardi A. Immunocheckpoint Inhibitors in Microsatellite-Stable or Proficient Mismatch Repair Metastatic Colorectal Cancer: Are We Entering a New Era? Cancers (Basel) 2023; 15:5189. [PMID: 37958363 PMCID: PMC10648369 DOI: 10.3390/cancers15215189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/21/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition has been related to a high sensitivity to immunotherapy, in particular to the Immune Checkpoint Inhibitors (ICIs). In fact, in MSI-H or dMMR mCRC, treatment with ICIs induced remarkable response rates and prolonged survival. However, the majority of mCRC cases are mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS), and unfortunately these conditions involve resistance to ICIs. This review aims to provide an overview of the strategies implemented to overcome ICI resistance and/or define subgroups of patients with MSS or dMMR mCRC who may benefit from immunotherapy.
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Affiliation(s)
- Laura Matteucci
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Alessandro Bittoni
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Graziana Gallo
- Operative Unit of Pathologic Anatomy, Azienda USL della Romagna, “Maurizio Bufalini” Hospital, 47521 Cesena, Italy
| | - Laura Ridolfi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
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7
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He X, Lan H, Jin K, Liu F. Can immunotherapy reinforce chemotherapy efficacy? a new perspective on colorectal cancer treatment. Front Immunol 2023; 14:1237764. [PMID: 37790928 PMCID: PMC10543914 DOI: 10.3389/fimmu.2023.1237764] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/25/2023] [Indexed: 10/05/2023] Open
Abstract
As one of the main threats to human life (the fourth most dangerous and prevalent cancer), colorectal cancer affects many people yearly, decreases patients' quality of life, and causes irreparable financial and social damages. In addition, this type of cancer can metastasize and involve the liver in advanced stages. However, current treatments can't completely eradicate this disease. Chemotherapy and subsequent surgery can be mentioned among the current main treatments for this disease. Chemotherapy has many side effects, and regarding the treatment of this type of tumor, chemotherapy can lead to liver damage, such as steatohepatitis, steatosis, and sinus damage. These damages can eventually lead to liver failure and loss of its functions. Therefore, it seems that other treatments can be used in addition to chemotherapy to increase its efficiency and reduce its side effects. Biological therapies and immunotherapy are one of the leading suggestions for combined treatment. Antibodies (immune checkpoint blockers) and cell therapy (DC and CAR-T cells) are among the immune system-based treatments used to treat tumors. Immunotherapy targets various aspects of the tumor that may lead to 1) the recruitment of immune cells, 2) increasing the immunogenicity of tumor cells, and 3) leading to the elimination of inhibitory mechanisms established by the tumor. Therefore, immunotherapy can be used as a complementary treatment along with chemotherapy. This review will discuss different chemotherapy and immunotherapy methods for colorectal cancer. Then we will talk about the studies that have dealt with combined treatment.
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Affiliation(s)
- Xing He
- Department of Gastroenterology, Jinhua Wenrong Hospital, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Fanlong Liu
- Department of Colorectal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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8
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Sabanayagam R, Krishnamoorthy S, Gnanagurusamy J, Muruganatham B, Muthusami S. EGCG attenuate EGF triggered matrix abundance and migration in HPV positive and HPV negative cervical cancer cells. Med Oncol 2023; 40:261. [PMID: 37544940 DOI: 10.1007/s12032-023-02135-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 07/21/2023] [Indexed: 08/08/2023]
Abstract
Our previous laboratory findings suggested the beneficial effects of epigallocatechin gallate (EGCG) against cervical cancer (CC) cells survival. The present study is aimed at identifying the effects of EGCG in preventing the actions of epidermal growth factor (EGF) in human papilloma virus (HPV) 68 positive ME180 and HPV negative C33A CC cells. An elevated level of EGF in tumor micro-environment (TME) is linked to the metastasis of several cancers including CC. We hypothesized that EGCG has the ability to block the actions of EGF. To test this, survival assay was performed in cells treated with or without EGF and EGCG. The mitochondrial activity of cells was ascertained using MTT assay and mitored staining. Protein and non-protein components in the extracellular matrix such as collagen and sulphated glycosaminoglycans (GAGs) were evaluated using sirius red and alcian blue staining, respectively. Matrix metalloproteinase-2 (MMP-2) gene expression and enzymatic activity were assessed using real time-reverse transcriptase-polymerase chain reaction (RT-PCR) and gelatin zymography. Wound healing assay was performed to assess the EGF induced migratory ability and its inhibition by EGCG pre-treatment. Clonogenic assay showed that EGCG pre-treatment blocked the EGF driven colony formation. In silico analysis performed identified the efficacy of EGCG in binding with different domains of EGF receptor (EGFR). EGCG pre-treatment prevented the epithelial-mesenchymal transition (EMT) and metabolic activity induced by EGF, this is associated with concomitant reduction in the gene expression and enzyme activity of MMP-2. Further, reduced migration and ability to form colonies were observed in EGCG pre-treated cells when stimulated with EGF. HPV positive ME180 cells showed increased migratory and clonogenic ability upon EGF stimulation, whose effects were not much significant in HPV negative C33A cells. EGCG effectively blocked the actions of EGF in both HPV positive and HPV negative conditions and can be advocated as supplementary therapy for the management of EGF driven CC. However, further studies using cell line-derived xenograft (CDX)/patient-derived xenograft (PDX) model system is warranted to validate the therapeutic utility of EGCG.
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Affiliation(s)
- Rajalakshmi Sabanayagam
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Sneha Krishnamoorthy
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Jayapradha Gnanagurusamy
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Bharathi Muruganatham
- Karpagam Cancer Research Centre, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Sridhar Muthusami
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India.
- Karpagam Cancer Research Centre, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India.
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9
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Dhawan N, Afzal MZ, Amin M. Immunotherapy in Anal Cancer. Curr Oncol 2023; 30:4538-4550. [PMID: 37232801 DOI: 10.3390/curroncol30050343] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/27/2023] Open
Abstract
The incidence and mortality of squamous cell carcinoma of the anus has been gradually increasing globally over the last few decades. The evolution of different modalities, including immunotherapies, has changed the treatment paradigm of metastatic anal cancers. Chemotherapy, radiation therapy, and immune-modulating therapies form the backbone of treatment of anal cancer in various stages. Most anal cancers are linked to high-risk human papilloma virus (HPV) infections. HPV oncoproteins E6 and E7 are responsible for an anti-tumor immune response triggering the recruitment of tumor-infiltrating lymphocytes. This has led to the development and utilization of immunotherapy in anal cancers. Current research in anal cancer is moving forward to discover ways to incorporate immunotherapy in the treatment sequencing in various stages of anal cancers. Immune checkpoint inhibitors alone or in combination, adoptive cell therapy, and vaccines are the areas of active investigations in anal cancer in both locally advanced and metastatic settings. Immunomodulating properties of non-immunotherapies are incorporated to enhance immune checkpoint inhibitors' effectiveness in some of the clinical trials. The aim of this review is to summarize the potential role of immunotherapy in anal squamous cell cancers and future directions.
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Affiliation(s)
- Natasha Dhawan
- Department of Medical Oncology, Dartmouth Cancer Center, Lebanon, NH 03756, USA
| | - Muhammad Z Afzal
- Department of Medical Oncology, Dartmouth Cancer Center, Lebanon, NH 03756, USA
| | - Manik Amin
- Department of Medical Oncology, Dartmouth Cancer Center, Lebanon, NH 03756, USA
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10
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Zhang X, Liang Y, Jiang J, Lu C, Shi F, Cao Q, Zhang Y, Diao H. A High-Salt Diet Exacerbates Liver Fibrosis through Enterococcus-Dependent Macrophage Activation. Microbiol Spectr 2023; 11:e0340322. [PMID: 36786636 PMCID: PMC10100947 DOI: 10.1128/spectrum.03403-22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 01/14/2023] [Indexed: 02/15/2023] Open
Abstract
People consume more salt than the recommended levels due to poor dietary practices. The effects of long-term consumption of high-salt diets (HSD) on liver fibrosis are unclear. This study aimed to explore the impact of HSD on liver fibrosis. In this study, a carbon tetrachloride (CCL4)-induced liver fibrosis mouse model was used to evaluate fibrotic changes in the livers of mice fed a normal diet (ND) and an HSD. The HSD exacerbated liver injury and fibrosis. Moreover, the protein expression levels of transforming growth factor β (TGF-β), tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein 1 (MCP-1) were significantly higher in the HSD group than in the normal group. The proportion of macrophages and activation significantly increased in the livers of HSD-fed mice. Meanwhile, the number of macrophages significantly increased in the small intestinal lamina propria of HSD-fed mice. The levels of profibrotic factors also increased in the small intestine of HSD-fed mice. Additionally, HSD increased the profibrotic chemokines and monocyte chemoattractant levels in the portal vein blood. Further characterization suggested that the HSD decreased the expression of tight junction proteins (ZO-1 and CLDN1), enhancing the translocation of bacteria. Enterococcus promoted liver injury and inflammation. In vitro experiments demonstrated that Enterococcus induced macrophage activation through the NF-κB pathway, thus promoting the expression of fibrosis-related genes, leading to liver fibrogenesis. Similarly, Enterococcus disrupted the gut microbiome in vivo and significantly increased the fibrotic markers, TGF-β, and alpha smooth muscle actin (α-SMA) expression in the liver. IMPORTANCE This study further confirms that Enterococcus induce liver fibrosis in mice. These results indicate that an HSD can exacerbate liver fibrosis by altering the gut microbiota composition, thus impairing intestinal barrier function. Therefore, this may serve as a new target for liver fibrosis therapy and gut microbiota management.
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Affiliation(s)
- Xujun Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Yan Liang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jingjing Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Chong Lu
- Department of Gastroenterology, Jinhua Hospital of Zhejiang University, Jinhua, Zhejiang, China
| | - Fan Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Qingyi Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Yanhui Zhang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
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11
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Bazzi ZA, Sneddon S, Zhang PGY, Tai IT. Characterization of the immune cell landscape in CRC: Clinical implications of tumour-infiltrating leukocytes in early- and late-stage CRC. Front Immunol 2023; 13:978862. [PMID: 36846019 PMCID: PMC9945970 DOI: 10.3389/fimmu.2022.978862] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 12/20/2022] [Indexed: 02/10/2023] Open
Abstract
Introduction Colorectal cancer (CRC) is the third leading cause of cancer-related deaths globally. Tumour-infiltrating leukocytes play an important role in cancers, including CRC. We therefore sought to characterize the impact of tumour-infiltrating leukocytes on CRC prognosis. Methods To determine whether the immune cell profile within CRC tissue could influence prognosis, we employed three computational methodologies (CIBERSORT, xCell and MCPcounter) to predict abundance of immune cell types, based on gene expression. This was done using two patient cohorts, TCGA and BC Cancer Personalized OncoGenomics (POG). Results We observed significant differences in immune cell composition between CRC and normal adjacent colon tissue, as well as differences in based on method of analysis. Evaluation of survival based on immune cell types revealed dendritic cells as a positive prognostic marker, consistently across methodologies. Mast cells were also found to be a positive prognostic marker, but in a stage-dependent manner. Unsupervised cluster analysis demonstrated that significant differences in immune cell composition has a more pronounced effect on prognosis in early-stage CRC, compared to late-stage CRC. This analysis revealed a distinct group of individuals with early-stage CRC which have an immune infiltration signature that indicates better survival probability. Conclusions Taken together, characterization of the immune landscape in CRC has provided a powerful tool to assess prognosis. We anticipate that further characterization of the immune landscape will facilitate use of immunotherapies in CRC.
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Affiliation(s)
- Zainab Ali Bazzi
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Sophie Sneddon
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Peter G Y Zhang
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Isabella T Tai
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
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12
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Shanina EV, Breker F, Lysov NA, Shanin VY, Ponomareva YV, Supil'nikov AA. Chemotherapy-Induced Broadly Reactive Autoantibodies in a Colon Cancer Patient. BULLETIN OF THE MEDICAL INSTITUTE "REAVIZ" (REHABILITATION, DOCTOR AND HEALTH) 2022. [DOI: 10.20340/vmi-rvz.2023.1.clin.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
The link between cancer and autoimmunity is well known. However, the extent to which chemotherapy induces autoimmune responses is still unclear. Here, we quantified IgM responses to various human tissues and patient tumors before and during adjuvant chemotherapy (seven cycles of the FOLFIRI plus cetuximab regimen) with metastasized colorectal cancer. IgM levels against all tissues tested increased shortly after the first cycle and further increased in the second and third cycles. Autoimmune responses then declined during cycles four through seven, but remained above baseline for most tissues. Our results suggest that chemotherapy can induce wide-reactive autoimmune responses. Monitoring self-reactive IgM responses during treatment may help alleviate the side effects associated with autoimmunity.
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13
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Muacevic A, Adler JR, Lysov N, Shanin V. Chemotherapy-Induced, Broadly Reactive Autoantibodies in a Colon Cancer Patient. Cureus 2022; 14:e31954. [PMID: 36582563 PMCID: PMC9795272 DOI: 10.7759/cureus.31954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2022] [Indexed: 11/29/2022] Open
Abstract
The link between cancer and autoimmunity is well-established. For example, increased levels of autoantibodies are frequently found in cancer patients, and autoimmune diseases are linked to an increased risk for certain neoplasms. However, the extent to which chemotherapy induces autoimmune reactions remains largely elusive. Here, we quantified immunoglobulin M (IgM) responses to various human tissues and the patient's tumor before and during adjuvanted chemotherapy (seven cycles of the FOLFIRI regimen (folinic acid/fluorouracil/irinotecan) plus cetuximab) of a patient with metastasized colon cancer. IgM levels against all investigated tissues increased shortly after the first cycle and were further boosted by cycles two and three. Autoimmune responses then decreased during cycles four to seven but remained above baseline levels for most tissues. Our findings suggest that chemotherapy can induce broadly reactive autoimmune responses. Monitoring self-reactive IgM responses during treatment may help alleviate autoimmunity-related adverse events.
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14
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Corogeanu D, Diebold SS. Direct and Indirect Engagement of Dendritic Cell Function by Antibodies Developed for Cancer Therapy. Clin Exp Immunol 2022; 209:64-71. [PMID: 35352109 PMCID: PMC9307232 DOI: 10.1093/cei/uxac026] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 01/24/2022] [Accepted: 03/28/2022] [Indexed: 12/15/2022] Open
Abstract
Abstract
Dendritic cells (DC) are crucial for the priming of T cells and thereby influence adaptive immune responses. Hence, they also represent important players in shaping anti-tumour immune responses. Cancer immunotherapy has been driven over many years by the aim to harness the T-cell stimulatory activity of these crucial antigen-presenting cells (APC). Efficient antigen delivery alone is not sufficient for full engagement of the T-cell stimulatory activity of DC and the inclusion of adjuvants triggering appropriate DC activation is essential to ensure effective anti-tumour immunity induction. While the direct engagement of DC function is a powerful tool for tumour immunotherapy, many therapeutic antibodies, such as antibodies directed against tumour-associated antigens (TAA) and immune checkpoint inhibitors (ICI) have been shown to engage DC function indirectly. The induction of anti-tumour immune responses by TAA-targeting and immune checkpoint inhibitory antibodies is thought to be integral to their therapeutic efficacy. Here, we provide an overview of the immunotherapeutic antibodies in the context of cancer immunotherapy, that has been demonstrated to directly or indirectly engage DC and discuss the current understanding of the functional mechanisms underlying anti-tumour immunity induction by these antibody therapies. In the future, the combination of therapeutic strategies that engage DC function directly and/or indirectly with strategies that allow tumour infiltrating immune effector cells to exert their anti-tumour activity in the tumour microenvironment (TME) may be key for the successful treatment of cancer patients currently not responding to immunotherapeutic antibody treatment.
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Affiliation(s)
- Diana Corogeanu
- National Institute for Biological Standards and Control (NIBSC), Biotherapeutics Division, Potters Bar, UK.,Current Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, High Heaton, Newcastle upon Tyne, UK
| | - Sandra S Diebold
- National Institute for Biological Standards and Control (NIBSC), Biotherapeutics Division, Potters Bar, UK
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15
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Cruz-Duarte R, Rebelo de Almeida C, Negrão M, Fernandes A, Borralho P, Sobral D, Gallego-Paez LM, Machado D, Gramaça J, Vílchez J, Xavier AT, Ferreira MG, Miranda AR, Mansinho H, Brito MJ, Pacheco TR, Abreu C, Lucia-Costa A, Mansinho A, Fior R, Costa L, Martins M. Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer. Clin Cancer Res 2022; 28:1203-1216. [PMID: 34980600 PMCID: PMC9365369 DOI: 10.1158/1078-0432.ccr-21-1992] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 11/14/2021] [Accepted: 12/27/2021] [Indexed: 01/07/2023]
Abstract
PURPOSE Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. EXPERIMENTAL DESIGN We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. RESULTS In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. CONCLUSIONS Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.
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Affiliation(s)
- Raquel Cruz-Duarte
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | | | - Magda Negrão
- Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal
| | - Afonso Fernandes
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Paula Borralho
- Institute of Pathology, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Daniel Sobral
- Universidade Nova Lisboa, UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal
| | | | - Daniel Machado
- Oncology Division, Centro Hospitalar Barreiro-Montijo, Barreiro, Portugal
| | - João Gramaça
- Oncology Division, Centro Hospitalar Barreiro-Montijo, Barreiro, Portugal
| | - José Vílchez
- Oncology Division, Centro Hospitalar Barreiro-Montijo, Barreiro, Portugal
| | - Ana T. Xavier
- Oncology Division, Centro Hospitalar Barreiro-Montijo, Barreiro, Portugal
| | - Miguel Godinho Ferreira
- Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal.,Institute for Research on Cancer and Aging of Nice (IRCAN), UMR7284 U1081 UNS, Université Côte d'Azur, Nice, France
| | - Ana R. Miranda
- Hemato-Oncologia Division, Hospital Garcia de Orta, Almada, Portugal
| | - Helder Mansinho
- Hemato-Oncologia Division, Hospital Garcia de Orta, Almada, Portugal
| | - Maria J. Brito
- Pathology Division, Hospital Garcia de Orta, Almada, Portugal
| | - Teresa R. Pacheco
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.,Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
| | - Catarina Abreu
- Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
| | - Ana Lucia-Costa
- Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
| | - André Mansinho
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.,Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
| | - Rita Fior
- Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal
| | - Luís Costa
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.,Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal.,Corresponding Authors: Marta Martins, Translational Oncology, Instituto de Medicina Molecular - João Lobo Antunes, Lisbon 1649-028, Portugal. E-mail: ; and Luís Costa, Instituto de Medicina Molecular-João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal. E-mail:
| | - Marta Martins
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.,Corresponding Authors: Marta Martins, Translational Oncology, Instituto de Medicina Molecular - João Lobo Antunes, Lisbon 1649-028, Portugal. E-mail: ; and Luís Costa, Instituto de Medicina Molecular-João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal. E-mail:
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16
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Muthusami S, Sabanayagam R, Periyasamy L, Muruganantham B, Park WY. A review on the role of epidermal growth factor signaling in the development, progression and treatment of cervical cancer. Int J Biol Macromol 2022; 194:179-187. [PMID: 34848237 DOI: 10.1016/j.ijbiomac.2021.11.117] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/17/2022]
Abstract
The sub-committee constituted by the Indian Council of Medical Research (ICMR) for the management of cervical cancer (CC) detailed in the consensus document (2016) reported CC as a significant cause of morbidity and mortality in women. The incidence of an increase in CC and associated mortality in women is a major cause of cancer. To date, human papilloma viral (HPV) infection accounts for more than 99% of CC. However, there are individuals infected with HPV do not develop CC. There is a greater correlation between HPV infection and upregulation of the epidermal growth factor receptor (EGFR) signaling cascade during the initiation, sustenance, and progression of CC. Therefore, EGFR is often targeted to treat CC using tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAB). The current review analyzed the existing clinical/pre-clinical studies and the significance of EGFR abundance using the Kaplan-Meier (KM) survival plot analysis for disease-free survival (DFS) and overall survival (OS). We performed a series of bioinformatics analyses to screen the crucial role of the EGFR gene in CC. Further, different transcription factors that are dysregulated due to EGFR abundance and their relevance were determined using computational tools in this review. Endogenous microRNAs (miRNA) that undergo changes due to alterations in EGFR during CC were identified using computational database and consolidated the information obtained with the published in the area of miRNA and EGFR with special reference to the initiation, sustenance and progression of CC. The current review aims to consolidate contemporary approaches for targeting CC using EGFR and highlight the current role of miRNA and genes that are differently regulated during CC involving EGFR mutations. Potential resistance to the available EGFR therapies such as TKIs and mABs and the need for better therapies are also extensively reviewed for the development of newer therapeutic molecules with better efficacy.
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Affiliation(s)
- Sridhar Muthusami
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641021, India; Karpagam Cancer Research Centre, Karpagam Academy of Higher Education, Coimbatore 641021, India.
| | | | - Loganayaki Periyasamy
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641021, India
| | - Bharathi Muruganantham
- Karpagam Cancer Research Centre, Karpagam Academy of Higher Education, Coimbatore 641021, India
| | - Woo Yoon Park
- Department of Radiation Oncology, College of Medicine, Chungbuk National University, Cheongju, South Korea
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17
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Dutta S, Singhal S, Shah RB, Haque M. Immunotherapy and Targeted Therapy in the Management of Oral Cancers. Crit Rev Oncog 2022; 27:23-37. [PMID: 37199300 DOI: 10.1615/critrevoncog.2022046361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Oral cancers (OCs), being one of the frequent malignancies in the head and neck region, need prompt diagnosis and treatment. Apart from basic therapeutic modalities, immunotherapy has now been utilized as a novel approach to combat the disease. With the comprehension of the strategies adopted by cancer cells to evade the immune elimination by the body's immune system, targeted immunotherapies have now become the core area of research. The immune expression of epidermal growth factor receptor (EGFR), programmed cell death protein ligand-1 (PDL-1), etc., are enhanced in OC and have been associated with evasion of the immune system. Targeted immunotherapies now include monoclonal antibodies targeting EGFR like cetuximab and panitumumab, programmed cell death-1 (PD-1) inhibitors like pembrolizumab, cemiplimab, and nivolumab, and PD-L1 inhibitors like atezolizumab, avelumab, and durvalumab. Targeted immunotherapies like chimeric antigen receptor T-cell treatment and small molecule inhibitors are in several clinical trials tried as monotherapy and adjuvant immunotherapy and have shown promising results. Other immunothera-peutic approaches such as cytokines like interferons or interleukins, vaccines, and gene therapy have also been an area of research for the management of OC. However, the cautious selection of appropriate patients with specific immune characteristics as a candidate for immunotherapeutic agents is a crucial component of targeted immunotherapy. This article elaborates on the immune contexture of oral cancer cells, the mechanism of immune evasion by cancer cells, targets for immunotherapies, existent immunotherapeutic agents, and prospects in the field of immunotherapy.
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Affiliation(s)
- Siddhartha Dutta
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Shubha Singhal
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Rima B Shah
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Mainul Haque
- Unit of Pharmacology, Faculty of Medicine and Defence Health, National Defence University of Malaysia, Kuala Lumpur, Malaysia
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Baraibar I, Mirallas O, Saoudi N, Ros J, Salvà F, Tabernero J, Élez E. Combined Treatment with Immunotherapy-Based Strategies for MSS Metastatic Colorectal Cancer. Cancers (Basel) 2021; 13:6311. [PMID: 34944931 PMCID: PMC8699573 DOI: 10.3390/cancers13246311] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/08/2021] [Accepted: 12/14/2021] [Indexed: 12/24/2022] Open
Abstract
In recent years, deepening knowledge of the complex interactions between the immune system and cancer cells has led to the advent of effective immunotherapies that have revolutionized the therapeutic paradigm of several cancer types. However, colorectal cancer (CRC) is one of the tumor types in which immunotherapy has proven less effective. While there is solid clinical evidence for the therapeutic role of immune checkpoint inhibitors in mismatch repair-deficient (dMMR) and in highly microsatellite instable (MSI-H) metastatic CRC (mCRC), blockade of CTLA-4 or PD-L1/PD-1 as monotherapy has not conferred any major clinical benefit to patients with MMR-proficient (pMMR) or microsatellite stable (MSS) mCRC, reflecting 95% of the CRC population. There thus remains a high unmet medical need for the development of novel immunotherapy approaches for the vast majority of patients with pMMR or MSS/MSI-low (MSI-L) mCRC. Defining the molecular mechanisms for immunogenicity in mCRC and mediating immune resistance in MSS mCRC is needed to develop predictive biomarkers and effective therapeutic combination strategies. Here we review available clinical data from combinatorial therapeutic approaches using immunotherapy-based strategies for MSS mCRC.
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Affiliation(s)
- Iosune Baraibar
- Department of Medical Oncology, Vall d’Hebron University Hospital, Passeig de la Vall d’Hebron, 119, 08035 Barcelona, Spain; (O.M.); (N.S.); (J.R.); (F.S.); (J.T.); (E.É.)
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
| | - Oriol Mirallas
- Department of Medical Oncology, Vall d’Hebron University Hospital, Passeig de la Vall d’Hebron, 119, 08035 Barcelona, Spain; (O.M.); (N.S.); (J.R.); (F.S.); (J.T.); (E.É.)
| | - Nadia Saoudi
- Department of Medical Oncology, Vall d’Hebron University Hospital, Passeig de la Vall d’Hebron, 119, 08035 Barcelona, Spain; (O.M.); (N.S.); (J.R.); (F.S.); (J.T.); (E.É.)
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
| | - Javier Ros
- Department of Medical Oncology, Vall d’Hebron University Hospital, Passeig de la Vall d’Hebron, 119, 08035 Barcelona, Spain; (O.M.); (N.S.); (J.R.); (F.S.); (J.T.); (E.É.)
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
| | - Francesc Salvà
- Department of Medical Oncology, Vall d’Hebron University Hospital, Passeig de la Vall d’Hebron, 119, 08035 Barcelona, Spain; (O.M.); (N.S.); (J.R.); (F.S.); (J.T.); (E.É.)
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
| | - Josep Tabernero
- Department of Medical Oncology, Vall d’Hebron University Hospital, Passeig de la Vall d’Hebron, 119, 08035 Barcelona, Spain; (O.M.); (N.S.); (J.R.); (F.S.); (J.T.); (E.É.)
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
| | - Elena Élez
- Department of Medical Oncology, Vall d’Hebron University Hospital, Passeig de la Vall d’Hebron, 119, 08035 Barcelona, Spain; (O.M.); (N.S.); (J.R.); (F.S.); (J.T.); (E.É.)
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
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Zhang X, Bi K, Tu X, Zhang Q, Cao Q, Liang Y, Zeng P, Wang L, Liu T, Fang W, Diao H. Interleukin-33 as an early predictor of cetuximab treatment efficacy in patients with colorectal cancer. Cancer Med 2021; 10:8338-8351. [PMID: 34664425 PMCID: PMC8633246 DOI: 10.1002/cam4.4331] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 08/25/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cetuximab is used for colorectal cancer (CRC) treatment. However, the early biomarker of treatment efficacy of cetuximab has not been identified. METHODS After 1 year of cetuximab treatment, patients were divided into an effective group and an ineffective group. The interleukin-33 (IL-33) level and the distribution of lymphatic cells in patients were investigated by analyzing the peripheral blood mononuclear cells via flow cytometry analysis and ELISA. The correlation between IL-33 immunomodulatory effect and cetuximab treatment efficacy was determined through experiments in vivo and in vitro. RESULTS The IL-33 level in the peripheral blood was increased at 4 weeks after cetuximab administration of effective group, meanwhile, the osteopontin (OPN) was reduced. Whereas neither IL-33 level nor OPN level of ineffective patients changed. In the effective group, the number of natural killer (NK) and CD8+ T cells were increased. Moreover, CD137 and CD107a expression on NK cells were higher in the effective group compared to the ineffective group. In vitro cetuximab treatment also increased the number of NK and CD8+ T cells as well as CD137 and CD107a expression upon IL-33 stimulation. Moreover, the secretion of OPN was inhibited by IL-33 administration in cetuximab-treated PBMCs from the effective group patients. IL-33 upregulated the cytotoxicity of NK cells and inhibited tumor cells growth in the effective cetuximab treatment mice. CONCLUSION Effective cetuximab treatment induced a change of IL-33 and OPN at the early stage and triggered the NK cells antitumor activity. Consequently, significantly increased IL-33 level and decreased OPN level in the peripheral blood at the early treatment are proposed as potential predictors of cetuximab treatment efficacy.
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Affiliation(s)
- Xujun Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Kefan Bi
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaoxuan Tu
- Department of Medical OncologyFirst Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Qiong Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Qingyi Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yan Liang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Ping Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Lin Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Tianxing Liu
- Department of Biological SciencesUniversity of TorontoTorontoOntarioCanada
| | - Weijia Fang
- Department of Medical OncologyFirst Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
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Roma S, Carpen L, Raveane A, Bertolini F. The Dual Role of Innate Lymphoid and Natural Killer Cells in Cancer. from Phenotype to Single-Cell Transcriptomics, Functions and Clinical Uses. Cancers (Basel) 2021; 13:cancers13205042. [PMID: 34680190 PMCID: PMC8533946 DOI: 10.3390/cancers13205042] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Innate lymphoid cells (ILCs), a family of innate immune cells including natural killers (NKs), play a multitude of roles in first-line cancer control, in escape from immunity and in cancer progression. In this review, we summarize preclinical and clinical data on ILCs and NK cells concerning their phenotype, function and clinical applications in cellular therapy trials. We also describe how single-cell transcriptome sequencing has been used and forecast how it will be used to better understand ILC and NK involvement in cancer control and progression as well as their therapeutic potential. Abstract The role of innate lymphoid cells (ILCs), including natural killer (NK) cells, is pivotal in inflammatory modulation and cancer. Natural killer cell activity and count have been demonstrated to be regulated by the expression of activating and inhibitory receptors together with and as a consequence of different stimuli. The great majority of NK cell populations have an anti-tumor activity due to their cytotoxicity, and for this reason have been used for cellular therapies in cancer patients. On the other hand, the recently classified helper ILCs are fundamentally involved in inflammation and they can be either helpful or harmful in cancer development and progression. Tissue niche seems to play an important role in modulating ILC function and conversion, as observed at the transcriptional level. In the past, these cell populations have been classified by the presence of specific cellular receptor markers; more recently, due to the advent of single-cell RNA sequencing (scRNA-seq), it has been possible to also explore them at the transcriptomic level. In this article we review studies on ILC (and NK cell) classification, function and their involvement in cancer. We also summarize the potential application of NK cells in cancer therapy and give an overview of the most recent studies involving ILCs and NKs at scRNA-seq, focusing on cancer. Finally, we provide a resource for those who wish to start single-cell transcriptomic analysis on the context of these innate lymphoid cell populations.
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Pramil E, Dillard C, Escargueil AE. Colorectal Cancer and Immunity: From the Wet Lab to Individuals. Cancers (Basel) 2021; 13:cancers13071713. [PMID: 33916641 PMCID: PMC8038567 DOI: 10.3390/cancers13071713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/27/2021] [Accepted: 03/30/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Tackling the current dilemma of colorectal cancer resistance to immunotherapy is puzzling and requires novel therapeutic strategies to emerge. However, characterizing the intricate interactions between cancer and immune cells remains difficult because of the complexity and heterogeneity of both compartments. Developing rationales is intellectually feasible but testing them can be experimentally challenging and requires the development of innovative procedures and protocols. In this review, we delineated useful in vitro and in vivo models used for research in the field of immunotherapy that are or could be applied to colorectal cancer management and lead to major breakthroughs in the coming years. Abstract Immunotherapy is a very promising field of research and application for treating cancers, in particular for those that are resistant to chemotherapeutics. Immunotherapy aims at enhancing immune cell activation to increase tumor cells recognition and killing. However, some specific cancer types, such as colorectal cancer (CRC), are less responsive than others to the current immunotherapies. Intrinsic resistance can be mediated by the development of an immuno-suppressive environment in CRC. The mutational status of cancer cells also plays a role in this process. CRC can indeed be distinguished in two main subtypes. Microsatellite instable (MSI) tumors show a hyper-mutable phenotype caused by the deficiency of the DNA mismatch repair machinery (MMR) while microsatellite stable (MSS) tumors show a comparatively more “stable” mutational phenotype. Several studies demonstrated that MSI CRC generally display good prognoses for patients and immunotherapy is considered as a therapeutic option for this type of tumors. On the contrary, MSS metastatic CRC usually presents a worse prognosis and is not responsive to immunotherapy. According to this, developing new and innovative models for studying CRC response towards immune targeted therapies has become essential in the last years. Herein, we review the in vitro and in vivo models used for research in the field of immunotherapy applied to colorectal cancer.
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Affiliation(s)
- Elodie Pramil
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Alliance Pour la Recherche en Cancérologie—APREC, Tenon Hospital, F-75012 Paris, France
| | - Clémentine Dillard
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Alliance Pour la Recherche en Cancérologie—APREC, Tenon Hospital, F-75012 Paris, France
| | - Alexandre E. Escargueil
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Correspondence: ; Tel.: +33-(0)1-49-28-46-44
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22
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Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions. Pharmaceutics 2021; 13:pharmaceutics13030422. [PMID: 33800976 PMCID: PMC8003994 DOI: 10.3390/pharmaceutics13030422] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/18/2021] [Accepted: 03/18/2021] [Indexed: 12/29/2022] Open
Abstract
With more than 90 approved drugs by 2020, therapeutic antibodies have played a central role in shifting the treatment landscape of many diseases, including autoimmune disorders and cancers. While showing many therapeutic advantages such as long half-life and highly selective actions, therapeutic antibodies still face many outstanding issues associated with their pharmacokinetics (PK) and pharmacodynamics (PD), including high variabilities, low tissue distributions, poorly-defined PK/PD characteristics for novel antibody formats, and high rates of treatment resistance. We have witnessed many successful cases applying PK/PD modeling to answer critical questions in therapeutic antibodies’ development and regulations. These models have yielded substantial insights into antibody PK/PD properties. This review summarized the progress, challenges, and future directions in modeling antibody PK/PD and highlighted the potential of applying mechanistic models addressing the development questions.
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Bourhis J, Stein A, Paul de Boer J, Van Den Eynde M, Gold KA, Stintzing S, Becker JC, Moran M, Schroeder A, Pennock G, Salmio S, Esser R, Ciardiello F. Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer. Cancer Treat Rev 2021; 97:102172. [PMID: 33989949 DOI: 10.1016/j.ctrv.2021.102172] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 02/15/2021] [Accepted: 02/21/2021] [Indexed: 01/09/2023]
Abstract
Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects. Here, we outline ongoing trials and review the rationale and evidence for the combination of avelumab, an anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), with cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 mAb. Avelumab is approved as a monotherapy for the treatment of Merkel cell carcinoma and urothelial carcinoma, and in combination with axitinib for renal cell carcinoma; cetuximab is approved in combination with chemotherapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN) and RAS wild-type metastatic colorectal cancer, and in combination with radiation therapy for SCCHN. Avelumab binds to PD-L1 expressed on tumor cells and immune regulatory cells, thus blocking its interaction with programmed death 1 and reventing T-cell suppression; cetuximab inhibits the EGFR signaling pathway, inhibiting proliferation and inducing apoptosis. Both therapies have complementary mechanisms of action and may also activate the immune system to induce innate effector function through the binding of their Fc regions to natural killer (NK) cells. Furthermore, cetuximab combined with chemotherapy has been shown to induce immunogenic cell death and leads to an increase in tumor-infiltrating CD8+ T and NK cells, which should synergize with the immunostimulatory effects of avelumab. Prospective studies will investigate this combination and inform future treatment strategies.
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Affiliation(s)
- Jean Bourhis
- Centre Hospitalier Universitaire Vaudois, Service de Radio-oncologie, Lausanne, Switzerland.
| | - Alexander Stein
- Hematology-Oncology Practice Hamburg (HOPE), University Cancer Center Hamburg, Hamburg, Germany
| | - Jan Paul de Boer
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Marc Van Den Eynde
- Cliniques universitaires Saint-Luc, Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium
| | - Kathryn A Gold
- Department of Medicine, Division of Hematology-Oncology, University of California, San Diego, La Jolla, CA, USA
| | - Sebastian Stintzing
- Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Jürgen C Becker
- Department of Translational Skin Cancer Research, German Cancer Consortium (DKTK), Essen University Hospital, Essen, Germany, and German Cancer Research Institute (DKFZ), Heidelberg, Germany
| | | | | | - Gregory Pennock
- EMD Serono Research & Development Institute, Inc., Billerica, MA, USA(2)
| | | | | | - Fortunato Ciardiello
- Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
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Liang L, Liu M, Sun X, Yuan Y, Peng K, Rashid K, Yu Y, Cui Y, Chen Y, Liu T. Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer. Cancer Cell Int 2021; 21:135. [PMID: 33632198 PMCID: PMC7905896 DOI: 10.1186/s12935-021-01829-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 01/12/2021] [Accepted: 02/10/2021] [Indexed: 12/16/2022] Open
Abstract
Background The anti-epidermal growth factor receptor (EGFR) antibody introduces adaptable variations to the transcriptome and triggers tumor immune infiltration, resulting in colorectal cancer (CRC) treatment resistance. We intended to identify genes that play essential roles in cetuximab resistance and tumor immune cell infiltration. Methods A cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples. Results We identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2, AKR1B10, ADH1A, ADH1C, MYB, ATP10B, CDX-2, FAR2, EPHB2, SLC26A3, ORP-1, VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined that SATB-2, ORP-1, MYB, and CDX-2 expressions were associated with intensive infiltration of B cell, CD4+ T cell, CD8+ T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2 were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and high ORP-1 expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with low ORP-1 expression. Conclusions SATB-2, ORP-1, MYB, and CDX-2 were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.
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Affiliation(s)
- Li Liang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China
| | - Mengling Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China
| | - Xun Sun
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China
| | - Yitao Yuan
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China
| | - Ke Peng
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China
| | - Khalid Rashid
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China
| | - Yuehong Cui
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China
| | - Yanjie Chen
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China. .,Shanghai Institute of Liver Diseases, Shanghai, China.
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China. .,Center of Evidence-based Medicine, Fudan University, Shanghai, China.
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Gauthier M, Laroye C, Bensoussan D, Boura C, Decot V. Natural Killer cells and monoclonal antibodies: Two partners for successful antibody dependent cytotoxicity against tumor cells. Crit Rev Oncol Hematol 2021; 160:103261. [PMID: 33607229 DOI: 10.1016/j.critrevonc.2021.103261] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 01/27/2021] [Accepted: 02/12/2021] [Indexed: 02/07/2023] Open
Abstract
Monoclonal antibodies targeting tumors are one of the most important discoveries in the field of cancer. Although several effective antibodies have been developed, a relapse may occur. One of their mechanisms of action is Antibody Dependent Cell Cytotoxicity (ADCC), by engaging the Fc γ receptor CD16 expressing Natural Killer cells, innate lymphoid cells involved in cancer immunosurveillance and able to kill tumor cells. A lack of NK cells observed in many cancers may therefore be a cause of the low efficacy of antibodies observed in some clinical situations. Here we review clear evidences of the essential partnership between NK cells and antibodies showed in vitro, in vivo, and in clinical trials in different indications, describe the hurdles and ways to enhance ADCC and the evolution of monoclonal antibody therapy. NK cell adoptive immunotherapy combined with monoclonal antibodies may overcome the resistance to the treatment and enhance their efficacy.
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Affiliation(s)
- Mélanie Gauthier
- Lorraine University, CNRS UMR 7365, Team 6, Campus Santé, Vandoeuvre-les-Nancy, France; CHRU Nancy, Cell Therapy and Tissue Bank Unit, Vandoeuvre-Les-Nancy, France
| | - Caroline Laroye
- Lorraine University, CNRS UMR 7365, Team 6, Campus Santé, Vandoeuvre-les-Nancy, France; CHRU Nancy, Cell Therapy and Tissue Bank Unit, Vandoeuvre-Les-Nancy, France
| | - Danièle Bensoussan
- Lorraine University, CNRS UMR 7365, Team 6, Campus Santé, Vandoeuvre-les-Nancy, France; CHRU Nancy, Cell Therapy and Tissue Bank Unit, Vandoeuvre-Les-Nancy, France
| | - Cédric Boura
- Lorraine University, CNRS UMR7039, Team BioSIS, Campus Santé, Vandoeuvre-Les-Nancy, France
| | - Véronique Decot
- Lorraine University, CNRS UMR 7365, Team 6, Campus Santé, Vandoeuvre-les-Nancy, France; CHRU Nancy, Cell Therapy and Tissue Bank Unit, Vandoeuvre-Les-Nancy, France.
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Wang F, Lau JKC, Yu J. The role of natural killer cell in gastrointestinal cancer: killer or helper. Oncogene 2021; 40:717-730. [PMID: 33262461 PMCID: PMC7843415 DOI: 10.1038/s41388-020-01561-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/29/2020] [Accepted: 11/06/2020] [Indexed: 02/08/2023]
Abstract
Gastrointestinal cancer is one of the leading health problems worldwide, with a high morbidity and mortality. To date, harnessing both the innate and adaptive immune system against cancer provides a selective and effective therapeutic strategy for patients. As a first line defense against cancer, natural killer (NK) cells can swiftly target and lyse tumor cells without prior activation. In addition to its pivotal role in innate immunity, NK cells also play unique roles in the adaptive immune system as it enhance anti-tumor adaptive immune responses through secretion of cytokines and retaining an immunological memory. All these characteristics make NK cell a promising anti-cancer agent for patients. In spite of scarce infiltration and impaired function of NK cells in tumors, and the fact that tumors easily develop resistant mechanisms to evade the attacks from endogenous NK cells, multiple strategies have been developed to boost anti-tumor effect of NK cells and abolish tumor resistance. Some examples include adoptive transfer of NK cells after ex vivo activation and expansion; restoration of NK cell function using immune checkpoint inhibitors, and monoclonal antibody or cytokine treatment. Preclinical data have shown encouraging results, suggesting that NK cells hold great potential in cancer therapy. In this review, we discuss NK cells' cytotoxicity and modulation function in GI cancer and the current application in clinical therapy.
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Affiliation(s)
- Feixue Wang
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Jennie Ka Ching Lau
- Faculty of Medicine, SHHO College, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Jun Yu
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
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Volz NB, Hanna DL, Stintzing S, Zhang W, Yang D, Cao S, Ning Y, Matsusaka S, Sunakawa Y, Berger MD, Cremolini C, Loupakis F, Falcone A, Lenz HJ. Polymorphisms within Immune Regulatory Pathways Predict Cetuximab Efficacy and Survival in Metastatic Colorectal Cancer Patients. Cancers (Basel) 2020; 12:2947. [PMID: 33065994 PMCID: PMC7601940 DOI: 10.3390/cancers12102947] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 10/03/2020] [Accepted: 10/06/2020] [Indexed: 12/19/2022] Open
Abstract
Cetuximab, an IgG1 EGFR-directed antibody, promotes antibody-dependent cell-mediated cytotoxicity. We hypothesized that single-nucleotide polymorphisms (SNPs) in immune regulatory pathways may predict outcomes in patients with metastatic colorectal cancer treated with cetuximab-based regimens. A total of 924 patients were included: 105 received cetuximab in IMCL-0144 and cetuximab/irinotecan in GONO-ASL608LIOM01 (training cohort), 225 FOLFIRI/cetuximab in FIRE-3 (validation cohort 1), 74 oxaliplatin/cetuximab regimens in JACCRO CC-05/06 (validation cohort 2), and 520 FOLFIRI/bevacizumab in FIRE-3 and TRIBE (control cohorts). Twelve SNPs in five genes (IDO1; PD-L1; PD-1; CTLA-4; CD24) were evaluated by PCR-based direct sequencing. We analyzed associations between genotype and clinical outcomes. In the training cohort; patients with the CD24 rs52812045 A/A genotype had a significantly shorter median PFS and OS than those with the G/G genotype (PFS 1.3 vs. 3.6 months; OS 2.3 vs. 7.8 months) in univariate (PFS HR 3.62; p = 0.001; OS HR 3.27; p = 0.0004) and multivariate (PFS HR 3.18; p = 0.009; OS HR 4.93; p = 0.001) analyses. Similarly; any A allele carriers in the JACCRO validation cohort had a significantly shorter PFS than G/G carriers (9.2 vs. 11.8 months; univariate HR 1.90; p = 0.011; multivariate HR 2.12; p = 0.018). These associations were not demonstrated in the control cohorts. CD24 genetic variants may help select patients with metastatic colorectal cancer most likely to benefit from cetuximab-based therapy.
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Affiliation(s)
- Nico B. Volz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; (N.B.V.); (D.L.H.); (S.S.); (W.Z.); (Y.N.); (S.M.); (Y.S.); (M.D.B.)
- Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Diana L. Hanna
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; (N.B.V.); (D.L.H.); (S.S.); (W.Z.); (Y.N.); (S.M.); (Y.S.); (M.D.B.)
| | - Sebastian Stintzing
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; (N.B.V.); (D.L.H.); (S.S.); (W.Z.); (Y.N.); (S.M.); (Y.S.); (M.D.B.)
- Department of Medicine III, University Hospital LMU Munich, 80539 Munich, Germany
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; (N.B.V.); (D.L.H.); (S.S.); (W.Z.); (Y.N.); (S.M.); (Y.S.); (M.D.B.)
| | - Dongyun Yang
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; (D.Y.); (S.C.)
| | - Shu Cao
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; (D.Y.); (S.C.)
| | - Yan Ning
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; (N.B.V.); (D.L.H.); (S.S.); (W.Z.); (Y.N.); (S.M.); (Y.S.); (M.D.B.)
| | - Satoshi Matsusaka
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; (N.B.V.); (D.L.H.); (S.S.); (W.Z.); (Y.N.); (S.M.); (Y.S.); (M.D.B.)
| | - Yu Sunakawa
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; (N.B.V.); (D.L.H.); (S.S.); (W.Z.); (Y.N.); (S.M.); (Y.S.); (M.D.B.)
| | - Martin D. Berger
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; (N.B.V.); (D.L.H.); (S.S.); (W.Z.); (Y.N.); (S.M.); (Y.S.); (M.D.B.)
| | - Chiara Cremolini
- U.O. Oncologia Medica 2—Aziendo Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (C.C.); (F.L.); (A.F.)
| | - Fotios Loupakis
- U.O. Oncologia Medica 2—Aziendo Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (C.C.); (F.L.); (A.F.)
| | - Alfredo Falcone
- U.O. Oncologia Medica 2—Aziendo Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (C.C.); (F.L.); (A.F.)
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; (N.B.V.); (D.L.H.); (S.S.); (W.Z.); (Y.N.); (S.M.); (Y.S.); (M.D.B.)
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Marmorino F, Boccaccino A, Germani MM, Falcone A, Cremolini C. Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge. Cancers (Basel) 2020; 12:E2317. [PMID: 32824490 PMCID: PMC7465130 DOI: 10.3390/cancers12082317] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022] Open
Abstract
The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of "immune-competent" TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies.
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Affiliation(s)
- Federica Marmorino
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy; (F.M.); (A.B.); (M.M.G.); (A.F.)
- Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy
| | - Alessandra Boccaccino
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy; (F.M.); (A.B.); (M.M.G.); (A.F.)
- Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy
| | - Marco Maria Germani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy; (F.M.); (A.B.); (M.M.G.); (A.F.)
- Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy
| | - Alfredo Falcone
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy; (F.M.); (A.B.); (M.M.G.); (A.F.)
- Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy; (F.M.); (A.B.); (M.M.G.); (A.F.)
- Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy
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Zhang H, Yuan L, Liu L, Yan C, Cheng J, Fu Q, Tong Z, Jiang W, Zheng Y, Zhao P, Zhang G, Fang W. Dynamic alterations of genome and transcriptome in KRAS G13D mutant CRC PDX model treated with cetuximab. BMC Cancer 2020; 20:416. [PMID: 32404198 PMCID: PMC7222508 DOI: 10.1186/s12885-020-06909-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 04/27/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND KRAS mutations have been characterized as the major predictive biomarkers for resistance to cetuximab treatment. However, studies indicate that not all KRAS mutations are associated with equivalent treatment outcomes. KRAS G13D mutations were observed to account for approximately 16% of all KRAS mutations in advanced colorectal cancer patients, and whether these patients can benefit from cetuximab has not been determined. METHODS An established KRAS G13D mutant colorectal cancer (CRC) patient-derived xenograft (PDX) model was treated with cetuximab. After repeated use of cetuximab, treatment-resistant PDX models were established. Tissue samples were collected before and during treatment, and multiomics data were subsequently sequenced and processed, including whole-exome, mRNA and miRNA data, to explore potential dynamic changes. RESULTS Cetuximab treatment initially slowed tumor growth, but resistance developed not long after treatment. WES (whole-exome sequencing) and RNA sequencing found that 145 genes had low P values (< 0.01) when analyzed between the locus genotype and its related gene expression level. Among these genes, SWAP70 was believed to be a probable cause of acquired resistance. JAK2, PRKAA1, FGFR2 and RALBP1, as well as 10 filtered immune-related genes, also exhibited dynamic changes during the treatment. CONCLUSIONS Cetuximab may be effective in KRAS G13D mutation patients. Dynamic changes in transcription, as determined by WES and RNA sequencing, occurred after repeated drug exposure, and these changes were believed to be the most likely cause of drug resistance.
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Affiliation(s)
- Hangyu Zhang
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China
| | - Liyun Yuan
- National Genomics Data Center, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China
| | - Lulu Liu
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China
| | - Cong Yan
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China
| | - Jinming Cheng
- National Genomics Data Center, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China
| | - Qihan Fu
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China
| | - Zhou Tong
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China
| | - Weiqin Jiang
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China
| | - Yi Zheng
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China
- Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, China
| | - Peng Zhao
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China
| | - Guoqing Zhang
- National Genomics Data Center, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China.
| | - Weijia Fang
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China.
- Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, China.
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Xu W, Zhang X, Hu X, Zhiyi C, Huang P. Translational Prospects of ultrasound-mediated tumor immunotherapy: Preclinical advances and safety considerations. Cancer Lett 2019; 460:86-95. [DOI: 10.1016/j.canlet.2019.06.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 06/19/2019] [Accepted: 06/21/2019] [Indexed: 12/12/2022]
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Shitara K, Satoh T, Iwasa S, Yamaguchi K, Muro K, Komatsu Y, Nishina T, Esaki T, Hasegawa J, Kakurai Y, Kamiyama E, Nakata T, Nakamura K, Sakaki H, Hyodo I. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the afucosylated, humanized anti-EPHA2 antibody DS-8895a: a first-in-human phase I dose escalation and dose expansion study in patients with advanced solid tumors. J Immunother Cancer 2019; 7:219. [PMID: 31412935 PMCID: PMC6694490 DOI: 10.1186/s40425-019-0679-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 07/16/2019] [Indexed: 12/19/2022] Open
Abstract
Background Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface in many cancers and predicts poor prognosis. DS-8895a is a humanized anti-EPHA2 IgG1 monoclonal antibody afucosylated to enhance antibody-dependent cellular cytotoxicity activity. We conducted a two-step, phase I, multicenter, open-label study to determine the safety, tolerability, and pharmacokinetics of DS-8895a in patients with advanced solid tumors. Methods Step 1 was a dose escalation cohort in advanced solid tumor patients (six dose levels, 0.1–20 mg/kg) to determine Step 2 dosing. Step 2 was a dose expansion cohort in EPHA2-positive esophageal and gastric cancer patients. DS-8895a was intravenously administered every 2 weeks for the duration of the study, with a 28-day period to assess dose-limiting toxicity (DLT). Safety, pharmacokinetics, tumor response, and potential biomarkers were evaluated. Results Thirty-seven patients (Step 1: 22, Step 2: 15 [9: gastric cancer, 6: esophageal cancer]) were enrolled. Although one DLT (Grade 4 platelet count decreased) was observed in Step 1 (dose level 6, 20 mg/kg), the maximum tolerated dose was not reached; the highest dose (20 mg/kg) was used in Step 2. Of the 37 patients, 24 (64.9%) experienced drug-related adverse events (AEs) including three (8.1%) with Grade ≥ 3 AEs. Infusion-related reactions occurred in 19 patients (51.4%) but were manageable. All patients discontinued the study (evident disease progression, 33; AEs, 4). Maximum and trough serum DS-8895a concentrations increased dose-dependently. One gastric cancer patient achieved partial response and 13 patients achieved stable disease. Serum inflammatory cytokines transiently increased at completion of and 4 h after the start of DS-8895a administration. The proportion of CD16-positive natural killer (NK) cells (CD3−CD56+CD16+) decreased 4 h after the start of DS-8895a administration, and the ratio of CD3−CD56+CD137+ to CD3−CD56+CD16+ cells increased on day 3. Conclusions Twenty mg/kg DS-8895a infused intravenously every 2 weeks was generally safe and well tolerated in patients (n = 21) with advanced solid tumors. The exposure of DS-8895a seemed to increase dose-dependently and induce activated NK cells. Trial registration Phase 1 Study of DS-8895a in patients with advanced solid tumors (NCT02004717; 7 November 2013 to 2 February 2017); retrospectively registered on 9 December 2013. Electronic supplementary material The online version of this article (10.1186/s40425-019-0679-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kohei Shitara
- National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa City, Chiba, Japan.
| | - Taroh Satoh
- Osaka University Graduate School of Medicine, Osaka, Japan
| | | | - Kensei Yamaguchi
- Cancer Institute Hospital of Japan Foundation for Cancer Research, Tokyo, Japan
| | - Kei Muro
- Aichi Cancer Center Hospital and Research Institute, Aichi, Japan
| | | | | | - Taito Esaki
- National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
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Yasunaga M. Antibody therapeutics and immunoregulation in cancer and autoimmune disease. Semin Cancer Biol 2019; 64:1-12. [PMID: 31181267 DOI: 10.1016/j.semcancer.2019.06.001] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 06/03/2019] [Indexed: 02/04/2023]
Abstract
Cancer and autoimmune disease are closely related, and many therapeutic antibodies are widely used in clinics for the treatment of both diseases. Among them, the anti-CD20 antibody has proven to be effective against both lymphoid malignancy and autoimmune disease. Moreover, immune checkpoint blockade using the anti-PD1/PD-L1/CTLA4 antibody has improved the prognosis of patients with refractory solid tumors. At the same time, however, over-enhancement of immunoreaction can induce autoimmune reaction. Although anti-TNF antibody therapies represent a breakthrough in the treatment of autoimmune diseases, optimal management is required to control the serious associated issues, including development and progression of cancer, and it is becoming more and more important to control the immunoreaction. In addition, next-generation antibody therapeutics such as antibody-drug conjugates and bispecific antibodies, are anticipated to treat uncontrolled cancer and autoimmune disease. IL-7R signaling plays an important role in the development and progression of both lymphoid malignancy and autoimmune disease. In addition, abnormal homing activity and steroid resistance caused by IL-7R signaling may worsen prognosis. Therefore, anti-IL-7R targeting antibody therapies that enable suppression of such pathophysiological status have the potential to be beneficial for the treatment of both diseases. In this review, we discuss current antibody therapeutics in cancer and autoimmune disease, and describe a new therapeutic strategy for immunoregulation including IL-7R targeting antibodies.
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Affiliation(s)
- Masahiro Yasunaga
- Division of Developmental Therapeutics, EPOC, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan.
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Xu X, Liu T, Liu F, Guo X, Xia L, Xie Q, Li N, Huang H, Yang X, Xin Y, Zhu H, Yang Z. Synthesis and evaluation of 64Cu-radiolabeled NOTA-cetuximab ( 64Cu-NOTA-C225) for immuno-PET imaging of EGFR expression. Chin J Cancer Res 2019; 31:400-409. [PMID: 31156310 PMCID: PMC6513748 DOI: 10.21147/j.issn.1000-9604.2019.02.14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Objective Epidermal growth factor receptor (EGFR) is overexpressed in a wide variety of solid tumors, serving as a well-characterized target for cancer imaging or therapy. In this study, we aimed to design and synthesize a radiotracer, 64Cu-NOTA-C225, targeting EGFR for tumor positron emission tomography (PET) imaging.
Methods Cetuximab (C225) was conjugated to a bifunctional chelator, p-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and further radiolabeled with copper-64 for PET imaging. 64Cu-NOTA-IgG and Cy5.5-C225 were also synthesized as control probes. A431 and A549 mouse models were established for micro-PET and/or near-infrared fluorescence (NIRF) imaging.
Results 64Cu-NOTA-C225 exhibited stability in vivo and in vitro up to 24 h and 50 h post-injection, respectively. A431 tumors with average standard uptake values (SUVs) of 5.61±0.69, 6.68±1.14, 7.80±1.51 at 6, 18 and 36 h post-injection, respectively, which were significantly higher than that of moderate EGFR expressing tumors (A549), with SUVs of 0.89±0.16, 4.70±0.81, 2.01±0.50 at 6, 18 and 36 h post-injection, respectively. The expression levels of A431 and A549 were confirmed by western blotting. Additionally, the tracer uptake in A431 tumors can be blocked by unlabeled cetuximab, suggesting that tracer uptake by tumors was receptor-mediated. Furthermore, NIRF imaging using Cy5.5-C225 showed that the fluorescence intensity in tumors increased with time, with a maximal intensity of 8.17E+10 (p/s/cm2/sr)/(μW/cm2) at 48 h post-injection, which is consistent with the paradigm from micro-PET imaging in A431 tumor-bearing mice.
Conclusions The 64Cu-NOTA-C225 PET imaging may be able to specifically and sensitively differentiate tumor models with different EGFR expression levels. It offers potentials as a PET radiotracer for imaging of tracer EGFR-positive tumors.
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Affiliation(s)
- Xiaoxia Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Teli Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Fei Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xiaoyi Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Lei Xia
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Qing Xie
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Nan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Haifeng Huang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China.,Department of Orthopaedics, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Xianteng Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China.,Department of Orthopaedics, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Yangchun Xin
- Katzin Diagnostic & Research PET/MR Center, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA
| | - Hua Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhi Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
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Seliger B. Combinatorial Approaches With Checkpoint Inhibitors to Enhance Anti-tumor Immunity. Front Immunol 2019; 10:999. [PMID: 31178856 PMCID: PMC6538766 DOI: 10.3389/fimmu.2019.00999] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 04/18/2019] [Indexed: 12/13/2022] Open
Abstract
Treatment of cancer patients has been recently revolutionized by the application of various immunotherapeutics. However, the response rates are still limited ranging between approximately 20 and 40% suggesting that combinations of immunotherapy with conventional treatment, like chemotherapy, radiation, epigenetic modulators, targeted therapies using small molecules as well as other (immuno) therapeutics, might be an option to increase systemic anti-tumor immunity. It is postulated that different non-immune based therapies in combination with immunotherapies could reprogram the immune suppressive tumor microenvironment and enhance the immunogenicity of tumor cells leading to an improved therapeutic efficacy and a better patients' outcome. Despite there exist various examples of increased objective responses achieved by adding these different therapies to immunotherapies, strategies for rational and evidence-based design of checkpoint inhibitor combinations to maximize the clinical benefit for patients are urgently required. Therefore, the main purpose of this review is to summarize recent results obtained from experimental models and clinical trials to enhance tumor immunogenicity by combining immunotherapy with other therapeutic options to maximize patients' outcome and minimize adverse events.
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Affiliation(s)
- Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
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35
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Schumacher D, Andrieux G, Boehnke K, Keil M, Silvestri A, Silvestrov M, Keilholz U, Haybaeck J, Erdmann G, Sachse C, Templin M, Hoffmann J, Boerries M, Schäfer R, Regenbrecht CRA. Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures. PLoS Genet 2019; 15:e1008076. [PMID: 30925167 PMCID: PMC6457557 DOI: 10.1371/journal.pgen.1008076] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 04/10/2019] [Accepted: 03/08/2019] [Indexed: 12/14/2022] Open
Abstract
Organoid cultures derived from colorectal cancer (CRC) samples are increasingly used as preclinical models for studying tumor biology and the effects of targeted therapies under conditions capturing in vitro the genetic make-up of heterogeneous and even individual neoplasms. While 3D cultures are initiated from surgical specimens comprising multiple cell populations, the impact of tumor heterogeneity on drug effects in organoid cultures has not been addressed systematically. Here we have used a cohort of well-characterized CRC organoids to study the influence of tumor heterogeneity on the activity of the KRAS/MAPK-signaling pathway and the consequences of treatment by inhibitors targeting EGFR and downstream effectors. MAPK signaling, analyzed by targeted proteomics, shows unexpected heterogeneity irrespective of RAS mutations and is associated with variable responses to EGFR inhibition. In addition, we obtained evidence for intratumoral heterogeneity in drug response among parallel “sibling” 3D cultures established from a single KRAS-mutant CRC. Our results imply that separate testing of drug effects in multiple subpopulations may help to elucidate molecular correlates of tumor heterogeneity and to improve therapy response prediction in patients. Commonly occurring genetic alterations and patient-specific genetic features are increasingly used to predict the possible action of targeted cancer therapies. Although several lines of evidence have suggested that preclinical and clinical responses concur, the heterogeneity of tumors remains a severe obstacle in routinely translating preclinical data to patient treatments. Here we present a rapid work flow that integrates drug testing of three-dimensional patient tumor-derived (organoid) cultures and assessment of their genetic make-up as well as that of their donor tumors by amplicon sequencing and targeted proteomics. While the organoid cultures largely recapitulated the genomic profiles of donor tumors, the overall treatment responses and inhibitor effects on the intracellular signaling system were quite variable. Notably, organoid cultures obtained by synchronous multi-regional sampling of the same colorectal tumor showed an up to 30-fold difference in drug response. A combinatorial drug treatment improved the response. These data were confirmed in matched mouse xenograft models from the same tumor. Our findings may help to refine preclinical testing of individual tumors by modelling heterogeneity in cultures, to better understand therapeutic failure in clinical settings and to find ways to overcome treatment resistance.
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Affiliation(s)
- Dirk Schumacher
- Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Geoffroy Andrieux
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Karsten Boehnke
- Eli Lilly and Company, Lilly Research Laboratories, Oncology Translational Research, New York, NY, United States of America
| | - Marlen Keil
- EPO Experimental Pharmacology and Oncology Berlin-Buch GmbH, Berlin, Germany
| | | | | | | | - Johannes Haybaeck
- Department of Pathology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.,Department of Pathology, Neuropathology, and Molecular Pathology, Medical University of Innsbruck, Austria.,Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, Austria
| | - Gerrit Erdmann
- NMI TT Pharmaservices, Berlin, Germany.,ASC Oncology GmbH, Berlin, Germany
| | - Christoph Sachse
- NMI TT Pharmaservices, Berlin, Germany.,ASC Oncology GmbH, Berlin, Germany
| | - Markus Templin
- ASC Oncology GmbH, Berlin, Germany.,NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Jens Hoffmann
- EPO Experimental Pharmacology and Oncology Berlin-Buch GmbH, Berlin, Germany
| | - Melanie Boerries
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Reinhold Schäfer
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Charité Comprehensive Cancer Center, Berlin, Germany
| | - Christian R A Regenbrecht
- cpo-Cellular Phenomics & Oncology Berlin-Buch GmbH, Berlin, Germany.,Department of Pathology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.,ASC Oncology GmbH, Berlin, Germany
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36
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Chivu-Economescu M, Matei L, Necula LG, Dragu DL, Bleotu C, Diaconu CC. New therapeutic options opened by the molecular classification of gastric cancer. World J Gastroenterol 2018; 24:1942-1961. [PMID: 29760539 PMCID: PMC5949709 DOI: 10.3748/wjg.v24.i18.1942] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/12/2018] [Accepted: 04/23/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most lethal and aggressive cancers, being the third cause of cancer related death worldwide. Even with radical gastrectomy and the latest generation of molecular chemotherapeutics, the numbers of recurrence and mortality remains high. This is due to its biological heterogeneity based on the interaction between multiple factors, from genomic to environmental factors, diet or infections with various pathogens. Therefore, understanding the molecular characteristics at a genomic level is critical to develop new treatment strategies. Recent advances in GC molecular classification provide the unique opportunity to improve GC therapy by exploiting the biomarkers and developing novel targeted therapy specific to each subtype. This article highlights the molecular characteristics of each subtype of gastric cancer that could be considered in shaping a therapeutic decision, and also presents the completed and ongoing clinical trials addressed to those targets. The implementation of the novel molecular classification system will allow a preliminary patient selection for clinical trials, a mandatory issue if it is desired to test the efficacy of a certain inhibitor to the given target. This will represent a substantial advance as well as a powerful tool for targeted therapy. Nevertheless, translating the scientific results into new personalized treatment opportunities is needed in order to improve clinical care, the survival and quality of life of patients with GC.
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Laura G Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
- Nicolae Cajal Institute, Titu Maiorescu University, Bucharest 040441, Romania
| | - Denisa L Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen C Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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