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Carneiro A, Hahn A, Ellmark P, Enell Smith K, Schultz L, Ambarkhane S, Yachnin J, Ullenhag GJ. First-in-human, multicenter, open-label, phase I study of ATOR-1017 (evunzekibart), a 4-1BB antibody, in patients with advanced solid malignancies. J Immunother Cancer 2025; 13:e010113. [PMID: 39848688 PMCID: PMC11784162 DOI: 10.1136/jitc-2024-010113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 12/14/2024] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND ATOR-1017 (evunzekibart) is a human agonistic immunoglobulin G4 antibody targeting the costimulatory receptor 4-1BB (CD137). ATOR-1017 activates T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell death. METHODS In this first-in-human, multicenter, phase I study, ATOR-1017 was administered intravenously every 21 days as a monotherapy to patients with advanced, unresectable solid tumors having received multiple standard-of-care treatments. The study used single patient cohorts for rapid dose escalation up to 40 mg; thereafter a modified 3+3 design up to 900 mg. Escalating doses were given until disease progression, unacceptable toxicity, or withdrawal of consent. The primary objective of the study included determination of the maximum tolerated dose (MTD) via assessment of adverse events and dose-limiting toxicities (DLTs). Secondary objectives included determination of the pharmacokinetics, immunogenicity and clinical efficacy assessed with CT scans using immune Response Evaluation Criteria in Solid Tumors. Exploratory objectives included pharmacodynamic (PD) assessment of immune system biomarkers. RESULTS Of the 27 patients screened, 25 received treatment with ATOR-1017. The median time on study was 13.1 weeks (range 4.3-92.3). The MTD of ATOR-1017 was not reached. Treatment-related adverse events (TRAEs) were reported in 13 (52%) of 25 patients; most common (≥10%) were fatigue (n=4 (16.0%) patients) and neutropenia (n=3 (12.0%) patients). Five patients experienced a severe (≥ grade 3) TRAE; neutropenia (n=2), febrile neutropenia (n=1), chest pain (n=1), increased liver enzymes (n=1), and leukopenia and thrombocytopenia (n=1). No patients discontinued due to TRAEs and no DLTs were observed. Pharmacokinetic data demonstrated approximate dose-proportional kinetics. Dose-dependent increases in PD biomarkers, including soluble 4-1BB, are indicative of target-mediated biological activity. Best response was stable disease in 13 out of 25 patients (52%), maintained for 6 months or longer in six patients (24%). CONCLUSIONS Treatment with ATOR-1017 was safe and well tolerated at all dose levels and demonstrated biological activity. Furthermore, almost one-third of patients experienced long-lasting stable disease in this heavily pretreated population. The encouraging safety and preliminary efficacy data warrant further clinical development of ATOR-1017, possibly in combination with other anticancer agents.
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Affiliation(s)
- Ana Carneiro
- Skåne University Hospital and Lund University, Lund, Sweden
| | - Amanda Hahn
- Department of Oncology, Uppsala University Hospital, Uppsala, Sweden
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Peter Ellmark
- Alligator Bioscience AB, Lund, Sweden
- Department of Immunotechnolgy, Lund University, Lund, Sweden
| | | | | | | | | | - Gustav J Ullenhag
- Department of Oncology, Uppsala University Hospital, Uppsala, Sweden
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Lee KY, Mei Y, Liu H, Schwarz H. CD137-expressing regulatory T cells in cancer and autoimmune diseases. Mol Ther 2025; 33:51-70. [PMID: 39668561 PMCID: PMC11764688 DOI: 10.1016/j.ymthe.2024.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 11/25/2024] [Accepted: 12/06/2024] [Indexed: 12/14/2024] Open
Abstract
Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, with critical roles in preventing aberrant immune responses that occur in autoimmune diseases and chronic inflammation. Conversely, the abundance of Tregs in cancer is associated with impaired anti-tumor immunity, and tumor immune evasion. Recent work demonstrates that CD137, a well-known costimulatory molecule for T cells, is highly expressed on Tregs in pathological conditions, while its expression is minimal or negligible on peripheral Tregs. The expression of CD137 marks Tregs with potent immunosuppressive phenotype that foster cancer progression and are protective against certain autoimmune diseases. Hence CD137 has emerged as a marker for Tregs. However, several important questions still remain regarding the expression and function of CD137 in Tregs. Here, we provide an overview of our current knowledge of Treg mechanisms of action, with a focus on the role of CD137 in modulating Treg activity. We also explore the implications of CD137+ Tregs in both cancer and autoimmune diseases, emphasizing the significance of targeting these cells for therapeutic intervention in these conditions.
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Affiliation(s)
- Kang Yi Lee
- NUS Immunology Programme, Life Sciences Institute, Department of Microbiology and Immunology, National University of Singapore, Singapore 117545, Singapore; NUSMED Immunology Translational Research Programme, National University of Singapore, Singapore 117456, Singapore
| | - Yu Mei
- NUS Immunology Programme, Life Sciences Institute, Department of Microbiology and Immunology, National University of Singapore, Singapore 117545, Singapore; NUSMED Immunology Translational Research Programme, National University of Singapore, Singapore 117456, Singapore
| | - Haiyan Liu
- NUS Immunology Programme, Life Sciences Institute, Department of Microbiology and Immunology, National University of Singapore, Singapore 117545, Singapore; NUSMED Immunology Translational Research Programme, National University of Singapore, Singapore 117456, Singapore.
| | - Herbert Schwarz
- NUS Immunology Programme, Life Sciences Institute, Department of Microbiology and Immunology, National University of Singapore, Singapore 117545, Singapore; NUSMED Immunology Translational Research Programme, National University of Singapore, Singapore 117456, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
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Rotta G, Puca E, Cazzamalli S, Neri D, Dakhel Plaza S. Cytokine Biopharmaceuticals with "Activity-on-Demand" for Cancer Therapy. Bioconjug Chem 2024; 35:1075-1088. [PMID: 38885090 DOI: 10.1021/acs.bioconjchem.4c00187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
Cytokines are small proteins that modulate the activity of the immune system. Because of their potent immunomodulatory properties, some recombinant cytokines have undergone clinical development and have gained marketing authorization for the therapy of certain forms of cancer. Recombinant cytokines are typically administered at ultralow doses, as many of them can cause substantial toxicity even at submilligram quantities. In an attempt to increase the therapeutic index, fusion proteins based on tumor-homing antibodies (also called "immunocytokines") have been considered, and some products in this class have reached late-stage clinical trials. While antibody-cytokine fusions, which preferentially localize in the neoplastic mass, can activate tumor-resident leukocytes and may be more efficacious than their nontargeted counterparts, such products typically conserve an intact cytokine activity, which may prevent escalation to curative doses. To further improve tolerability, several strategies have been conceived for the development of antibody-cytokine fusions with "activity-on-demand", acting on tumors but helping spare normal tissues from undesired toxicity. In this article, we have reviewed some of the most promising strategies, outlining their potential as well as possible limitations.
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Affiliation(s)
- Giulia Rotta
- Philochem AG, CH-8112 Otelfingen, Switzerland
- Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy
| | | | | | - Dario Neri
- Philogen S.p.A, 53100 Siena, Italy
- Institute of Pharmaceutical Sciences, ETH Zurich, CH-8093 Zurich, Switzerland
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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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Rakké YS, Buschow SI, IJzermans JNM, Sprengers D. Engaging stimulatory immune checkpoint interactions in the tumour immune microenvironment of primary liver cancers - how to push the gas after having released the brake. Front Immunol 2024; 15:1357333. [PMID: 38440738 PMCID: PMC10910082 DOI: 10.3389/fimmu.2024.1357333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 01/31/2024] [Indexed: 03/06/2024] Open
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the first and second most common primary liver cancer (PLC). For decades, systemic therapies consisting of tyrosine kinase inhibitors (TKIs) or chemotherapy have formed the cornerstone of treating advanced-stage HCC and CCA, respectively. More recently, immunotherapy using immune checkpoint inhibition (ICI) has shown anti-tumour reactivity in some patients. The combination regimen of anti-PD-L1 and anti-VEGF antibodies has been approved as new first-line treatment of advanced-stage HCC. Furthermore, gemcibatine plus cisplatin (GEMCIS) with an anti-PD-L1 antibody is awaiting global approval for the treatment of advanced-stage CCA. As effective anti-tumour reactivity using ICI is achieved in a minor subset of both HCC and CCA patients only, alternative immune strategies to sensitise the tumour microenvironment of PLC are waited for. Here we discuss immune checkpoint stimulation (ICS) as additional tool to enhance anti-tumour reactivity. Up-to-date information on the clinical application of ICS in onco-immunology is provided. This review provides a rationale of the application of next-generation ICS either alone or in combination regimen to potentially enhance anti-tumour reactivity in PLC patients.
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Affiliation(s)
- Yannick S. Rakké
- Department of Surgery, Erasmus MC-Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Sonja I. Buschow
- Department of Gastroenterology and Hepatology, Erasmus MC-Cancer Institute-University Medical Center, Rotterdam, Netherlands
| | - Jan N. M. IJzermans
- Department of Surgery, Erasmus MC-Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Dave Sprengers
- Department of Gastroenterology and Hepatology, Erasmus MC-Cancer Institute-University Medical Center, Rotterdam, Netherlands
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Galvez-Cancino F, Simpson AP, Costoya C, Matos I, Qian D, Peggs KS, Litchfield K, Quezada SA. Fcγ receptors and immunomodulatory antibodies in cancer. Nat Rev Cancer 2024; 24:51-71. [PMID: 38062252 DOI: 10.1038/s41568-023-00637-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/10/2023] [Indexed: 12/24/2023]
Abstract
The discovery of both cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) as negative regulators of antitumour immunity led to the development of numerous immunomodulatory antibodies as cancer treatments. Preclinical studies have demonstrated that the efficacy of immunoglobulin G (IgG)-based therapies depends not only on their ability to block or engage their targets but also on the antibody's constant region (Fc) and its interactions with Fcγ receptors (FcγRs). Fc-FcγR interactions are essential for the activity of tumour-targeting antibodies, such as rituximab, trastuzumab and cetuximab, where the killing of tumour cells occurs at least in part due to these mechanisms. However, our understanding of these interactions in the context of immunomodulatory antibodies designed to boost antitumour immunity remains less explored. In this Review, we discuss our current understanding of the contribution of FcγRs to the in vivo activity of immunomodulatory antibodies and the challenges of translating results from preclinical models into the clinic. In addition, we review the impact of genetic variability of human FcγRs on the activity of therapeutic antibodies and how antibody engineering is being utilized to develop the next generation of cancer immunotherapies.
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Affiliation(s)
- Felipe Galvez-Cancino
- Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Alexander P Simpson
- Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Cristobal Costoya
- Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK
| | - Ignacio Matos
- Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK
| | - Danwen Qian
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Tumour Immunogenomics and Immunosurveillance Laboratory, University College London Cancer Institute, London, UK
| | - Karl S Peggs
- Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK
| | - Kevin Litchfield
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Tumour Immunogenomics and Immunosurveillance Laboratory, University College London Cancer Institute, London, UK
| | - Sergio A Quezada
- Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
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Enell Smith K, Fritzell S, Nilsson A, Barchan K, Rosén A, Schultz L, Varas L, Säll A, Rose N, Håkansson M, von Schantz L, Ellmark P. ATOR-1017 (evunzekibart), an Fc-gamma receptor conditional 4-1BB agonist designed for optimal safety and efficacy, activates exhausted T cells in combination with anti-PD-1. Cancer Immunol Immunother 2023; 72:4145-4159. [PMID: 37796298 PMCID: PMC10700433 DOI: 10.1007/s00262-023-03548-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 09/11/2023] [Indexed: 10/06/2023]
Abstract
BACKGROUND 4-1BB (CD137) is a co-stimulatory receptor highly expressed on tumor reactive effector T cells and NK cells, which upon stimulation prolongs persistence of tumor reactive effector T and NK cells within the tumor and induces long-lived memory T cells. 4-1BB agonistic antibodies have been shown to induce strong anti-tumor effects that synergize with immune checkpoint inhibitors. The first generation of 4-1BB agonists was, however, hampered by dose-limiting toxicities resulting in suboptimal dose levels or poor agonistic activity. METHODS ATOR-1017 (evunzekibart), a second-generation Fc-gamma receptor conditional 4-1BB agonist in IgG4 format, was designed to overcome the limitations of the first generation of 4-1BB agonists, providing strong agonistic effect while minimizing systemic immune activation and risk of hepatoxicity. The epitope of ATOR-1017 was determined by X-ray crystallography, and the functional activity was assessed in vitro and in vivo as monotherapy or in combination with anti-PD1. RESULTS ATOR-1017 binds to a unique epitope on 4-1BB enabling ATOR-1017 to activate T cells, including cells with an exhausted phenotype, and NK cells, in a cross-linking dependent, FcγR-conditional, manner. This translated into a tumor-directed and potent anti-tumor therapeutic effect in vivo, which was further enhanced with anti-PD-1 treatment. CONCLUSIONS These preclinical data demonstrate a strong safety profile of ATOR-1017, together with its potent therapeutic effect as monotherapy and in combination with anti-PD1, supporting further clinical development of ATOR-1017.
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Affiliation(s)
| | | | | | | | | | | | | | - Anna Säll
- Alligator Bioscience AB, Lund, Sweden
| | | | | | | | - Peter Ellmark
- Alligator Bioscience AB, Lund, Sweden.
- Department of Immunotechnology, Lund University, Lund, Sweden.
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Gulen AE, Rudraboina R, Tarique M, Ulker V, Shirwan H, Yolcu ES. A novel agonist of 4-1BB costimulatory receptor shows therapeutic efficacy against a tobacco carcinogen-induced lung cancer. Cancer Immunol Immunother 2023; 72:3567-3579. [PMID: 37605009 PMCID: PMC10991934 DOI: 10.1007/s00262-023-03507-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 07/23/2023] [Indexed: 08/23/2023]
Abstract
Immunotherapy utilizing checkpoint inhibitors has shown remarkable success in the treatment of cancers. In addition to immune checkpoint inhibitors, immune co-stimulation has the potential to enhance immune activation and destabilize the immunosuppressive tumor microenvironment. CD137, also known as 4-1BB, is one of the potent immune costimulatory receptors that could be targeted for effective immune co-stimulation. The interaction of the 4-1BB receptor with its natural ligand (4-1BBL) generates a strong costimulatory signal for T cell proliferation and survival. 4-1BBL lacks costimulatory activity in soluble form. To obtain co-stimulatory activity in soluble form, a recombinant 4-1BBL protein was generated by fusing the extracellular domains of murine 4-1BBL to a modified version of streptavidin (SA-4-1BBL). Treatment with SA-4-1BBL inhibited the development of lung tumors in A/J mice induced by weekly injections of the tobacco carcinogen NNK for eight weeks. The inhibition was dependent on the presence of T cells and NK cells; depletion of these cells diminished the SA-4-1BBL antitumor protective effect. The number of lung tumor nodules was significantly reduced by the administration of SA-4-1BBL to mice during ongoing exposure to NNK. The data presented in this paper suggest that utilizing an immune checkpoint stimulator as a single agent generate a protective immune response against lung cancer in the presence of a carcinogen. More broadly, this study suggests that immune checkpoint stimulation can be extended to a number of other cancer types, including breast and prostate cancers, for which improved diagnostics can detect disease at the preneoplastic stage.
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Affiliation(s)
- Ayse Ece Gulen
- Department of Child Health, University of Missouri, Columbia, MO, USA
- NextGen Precision Health, University of Missouri, Columbia, MO, USA
| | - Rakesh Rudraboina
- Department of Child Health, University of Missouri, Columbia, MO, USA
- NextGen Precision Health, University of Missouri, Columbia, MO, USA
| | - Mohammad Tarique
- Department of Child Health, University of Missouri, Columbia, MO, USA
- NextGen Precision Health, University of Missouri, Columbia, MO, USA
| | - Vahap Ulker
- Department of Child Health, University of Missouri, Columbia, MO, USA
- NextGen Precision Health, University of Missouri, Columbia, MO, USA
| | - Haval Shirwan
- Department of Child Health, University of Missouri, Columbia, MO, USA.
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA.
- NextGen Precision Health, University of Missouri, Columbia, MO, USA.
| | - Esma S Yolcu
- Department of Child Health, University of Missouri, Columbia, MO, USA.
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA.
- NextGen Precision Health, University of Missouri, Columbia, MO, USA.
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Mou J, Xie L, Xu Y, Zhou T, Liu Y, Huang Q, Tang K, Tian Z, Xing H, Qiu S, Rao Q, Wang M, Wang J. 2B4 inhibits the apoptosis of natural killer cells through phosphorylated extracellular signal-related kinase/B-cell lymphoma 2 signal pathway. Cytotherapy 2023; 25:1080-1090. [PMID: 37516949 DOI: 10.1016/j.jcyt.2023.07.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/25/2023] [Accepted: 07/07/2023] [Indexed: 07/31/2023]
Abstract
BACKGROUND AIMS Decades after the identification of natural killer (NK) cells as potential effector cells against malignantly transformed cells, an increasing amount of research suggests that NK cells are a prospective choice of immunocytes for cancer immunotherapy in addition to T lymphocytes for cancer immunotherapy. Recent studies have led to a breakthrough in the combination of hematopoietic stem-cell transplantation with allogeneic NK cells infusion for the treatment of malignant tumors. However, the short lifespan of NK cells in patients is the major impediment, limiting their efficacy. Therefore, prolonging the survival of NK cells will promote the application of NK-cell immunotherapy. As we have known, NK cells use a "missing-self" mechanism to lyse target cells and exert their functions through a wide array of activating, co-stimulatory and inhibitory receptors. Our previous study has suggested that CD244 (2B4), one of the co-stimulatory receptors, can improve the function of chimeric antigen receptor NK cells. However, the underlying mechanism of how 2B4 engages in the function of NK cells requires further investigation. Overall, we established a feeder cell with the expression of CD48, the ligand of 2B4, to investigate the function of 2B4-CD48 axis in NK cells, and meanwhile, to explore whether the newly generated feeder cell can improve the function of ex vivo-expanded NK cells. METHODS First, K562 cells overexpressing 4-1BBL and membrane-bound IL-21 (mbIL-21) were constructed (K562-41BBL-mbIL-21) and were sorted to generate the single clone. These widely used feeder cells (K562-41BBL-mbIL-21) were named as Basic Feeder hereinafter. Based on the Basic feeder, CD48 was overexpressed and named as CD48 Feeder. Then, the genetically modified feeder cells were used to expand primary NK cells from peripheral blood or umbilical cord blood. In vitro experiments were performed to compare proliferation ability, cytotoxicity, survival and activation/inhibition phenotypes of NK cells stimulated via different feeder cells. K562 cells were injected into nude mice subcutaneously with tail vein injection of NK cells from different feeder system for the detection of NK in vivo persistence and function. RESULTS Compared with Basic Feeders, CD48 Feeders can promote the proliferation of primary NK cells from peripheral blood and umbilical cord blood and reduce NK cell apoptosis by activating the p-ERK/BCL2 pathway both in vitro and in vivo without affecting overall phenotypes. Furthermore, NK cells expanded via CD48 Feeders showed stronger anti-tumor capability and infiltration ability into the tumor microenvironment. CONCLUSIONS In this preclinical study, the engagement of the 2B4-CD48 axis can inhibit the apoptosis of NK cells through the p-ERK/BCL2 signal pathway, leading to an improvement in therapeutic efficiency.
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Affiliation(s)
- Junli Mou
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Leling Xie
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yingxi Xu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Tong Zhou
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yu Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Qianqian Huang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Kejing Tang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Zheng Tian
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Haiyan Xing
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Shaowei Qiu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Qing Rao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Min Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
| | - Jianxiang Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
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10
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Glez-Vaz J, Azpilikueta A, Ochoa MC, Olivera I, Gomis G, Cirella A, Luri-Rey C, Álvarez M, Pérez-Gracia JL, Ciordia S, Eguren-Santamaria I, Alexandru R, Berraondo P, de Andrea C, Teijeira Á, Corrales F, Zapata JM, Melero I. CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects. SCIENCE ADVANCES 2023; 9:eadf6692. [PMID: 37595047 PMCID: PMC11044178 DOI: 10.1126/sciadv.adf6692] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 07/20/2023] [Indexed: 08/20/2023]
Abstract
CD137 (4-1BB) is a member of the TNFR family that mediates potent T cell costimulatory signals upon ligation by CD137L or agonist monoclonal antibodies (mAbs). CD137 agonists attain immunotherapeutic antitumor effects in cancer mouse models, and multiple agents of this kind are undergoing clinical trials. We show that cIAP1 and cIAP2 are physically associated with the CD137 signaling complex. Moreover, cIAPs are required for CD137 signaling toward the NF-κB and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC mimetics that trigger cIAP degradation and by transfecting cIAP dominant-negative variants. Antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in cancer mouse models, and cIAPs are also required for signaling from CARs encompassing CD137's cytoplasmic tail.
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Affiliation(s)
- Javier Glez-Vaz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Arantza Azpilikueta
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - María C. Ochoa
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Departments of Immunology-Immunotherapy, Pathology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Irene Olivera
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Gabriel Gomis
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
| | - Asunta Cirella
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Departments of Immunology-Immunotherapy, Pathology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Carlos Luri-Rey
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Maite Álvarez
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Jose L. Pérez-Gracia
- Departments of Immunology-Immunotherapy, Pathology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Sergio Ciordia
- Functional Proteomics Laboratory, CNB-CSIC, Proteored-ISCIII, Madrid, Spain
| | - Iñaki Eguren-Santamaria
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Departments of Immunology-Immunotherapy, Pathology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Raluca Alexandru
- Departments of Immunology-Immunotherapy, Pathology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Pedro Berraondo
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Carlos de Andrea
- Departments of Immunology-Immunotherapy, Pathology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Álvaro Teijeira
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Fernando Corrales
- Functional Proteomics Laboratory, CNB-CSIC, Proteored-ISCIII, Madrid, Spain
| | - Juan M. Zapata
- Instituto de Investigaciones Biomédicas Alberto Sols (IIBm), CSIC-UAM, Madrid, Spain
- Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Departments of Immunology-Immunotherapy, Pathology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
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11
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Wang YA, Ranti D, Bieber C, Galsky M, Bhardwaj N, Sfakianos JP, Horowitz A. NK Cell-Targeted Immunotherapies in Bladder Cancer: Beyond Checkpoint Inhibitors. Bladder Cancer 2023; 9:125-139. [PMID: 38993289 PMCID: PMC11181717 DOI: 10.3233/blc-220109] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 05/15/2023] [Indexed: 07/13/2024]
Abstract
BACKGROUND For decades, immunotherapies have been integral for the treatment and management of bladder cancer, with immune checkpoint inhibitors (ICIs) transforming patient care in recent years. However, response rates are poor to T cell-targeted ICIs such as programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) blocking antibodies, framing a critical need for complementary immunotherapies. Promising strategies involve harnessing the activation potential of natural killer (NK) cells. They quickly exert their antitumor activity via signaling through germline-encoded activating receptors and are rapidly sensitized to new tissue microenvironments via their regulation by polymorphic HLA class I, KIR and NKG2A receptors. OBJECTIVE In this review, we examined the roles of currently available NK-targeted antitumor treatment strategies such as engineered viral vectors, small-molecule IMiDs, NK agonist antibodies, interleukins, and chimeric antigen receptor (CAR) NK cells, and their potential for improving the efficacy of immunotherapy in the treatment of bladder cancer. METHODS Through review of current literature, we summarized our knowledge of NK cells in solid tumors and hematologic malignancies as their roles pertain to novel immunotherapies already being applied to the treatment of bladder cancer or that offer rationale for considering as potential novel immunotherapeutic strategies. RESULTS NK cells play a critical role in shaping the tumor microenvironment (TME) that can be exploited to improve T cell-targeted immunotherapies. CONCLUSIONS Emerging evidence suggests that NK cells are a prime target for improving antitumor functions in immunotherapies for the treatment of bladder cancer. Further research into profiling NK cells in settings of immunotherapies for bladder cancer could help identify patients who might maximally benefit from NK cell-targeted immunotherapies and the various approaches for exploiting their antitumor properties.
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Affiliation(s)
- Yuanshuo A Wang
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniel Ranti
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Christine Bieber
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Matthew Galsky
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nina Bhardwaj
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John P Sfakianos
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Amir Horowitz
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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12
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Melero I, Sanmamed MF, Glez-Vaz J, Luri-Rey C, Wang J, Chen L. CD137 (4-1BB)-Based Cancer Immunotherapy on Its 25th Anniversary. Cancer Discov 2023; 13:552-569. [PMID: 36576322 DOI: 10.1158/2159-8290.cd-22-1029] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/28/2022] [Accepted: 11/21/2022] [Indexed: 12/29/2022]
Abstract
Twenty-five years ago, we reported that agonist anti-CD137 monoclonal antibodies eradicated transplanted mouse tumors because of enhanced CD8+ T-cell antitumor immunity. Mouse models indicated that anti-CD137 agonist antibodies synergized with various other therapies. In the clinic, the agonist antibody urelumab showed evidence for single-agent activity against melanoma and non-Hodgkin lymphoma but caused severe liver inflammation in a fraction of the patients. CD137's signaling domain is included in approved chimeric antigen receptors conferring persistence and efficacy. A new wave of CD137 agonists targeting tumors, mainly based on bispecific constructs, are in early-phase trials and are showing promising safety and clinical activity. SIGNIFICANCE CD137 (4-1BB) is a costimulatory receptor of T and natural killer lymphocytes whose activity can be exploited in cancer immunotherapy strategies as discovered 25 years ago. Following initial attempts that met unacceptable toxicity, new waves of constructs acting agonistically on CD137 are being developed in patients, offering signs of clinical and pharmacodynamic activity with tolerable safety profiles.
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Affiliation(s)
- Ignacio Melero
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
- Departments of Immunology-Immunotherapy and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Miguel F Sanmamed
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
- Departments of Immunology-Immunotherapy and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Javier Glez-Vaz
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Carlos Luri-Rey
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Jun Wang
- Department of Pathology, New York University Grossman School of Medicine, New York, New York
| | - Lieping Chen
- Department of Immunobiology, Yale University, New Haven, Connecticut
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13
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Improved Antitumor Effect of NK Cells Activated by Neutrophils in a Bone Marrow Transplant Model. Mediators Inflamm 2023; 2023:6316581. [PMID: 36762286 PMCID: PMC9904906 DOI: 10.1155/2023/6316581] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 12/23/2022] [Accepted: 01/16/2023] [Indexed: 02/04/2023] Open
Abstract
The licensing process mediated by inhibitory receptors of the Ly49 C-type lectin superfamily that recognizes self-major histocompatibility complex (MHC) class I in mice is essential for the proper antitumor function of natural killer (NK) cells. Several models for NK cell licensing can be exploited for adoptive immunotherapy for cancer. However, the appropriate adoptive transfer setting to induce efficient graft versus tumor/leukemia effects remains elusive, especially after hematopoietic stem cell transplantation (HSCT). In our previous experiment, we showed that intraperitoneal neutrophil administration with their corresponding NK receptor ligand-activated NK cells using congenic mice without HSCT. In this experiment, we demonstrate enhanced antitumor effects of licensed NK cells induced by weekly intraperitoneal injections of irradiated neutrophil-enriched peripheral blood mononuclear cells (PBMNCs) in recipient mice bearing lymphoma. Bone marrow transplantation was performed using BALB/c mice (H-2d) as the recipient and B10 mice (H-2b) as the donor. The tumor was A20, a BALB/c-derived lymphoma cell line, which was injected subcutaneously into the recipient at the same time as the HSCT. Acute graft versus host disease was not exacerbated in this murine MHC class I mismatched HSCT setting. The intraperitoneal injection of PBMNCs activated a transient licensing of NK subsets expressed Ly49G2, its corresponding NK receptor ligand to H-2d, and reduced A20 tumor growth in the recipient after HSCT. Pathological examination revealed that increased donor-oriented NK1.1+NK cells migrated into the recipient tumors, depending on neutrophil counts in the administered PBMNCs. Collectively, our data reveal a pivotal role of neutrophils in promoting NK cell effector functions and adoptive immunotherapy for cancer.
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14
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Peng X, Gong C, Zhang W, Zhou A. Advanced development of biomarkers for immunotherapy in hepatocellular carcinoma. Front Oncol 2023; 12:1091088. [PMID: 36727075 PMCID: PMC9885011 DOI: 10.3389/fonc.2022.1091088] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 12/20/2022] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Mono-immunotherapy and combination therapy with immune checkpoint inhibitors (ICIs) and multitargeted tyrosine kinase inhibitors (TKIs) or anti-vascular endothelial growth factor (anti-VEGF) inhibitors have become new standard therapies in advanced HCC (aHCC). However, the clinical benefit of these treatments is still limited. Thus, proper biomarkers which can predict treatment response to immunotherapy to maximize clinical benefit while sparing unnecessary toxicity are urgently needed. Contrary to other malignancies, up until now, no acknowledged biomarkers are available to predict resistance or response to immunotherapy for HCC patients. Furthermore, biomarkers, which are established in other cancer types, such as programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB), have no stable predictive effect in HCC. Thus, plenty of research focusing on biomarkers for HCC is under exploration. In this review, we summarize the predictive and prognostic biomarkers as well as the potential predictive mechanism in order to guide future research direction for biomarker exploration and clinical treatment options in HCC.
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15
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Antunes A, Alvarez-Vallina L, Bertoglio F, Bouquin N, Cornen S, Duffieux F, Ferré P, Gillet R, Jorgensen C, Leick MB, Maillère B, Negre H, Pelegrin M, Poirier N, Reusch D, Robert B, Serre G, Vicari A, Villalba M, Volpers C, Vuddamalay G, Watier H, Wurch T, Zabeau L, Zielonka S, Zhang B, Beck A, Martineau P. 10th antibody industrial symposium: new developments in antibody and adoptive cell therapies. MAbs 2023; 15:2211692. [PMID: 37184206 DOI: 10.1080/19420862.2023.2211692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023] Open
Abstract
The annual "Antibody Industrial Symposium", co-organized by LabEx MAbImprove and MabDesign, held its 10th anniversary edition in Montpellier, France, on June 28-29, 2022. The meeting focused on new results and concepts in antibody engineering (naked, mono- or multi-specific, conjugated to drugs or radioelements) and also on new cell-based therapies, such as chimeric antigenic receptor (CAR)-T cells. The symposium, which brought together scientists from academia and industry, also addressed issues concerning the production of these molecules and cells, and the necessary steps to ensure a strong intellectual property protection of these new molecules and approaches. These two days of exchanges allowed a rich discussion among the various actors in the field of therapeutic antibodies.
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Affiliation(s)
| | - Luis Alvarez-Vallina
- Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain
- H120-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Centre (CNIO), Madrid, Spain
| | - Federico Bertoglio
- Technische Universität Braunschweig, Institute of Biochemistry, Biotechnology and Bioinformatics, Department of Biotechnology, Braunschweig, Germany, Current address
| | | | | | | | | | | | - Christian Jorgensen
- IRMB, université de Montpellier, Inserm U1183, Montpellier, France
- Unité d'immunologie clinique et de thérapeutique des maladies ostéoarticulaires, département de rhumatologie, hôpital Lapeyronie, Montpellier, France
| | - Mark B Leick
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Bernard Maillère
- Université de Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Hélène Negre
- Institut de Recherches Internationales Servier, Suresnes, France
| | | | | | - Dietmar Reusch
- Pharma Technical Development Analytics Biologics, Roche Diagnostics GmbH, Penzberg, Germany
| | - Bruno Robert
- IRCM, INSERM, U1194 Univ Montpellier, ICM, 208, rue des Apothicaires, Montpellier, France
| | - Guy Serre
- Institut Toulousain des maladies infectieuses et inflammatoires - INFINITY- Inserm, CNRS, Université Toulouse III, Toulouse, France
| | - Alain Vicari
- Calypso Biotech SA, Plan-les-Ouates, Switzerland
| | | | | | | | - Hervé Watier
- CEPR, INSERM U1100 Université de Tours, et CHU de Tours, Tours cedex, France
| | | | | | - Stefan Zielonka
- Protein Engineering and Antibody Technologies, Merck Healthcare KGaA, Darmstadt, Germany
| | - Baolin Zhang
- Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Alain Beck
- Biologics CMC & Developability, Institut de Recherche Pierre Fabre, St Julien-en-Genevois Cedex, France
| | - Pierre Martineau
- IRCM, INSERM, U1194 Univ Montpellier, ICM, 208, rue des Apothicaires, Montpellier, France
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16
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Abdeladhim M, Karnell JL, Rieder SA. In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways. Front Immunol 2022; 13:1033705. [PMID: 36591244 PMCID: PMC9799097 DOI: 10.3389/fimmu.2022.1033705] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/16/2022] [Indexed: 12/16/2022] Open
Abstract
Regulatory T cells (Tregs) are the master regulators of immunity and they have been implicated in different disease states such as infection, autoimmunity and cancer. Since their discovery, many studies have focused on understanding Treg development, differentiation, and function. While there are many players in the generation and function of truly suppressive Tregs, the role of checkpoint pathways in these processes have been studied extensively. In this paper, we systematically review the role of different checkpoint pathways in Treg homeostasis and function. We describe how co-stimulatory and co-inhibitory pathways modulate Treg homeostasis and function and highlight data from mouse and human studies. Multiple checkpoint pathways are being targeted in cancer and autoimmunity; therefore, we share insights from the clinic and discuss the effect of experimental and approved therapeutics on Treg biology.
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17
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Mendoza-Valderrey A, Alvarez M, De Maria A, Margolin K, Melero I, Ascierto ML. Next Generation Immuno-Oncology Strategies: Unleashing NK Cells Activity. Cells 2022; 11:3147. [PMID: 36231109 PMCID: PMC9562848 DOI: 10.3390/cells11193147] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/06/2022] [Accepted: 10/02/2022] [Indexed: 11/19/2022] Open
Abstract
In recent years, immunotherapy has become a powerful therapeutic option against multiple malignancies. The unique capacity of natural killer (NK) cells to attack cancer cells without antigen specificity makes them an optimal immunotherapeutic tool for targeting tumors. Several approaches are currently being pursued to maximize the anti-tumor properties of NK cells in the clinic, including the development of NK cell expansion protocols for adoptive transfer, the establishment of a favorable microenvironment for NK cell activity, the redirection of NK cell activity against tumor cells, and the blockage of inhibitory mechanisms that constrain NK cell function. We here summarize the recent strategies in NK cell-based immunotherapies and discuss the requirement to further optimize these approaches for enhancement of the clinical outcome of NK cell-based immunotherapy targeting tumors.
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Affiliation(s)
- Alberto Mendoza-Valderrey
- Rosalie and Harold Rae Brown Cancer Immunotherapy Research Program, Borstein Family Melanoma Program, Translational Immunology Department, Saint John’s Cancer Institute, Santa Monica, CA 90404, USA
| | - Maite Alvarez
- Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Andrea De Maria
- Department of Health Sciences, University of Genoa, 16126 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Kim Margolin
- Borstein Family Melanoma Program, Saint John’s Cancer Institute, Santa Monica, CA 90404, USA
| | - Ignacio Melero
- Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, 31008 Pamplona, Spain
| | - Maria Libera Ascierto
- Rosalie and Harold Rae Brown Cancer Immunotherapy Research Program, Borstein Family Melanoma Program, Translational Immunology Department, Saint John’s Cancer Institute, Santa Monica, CA 90404, USA
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18
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Kim AMJ, Nemeth MR, Lim SO. 4-1BB: A promising target for cancer immunotherapy. Front Oncol 2022; 12:968360. [PMID: 36185242 PMCID: PMC9515902 DOI: 10.3389/fonc.2022.968360] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Immunotherapy, powered by its relative efficacy and safety, has become a prominent therapeutic strategy utilized in the treatment of a wide range of diseases, including cancer. Within this class of therapeutics, there is a variety of drug types such as immune checkpoint blockade therapies, vaccines, and T cell transfer therapies that serve the purpose of harnessing the body’s immune system to combat disease. Of these different types, immune checkpoint blockades that target coinhibitory receptors, which dampen the body’s immune response, have been widely studied and established in clinic. In contrast, however, there remains room for the development and improvement of therapeutics that target costimulatory receptors and enhance the immune response against tumors, one of which being the 4-1BB (CD137/ILA/TNFRSF9) receptor. 4-1BB has been garnering attention as a promising therapeutic target in the setting of cancer, amongst other diseases, due to its broad expression profile and ability to stimulate various signaling pathways involved in the generation of a potent immune response. Since its discovery and demonstration of potential as a clinical target, major progress has been made in the knowledge of 4-1BB and the development of clinical therapeutics that target it. Thus, we seek to summarize and provide a comprehensive update and outlook on those advancements in the context of cancer and immunotherapy.
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Affiliation(s)
- Alyssa Min Jung Kim
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
| | - Macy Rose Nemeth
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
| | - Seung-Oe Lim
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
- Purdue Institute of Drug Discovery, Purdue University, West Lafayette, IN, United States
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, United States
- *Correspondence: Seung-Oe Lim,
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19
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Watkins-Schulz R, Batty CJ, Stiepel RT, Schmidt ME, Sandor AM, Chou WC, Ainslie KM, Bachelder EM, Ting JPY. Microparticle Delivery of a STING Agonist Enables Indirect Activation of NK Cells by Antigen-Presenting Cells. Mol Pharm 2022; 19:3125-3138. [PMID: 35913984 DOI: 10.1021/acs.molpharmaceut.2c00207] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Natural killer (NK) cells are an important member of the innate immune system and can participate in direct tumor cell killing in response to immunotherapies. One class of immunotherapy is stimulator of interferon gene (STING) agonists, which result in a robust type I interferon (IFN-I) response. Most mechanistic studies involving STING have focused on macrophages and T cells. Nevertheless, NK cells are also activated by IFN-I, but the effect of STING activation on NK cells remains to be adequately investigated. We show that both direct treatment with soluble STING agonist cyclic di-guanosine monophosphate-adenosine monophosphate (cGAMP) and indirect treatment with cGAMP encapsulated in microparticles (MPs) result in NK cell activation in vitro, although the former requires 100× more cGAMP than the latter. Additionally, direct activation with cGAMP leads to NK cell death. Indirect activation with cGAMP MPs does not result in NK cell death but rather cell activation and cell killing in vitro. In vivo, treatment with soluble cGAMP and cGAMP MPs both cause short-term activation, whereas only cGAMP MP treatment produces long-term changes in NK cell activation markers. Thus, this work indicates that treatment with an encapsulated STING agonist activates NK cells more efficiently than that with soluble cGAMP. In both the in vitro and in vivo systems, the MP delivery system results in more robust effects at a greatly reduced dosage. These results have potential applications in aiding the improvement of cancer immunotherapies.
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Affiliation(s)
- Rebekah Watkins-Schulz
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Cole J Batty
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Rebeca T Stiepel
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Megan E Schmidt
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Adam M Sandor
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Wei-Chun Chou
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Kristy M Ainslie
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina 27695, United States
| | - Eric M Bachelder
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Jenny P-Y Ting
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Center for Translational Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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20
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Zhang W, Gong C, Peng X, Bi X, Sun Y, Zhou J, Wu F, Zeng H, Wang Y, Zhou H, Zhao H, Cai J, Zhou A. Serum Concentration of CD137 and Tumor Infiltration by M1 Macrophages Predict the Response to Sintilimab plus Bevacizumab Biosimilar in Advanced Hepatocellular Carcinoma Patients. Clin Cancer Res 2022; 28:3499-3508. [PMID: 35275208 PMCID: PMC9662860 DOI: 10.1158/1078-0432.ccr-21-3972] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/05/2022] [Accepted: 03/09/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE This study aimed to investigate the biomarkers of sintilimab (anti-PD-1) plus IBI305 (a bevacizumab biosimilar) in advanced hepatocellular carcinoma (HCC), as well as their safety and efficacy. PATIENTS AND METHODS A total of 50 patients with advanced HCC received sintilimab (200 mg) plus IBI305 (7.5 or 15 mg/kg), treated every 3 weeks in a phase Ib clinical study. We performed baseline serum cytokine analysis using bead-based multiplex immunoassay and multiplex immunofluorescence on tissue specimens to discover novel biomarkers of response to VEGF/PD-1 combination therapy in HCC. RESULTS The overall response rate was 34.0% (17/50). The median progression-free survival (PFS) and the median overall survival were 10.5 and 20.2 months, respectively. The incidence of grade 3 to 5 adverse events was lower in the 7.5 mg/kg (13.8%) than in the 15 mg/kg (28.6%) dose groups. Biomarker analysis showed that the serum CD137 concentration was significantly higher in patients with clinical benefit (CB) than in those without CB (median, 32.8 pg/mL vs. 19.8 pg/mL, P = 0.034). A markedly longer PFS was observed in patients with high CD137 concentrations compared with those with low concentrations (median, 14.2 months vs. 4.1 months, P = 0.001). The higher density of M1 macrophages (CD68+CD163-) in the stroma was also associated with higher efficacy (P = 0.033) and a longer PFS (P = 0.024). CONCLUSIONS Sintilimab plus IBI305 was well tolerated and was effective therapy for advanced HCC. Both serum concentrations of CD137 and tumor infiltration of M1 macrophages may serve as potential predictive biomarkers. See related commentary by Cappuyns and Llovet, p. 3405.
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Affiliation(s)
- Wen Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Caifeng Gong
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuenan Peng
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongkun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianguo Zhou
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fan Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huiying Zeng
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Wang
- Innovent Biologics, Suzhou, China
| | - Hui Zhou
- Innovent Biologics, Suzhou, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Corresponding Authors: Aiping Zhou, Department of Medical Oncology, National Cancer Center / National Clinical Research Center for Cancer / Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. E-mail: ; Jianqiang Cai, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. E-mail: ; and Hong Zhao, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. E-mail:
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Corresponding Authors: Aiping Zhou, Department of Medical Oncology, National Cancer Center / National Clinical Research Center for Cancer / Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. E-mail: ; Jianqiang Cai, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. E-mail: ; and Hong Zhao, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. E-mail:
| | - Aiping Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Corresponding Authors: Aiping Zhou, Department of Medical Oncology, National Cancer Center / National Clinical Research Center for Cancer / Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. E-mail: ; Jianqiang Cai, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. E-mail: ; and Hong Zhao, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. E-mail:
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21
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Peper-Gabriel JK, Pavlidou M, Pattarini L, Morales-Kastresana A, Jaquin TJ, Gallou C, Hansbauer EM, Richter M, Lelievre H, Scholer-Dahirel A, Bossenmaier B, Sancerne C, Riviere M, Grandclaudon M, Zettl M, Bel Aiba RS, Rothe C, Blanc V, Olwill SA. The PD-L1/4-1BB Bispecific Antibody-Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner. Clin Cancer Res 2022; 28:3387-3399. [PMID: 35121624 PMCID: PMC9662934 DOI: 10.1158/1078-0432.ccr-21-2762] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/25/2021] [Accepted: 02/02/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE While patients responding to checkpoint blockade often achieve remarkable clinical responses, there is still significant unmet need due to resistant or refractory tumors. A combination of checkpoint blockade with further T-cell stimulation mediated by 4-1BB agonism may increase response rates and durability of response. A bispecific molecule that blocks the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis and localizes 4-1BB costimulation to a PD-L1-positive (PD-L1+) tumor microenvironment (TME) or tumor draining lymph nodes could maximize antitumor immunity and increase the therapeutic window beyond what has been reported for anti-4-1BB mAbs. EXPERIMENTAL DESIGN We generated and characterized the PD-L1/4-1BB bispecific molecule PRS-344/S095012 for target binding and functional activity in multiple relevant in vitro assays. Transgenic mice expressing human 4-1BB were transplanted with human PD-L1-expressing murine MC38 cells to assess in vivo antitumoral activity. RESULTS PRS-344/S095012 bound to its targets with high affinity and efficiently blocked the PD-1/PD-L1 pathway, and PRS-344/S095012-mediated 4-1BB costimulation was strictly PD-L1 dependent. We demonstrated a synergistic effect of both pathways on T-cell stimulation with the bispecific PRS-344/S095012 being more potent than the combination of mAbs. PRS-344/S095012 augmented CD4-positive (CD4+) and CD8-positive (CD8+) T-cell effector functions and enhanced antigen-specific T-cell stimulation. Finally, PRS-344/S095012 demonstrated strong antitumoral efficacy in an anti-PD-L1-resistant mouse model in which soluble 4-1BB was detected as an early marker for 4-1BB agonist activity. CONCLUSIONS The PD-L1/4-1BB bispecific PRS-344/S095012 efficiently combines checkpoint blockade with a tumor-localized 4-1BB-mediated stimulation burst to antigen-specific T cells, more potent than the combination of mAbs, supporting the advancement of PRS-344/S095012 toward clinical development. See related commentary by Shu et al., p. 3182.
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Affiliation(s)
| | | | - Lucia Pattarini
- Institut de Recherches Servier, Center for Therapeutic Innovation Oncology, Croissy-sur-Seine, France
| | | | | | - Catherine Gallou
- Institut de Recherches Servier, Center for Therapeutic Innovation Oncology, Croissy-sur-Seine, France
| | | | | | - Helene Lelievre
- Institut de Recherches Internationales Servier Oncology R&D Unit, Suresnes, France
| | - Alix Scholer-Dahirel
- Institut de Recherches Internationales Servier Oncology R&D Unit, Suresnes, France
| | | | - Celine Sancerne
- Institut de Recherches Servier, Center for Therapeutic Innovation Oncology, Croissy-sur-Seine, France
| | - Matthieu Riviere
- Institut de Recherches Servier, Center for Therapeutic Innovation Oncology, Croissy-sur-Seine, France
| | - Maximilien Grandclaudon
- Institut de Recherches Servier, Center for Therapeutic Innovation Oncology, Croissy-sur-Seine, France
| | - Markus Zettl
- Pieris Pharmaceuticals GmbH, Hallbergmoos, Germany
| | | | | | - Veronique Blanc
- Institut de Recherches Servier, Center for Therapeutic Innovation Oncology, Croissy-sur-Seine, France
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22
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Sun R, Lim SO. FBXL20-mediated ubiquitination triggers the proteasomal degradation of 4-1BB. FEBS J 2022; 289:4549-4563. [PMID: 35112462 DOI: 10.1111/febs.16383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 12/27/2021] [Accepted: 02/01/2022] [Indexed: 12/16/2022]
Abstract
4-1BB [tumor necrosis factor receptor superfamily (TNFRSF9), CD137) is a critical immune stimulator that sustains T cell activity and antitumor immune response. The strategy to eliminate cancers by agonistically targeting 4-1BB is under clinical investigation. As a protein expressed in an inducible manner, 4-1BB is under tight control on both transcription and translation levels to maintain its homeostasis. So far, the mechanisms underlying the transcriptional activation of 4-1BB have been well-interpreted; however, it remains inexplicit how 4-1BB is regulated on the protein level. In this study, we presented experimental evidence supporting that 4-1BB, especially the heavily N-glycosylated (mature) form, is polyubiquitinated and subjected to the ubiquitin-proteasomal system for degradation. By performing proximity-dependent biotin identification screening coupled with biochemical assays, we identified that F-box/LRR-repeat protein 20 acts as the E3 ligase that promotes the polyubiquitination of 4-1BB at the intracellular domain. Our data provided mechanistic insight into 4-1BB regulation on the protein level by unmasking, for the first time, a posttranslational mechanism governing 4-1BB abundance in cells. The findings of this study could potentially guide the development of 4-1BB-targeted therapy for cancers as well as other immune disorders.
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Affiliation(s)
- Ruoxuan Sun
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA
| | - Seung-Oe Lim
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.,Purdue Institute of Drug Discovery, Purdue University, West Lafayette, IN, USA.,Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA
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23
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Rojas M, Heuer LS, Zhang W, Chen YG, Ridgway WM. The long and winding road: From mouse linkage studies to a novel human therapeutic pathway in type 1 diabetes. Front Immunol 2022; 13:918837. [PMID: 35935980 PMCID: PMC9353112 DOI: 10.3389/fimmu.2022.918837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Autoimmunity involves a loss of immune tolerance to self-proteins due to a combination of genetic susceptibility and environmental provocation, which generates autoreactive T and B cells. Genetic susceptibility affects lymphocyte autoreactivity at the level of central tolerance (e.g., defective, or incomplete MHC-mediated negative selection of self-reactive T cells) and peripheral tolerance (e.g., failure of mechanisms to control circulating self-reactive T cells). T regulatory cell (Treg) mediated suppression is essential for controlling peripheral autoreactive T cells. Understanding the genetic control of Treg development and function and Treg interaction with T effector and other immune cells is thus a key goal of autoimmunity research. Herein, we will review immunogenetic control of tolerance in one of the classic models of autoimmunity, the non-obese diabetic (NOD) mouse model of autoimmune Type 1 diabetes (T1D). We review the long (and still evolving) elucidation of how one susceptibility gene, Cd137, (identified originally via linkage studies) affects both the immune response and its regulation in a highly complex fashion. The CD137 (present in both membrane and soluble forms) and the CD137 ligand (CD137L) both signal into a variety of immune cells (bi-directional signaling). The overall outcome of these multitudinous effects (either tolerance or autoimmunity) depends upon the balance between the regulatory signals (predominantly mediated by soluble CD137 via the CD137L pathway) and the effector signals (mediated by both membrane-bound CD137 and CD137L). This immune balance/homeostasis can be decisively affected by genetic (susceptibility vs. resistant alleles) and environmental factors (stimulation of soluble CD137 production). The discovery of the homeostatic immune effect of soluble CD137 on the CD137-CD137L system makes it a promising candidate for immunotherapy to restore tolerance in autoimmune diseases.
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Affiliation(s)
- Manuel Rojas
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
- School of Medicine and Health Sciences, Doctoral Program in Biological and Biomedical Sciences, Universidad del Rosario, Bogota, Colombia
| | - Luke S. Heuer
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Weici Zhang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Yi-Guang Chen
- The Max McGee Research Center for Juvenile Diabetes, Children’s Research Institute of Children’s Wisconsin, Milwaukee, WI, United States
- Division of Endocrinology, Department of Pediatrics, The Medical College of Wisconsin, Milwaukee, WI, United States
| | - William M. Ridgway
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
- *Correspondence: William M. Ridgway,
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24
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Mohammadi P, Hesari M, Chalabi M, Salari F, Khademi F. An overview of immune checkpoint therapy in autoimmune diseases. Int Immunopharmacol 2022; 107:108647. [DOI: 10.1016/j.intimp.2022.108647] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 02/17/2022] [Accepted: 02/20/2022] [Indexed: 02/06/2023]
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25
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Dunai C, Ames E, Ochoa MC, Fernandez-Sendin M, Melero I, Simonetta F, Baker J, Alvarez M. Killers on the loose: Immunotherapeutic strategies to improve NK cell-based therapy for cancer treatment. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 370:65-122. [PMID: 35798507 DOI: 10.1016/bs.ircmb.2022.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Natural killer (NK) cells are innate lymphocytes that control tumor progression by not only directly killing cancer cells, but also by regulating other immune cells, helping to orchestrate a coordinated anti-tumor response. However, despite the tremendous potential that this cell type has, the clinical results obtained from diverse NK cell-based immunotherapeutic strategies have been, until recent years, rather modest. The intrinsic regulatory mechanisms that are involved in the control of their activation as well as the multiple mechanisms that tumor cells have developed to escape NK cell-mediated cytotoxicity likely account for the unsatisfactory clinical outcomes. The current approaches to improve long-term NK cell function are centered on modulating different molecules involved in both the activation and inhibition of NK cells, and the latest data seems to advocate for combining strategies that target multiple aspects of NK cell regulation. In this review, we summarize the different strategies (such as engineered NK cells, CAR-NK, NK cell immune engagers) that are currently being used to take advantage of this potent and complex immune cell.
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Affiliation(s)
- Cordelia Dunai
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom
| | - Erik Ames
- Department of Pathology, Stanford University, Stanford, CA, United States
| | - Maria C Ochoa
- Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Myriam Fernandez-Sendin
- Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Ignacio Melero
- Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain
| | - Federico Simonetta
- Division of Hematology, Department of Oncology, Geneva University Hospitals, Geneva, Switzerland; Translational Research Centre in Onco-Haematology, Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Jeanette Baker
- Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, United States
| | - Maite Alvarez
- Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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26
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Glez-Vaz J, Azpilikueta A, Olivera I, Cirella A, Teijeira A, Ochoa MC, Alvarez M, Eguren-Santamaria I, Luri-Rey C, Rodriguez-Ruiz ME, Nie X, Chen L, Guedan S, Sanamed MF, Luis Perez Gracia J, Melero I. Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies. J Immunother Cancer 2022; 10:jitc-2021-003532. [PMID: 35236742 PMCID: PMC8896037 DOI: 10.1136/jitc-2021-003532] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2022] [Indexed: 11/30/2022] Open
Abstract
Background On the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic. Methods We used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression. Results CD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137. Conclusion sCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents.
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Affiliation(s)
- Javier Glez-Vaz
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Arantza Azpilikueta
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Irene Olivera
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Assunta Cirella
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Departments of Immunology-Immunotherapy and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Alvaro Teijeira
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Maria C Ochoa
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Departments of Immunology-Immunotherapy and Oncology, Clínica Universidad de Navarra, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Maite Alvarez
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Departments of Immunology-Immunotherapy and Oncology, Clínica Universidad de Navarra, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Iñaki Eguren-Santamaria
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Carlos Luri-Rey
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Maria E Rodriguez-Ruiz
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Departments of Immunology-Immunotherapy and Oncology, Clínica Universidad de Navarra, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Xinxin Nie
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Lieping Chen
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.,Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut, USA
| | - Sonia Guedan
- Department of Hematology and Oncology, Hospital Clinic. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Miguel F Sanamed
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Departments of Immunology-Immunotherapy and Oncology, Clínica Universidad de Navarra, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Jose Luis Perez Gracia
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Departments of Immunology-Immunotherapy and Oncology, Clínica Universidad de Navarra, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain .,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Departments of Immunology-Immunotherapy and Oncology, Clínica Universidad de Navarra, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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27
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Fuchs S, Scheffschick A, Gunnarsson I, Brauner H. Natural Killer Cells in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - A Review of the Literature. Front Immunol 2022; 12:796640. [PMID: 35116030 PMCID: PMC8805084 DOI: 10.3389/fimmu.2021.796640] [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: 10/17/2021] [Accepted: 12/20/2021] [Indexed: 01/22/2023] Open
Abstract
Anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis (AAV) is a group of systemic autoimmune diseases characterized by inflammation of small- and medium-sized vessels. The three main types of AAV are granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). A growing number of studies focus on natural killer (NK) cells in AAV. NK cells are innate lymphoid cells with important roles in anti-viral and anti-tumor defense, but their roles in the pathogenesis of autoimmunity is less well established. In this review, we will present a summary of what is known about the number, phenotype and function of NK cells in patients with AAV. We review the literature on NK cells in the circulation of AAV patients, studies on tissue resident NK cells and how the treatment affects NK cells.
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Affiliation(s)
- Sina Fuchs
- Division of Rheumatology, Department of Medicine, Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Andrea Scheffschick
- Division of Rheumatology, Department of Medicine, Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Iva Gunnarsson
- Division of Rheumatology, Department of Medicine, Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Hanna Brauner
- Division of Rheumatology, Department of Medicine, Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Dermato-Venereology, Karolinska University Hospital, Stockholm, Sweden
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28
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Angelo LS, Hogg GD, Abeynaike S, Bimler L, Vargas-Hernandez A, Paust S. Phenotypic and Functional Plasticity of CXCR6+ Peripheral Blood NK Cells. Front Immunol 2022; 12:810080. [PMID: 35173710 PMCID: PMC8841448 DOI: 10.3389/fimmu.2021.810080] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 12/28/2021] [Indexed: 12/23/2022] Open
Abstract
Human NK cells are comprised of phenotypic subsets, whose potentially unique functions remain largely unexplored. C-X-C-motif-chemokine-receptor-6 (CXCR6)+ NK cells have been identified as phenotypically immature tissue-resident NK cells in mice and humans. A small fraction of peripheral blood (PB)-NK cells also expresses CXCR6. However, prior reports about their phenotypic and functional plasticity are conflicting. In this study, we isolated, expanded, and phenotypically and functionally evaluated CXCR6+ and CXCR6– PB-NK cells, and contrasted results to bulk liver and spleen NK cells. We found that CXCR6+ and CXCR6– PB-NK cells preserved their distinct phenotypic profiles throughout 14 days of in vitro expansion (“day 14”), after which phenotypically immature CXCR6+ PB-NK cells became functionally equivalent to CXCR6– PB-NK cells. Despite a consistent reduction in CD16 expression and enhanced expression of the transcription factor Eomesodermin (Eomes), day 14 CXCR6+ PB-NK cells had superior antibody-dependent cellular cytotoxicity (ADCC) compared to CXCR6– PB-NK cells. Further, bulk liver NK cells responded to IL-15, but not IL-2 stimulation, with STAT-5 phosphorylation. In contrast, bulk splenic and PB-NK cells robustly responded to both cytokines. Our findings may allow for the selection of superior NK cell subsets for infusion products increasingly used to treat human diseases.
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Affiliation(s)
- Laura S. Angelo
- Center for Human Immunobiology, Department of Pediatrics, Texas Children’s Hospital, Houston, TX, United States
| | - Graham D. Hogg
- Center for Human Immunobiology, Department of Pediatrics, Texas Children’s Hospital, Houston, TX, United States
| | - Shawn Abeynaike
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States
| | - Lynn Bimler
- Center for Human Immunobiology, Department of Pediatrics, Texas Children’s Hospital, Houston, TX, United States
| | - Alexander Vargas-Hernandez
- Center for Human Immunobiology, Department of Pediatrics, Texas Children’s Hospital, Houston, TX, United States
| | - Silke Paust
- Center for Human Immunobiology, Department of Pediatrics, Texas Children’s Hospital, Houston, TX, United States
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States
- *Correspondence: Silke Paust,
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29
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Mahmoud AB, Ajina R, Aref S, Darwish M, Alsayb M, Taher M, AlSharif SA, Hashem AM, Alkayyal AA. Advances in immunotherapy for glioblastoma multiforme. Front Immunol 2022; 13:944452. [PMID: 36311781 PMCID: PMC9597698 DOI: 10.3389/fimmu.2022.944452] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 09/23/2022] [Indexed: 02/05/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor of the central nervous system and has a very poor prognosis. The current standard of care for patients with GBM involves surgical resection, radiotherapy, and chemotherapy. Unfortunately, conventional therapies have not resulted in significant improvements in the survival outcomes of patients with GBM; therefore, the overall mortality rate remains high. Immunotherapy is a type of cancer treatment that helps the immune system to fight cancer and has shown success in different types of aggressive cancers. Recently, healthcare providers have been actively investigating various immunotherapeutic approaches to treat GBM. We reviewed the most promising immunotherapy candidates for glioblastoma that have achieved encouraging results in clinical trials, focusing on immune checkpoint inhibitors, oncolytic viruses, nonreplicating viral vectors, and chimeric antigen receptor (CAR) immunotherapies.
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Affiliation(s)
- Ahmad Bakur Mahmoud
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- *Correspondence: Ahmad Bakur Mahmoud, ; Almohanad A. Alkayyal,
| | - Reham Ajina
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Sarah Aref
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Manar Darwish
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - May Alsayb
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - Mustafa Taher
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - Shaker A. AlSharif
- King Fahad Hospital, Ministry of Health, Almadinah Almunwarah, Saudi Arabia
| | - Anwar M. Hashem
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center; King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Almohanad A. Alkayyal
- Department of Medical Laboratory Technology, University of Tabuk, Tabuk, Saudi Arabia
- Immunology Research Program, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- *Correspondence: Ahmad Bakur Mahmoud, ; Almohanad A. Alkayyal,
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30
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Waibl Polania J, Lerner EC, Wilkinson DS, Hoyt-Miggelbrink A, Fecci PE. Pushing Past the Blockade: Advancements in T Cell-Based Cancer Immunotherapies. Front Immunol 2021; 12:777073. [PMID: 34868044 PMCID: PMC8636733 DOI: 10.3389/fimmu.2021.777073] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/01/2021] [Indexed: 12/11/2022] Open
Abstract
Successful cancer immunotherapies rely on a replete and functional immune compartment. Within the immune compartment, T cells are often the effector arm of immune-based strategies due to their potent cytotoxic capabilities. However, many tumors have evolved a variety of mechanisms to evade T cell-mediated killing. Thus, while many T cell-based immunotherapies, such as immune checkpoint inhibition (ICI) and chimeric antigen receptor (CAR) T cells, have achieved considerable success in some solid cancers and hematological malignancies, these therapies often fail in solid tumors due to tumor-imposed T cell dysfunctions. These dysfunctional mechanisms broadly include reduced T cell access into and identification of tumors, as well as an overall immunosuppressive tumor microenvironment that elicits T cell exhaustion. Therefore, novel, rational approaches are necessary to overcome the barriers to T cell function elicited by solid tumors. In this review, we will provide an overview of conventional immunotherapeutic strategies and the various barriers to T cell anti-tumor function encountered in solid tumors that lead to resistance. We will also explore a sampling of emerging strategies specifically aimed to bypass these tumor-imposed boundaries to T cell-based immunotherapies.
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Affiliation(s)
| | - Emily C Lerner
- Duke Medical School, Duke University Medical Center, Durham, NC, United States
| | - Daniel S Wilkinson
- Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
| | | | - Peter E Fecci
- Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
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31
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Immunoprofiling of 4-1BB Expression Predicts Outcome in Chronic Lymphocytic Leukemia (CLL). Diagnostics (Basel) 2021; 11:diagnostics11112041. [PMID: 34829391 PMCID: PMC8622208 DOI: 10.3390/diagnostics11112041] [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: 09/14/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/28/2022] Open
Abstract
Recent success of novel therapies has improved treatment of chronic lymphocytic leukemia (CLL) patients, but most of them still require several treatment regimes. To improve treatment choice, prognostic markers suitable for prediction of disease outcome are required. Several molecular/genetic markers have been established, but accessibility for the entirety of all patients is limited. We here evaluated the relevance of GITR/4-1BB as well as their ligands for the prognosis of CLL patients. Surface expression of GITR/GITRL and 4-1BB/4-1BBL was correlated with established prognostic markers. Next, we separated our patient population according to GITR/GITRL and 4-1BB/4-1BBL expression in groups with high/low expression levels and performed Kaplan-Meier analyses. Interestingly, no correlation was observed with the defined prognostic markers. Whereas no significant difference between high and low expression of GITR, GITRL and 4-1BBL was observed, high 4-1BB levels on leukemic cells were associated with significantly shorter survival. Thereby we identify 4-1BB as prognostic marker for CLL.
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32
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Masoumi E, Tahaghoghi-Hajghorbani S, Jafarzadeh L, Sanaei MJ, Pourbagheri-Sigaroodi A, Bashash D. The application of immune checkpoint blockade in breast cancer and the emerging role of nanoparticle. J Control Release 2021; 340:168-187. [PMID: 34743998 DOI: 10.1016/j.jconrel.2021.10.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/13/2022]
Abstract
Breast cancer is the most common malignancy in the female population with a high mortality rate. Despite the satisfying depth of studies evaluating the contributory role of immune checkpoints in this malignancy, few articles have reviewed the pros and cons of immune checkpoint blockades (ICBs). In the current review, we provide an overview of immune-related inhibitory molecules and also discuss the original data obtained from international research laboratories on the aberrant expression of T and non-T cell-associated immune checkpoints in breast cancer. Then, we especially focus on recent studies that utilized ICBs as the treatment strategy in breast cancer and provide their efficiency reports. As there are always costs and benefits, we discuss the limitations and challenges toward ICB therapy such as adverse events and drug resistance. In the last section, we allocate an overview of the recent data concerning the application of nanoparticle systems for cancer immunotherapy and propose that nano-based ICB approaches may overcome the challenges related to ICB therapy in breast cancer. In conclusion, it seems it is time for nanoscience to more rapidly move forward into clinical trials and illuminates the breast cancer treatment area with its potent features for the target delivery of ICBs.
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Affiliation(s)
- Elham Masoumi
- Department of Immunology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran; Student Research Committee, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Sahar Tahaghoghi-Hajghorbani
- Microbiology and Virology Research Center, Qaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Leila Jafarzadeh
- Department of Laboratory Science, Sirjan Faculty of Medical Science, Sirjan, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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33
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Cabo M, Santana-Hernández S, Costa-Garcia M, Rea A, Lozano-Rodríguez R, Ataya M, Balaguer F, Juan M, Ochoa MC, Menéndez S, Comerma L, Rovira A, Berraondo P, Albanell J, Melero I, López-Botet M, Muntasell A. CD137 Costimulation Counteracts TGFβ Inhibition of NK-cell Antitumor Function. Cancer Immunol Res 2021; 9:1476-1490. [PMID: 34580116 DOI: 10.1158/2326-6066.cir-21-0030] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 06/19/2021] [Accepted: 09/22/2021] [Indexed: 11/16/2022]
Abstract
Enhancing natural killer (NK) cell-based cancer immunotherapy by overcoming immunosuppression is an area of intensive research. Here, we have demonstrated that the anti-CD137 agonist urelumab can overcome TGFβ-mediated inhibition of human NK-cell proliferation and antitumor function. Transcriptomic, immunophenotypic, and functional analyses showed that CD137 costimulation modified the transcriptional program induced by TGFβ on human NK cells by rescuing their proliferation in response to IL2, preserving their expression of activating receptors (NKG2D) and effector molecules (granzyme B, IFNγ) while allowing the acquisition of tumor-homing/retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGFβ1 and CD137 agonist recovered CCL5 and IFNγ secretion and showed enhanced direct and antibody-dependent cytotoxicity upon restimulation with cancer cells. Trastuzumab treatment of fresh breast carcinoma-derived multicellular cultures induced CD137 expression on tumor-infiltrating CD16+ NK cells, enabling the action of urelumab, which fostered tumor-infiltrating NK cells and recapitulated the enhancement of CCL5 and IFNγ production. Bioinformatic analysis pointed to IFNG as the driver of the association between NK cells and clinical response to trastuzumab in patients with HER2-positive primary breast cancer, highlighting the translational relevance of the CD137 costimulatory axis for enhancing IFNγ production. Our data reveals CD137 as a targetable checkpoint for overturning TGFβ constraints on NK-cell antitumor responses.
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Affiliation(s)
- Mariona Cabo
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Sara Santana-Hernández
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | | | - Anna Rea
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Roberto Lozano-Rodríguez
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | | | - Francesc Balaguer
- Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Manel Juan
- Immunology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Maria C Ochoa
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Centro de Investigación Médica Aplicada (CIMA)-Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Navarra Institute of Health Research (IDISNA), Universidad de Navarra, Pamplona, Spain
| | - Silvia Menéndez
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Laura Comerma
- Pathology Department, Hospital del Mar, Barcelona, Spain
| | - Ana Rovira
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Oncology Department, Hospital del Mar, Barcelona, Spain
| | - Pedro Berraondo
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Centro de Investigación Médica Aplicada (CIMA)-Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Navarra Institute of Health Research (IDISNA), Universidad de Navarra, Pamplona, Spain
| | - Joan Albanell
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain.,Oncology Department, Hospital del Mar, Barcelona, Spain
| | - Ignacio Melero
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Centro de Investigación Médica Aplicada (CIMA)-Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Navarra Institute of Health Research (IDISNA), Universidad de Navarra, Pamplona, Spain.,Clínica Universitaria de Navarra, Pamplona, Spain
| | - Miguel López-Botet
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Aura Muntasell
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. .,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Universitat Autònoma de Barcelona, Barcelona, Spain
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34
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Mascarelli DE, Rosa RSM, Toscaro JM, Semionatto IF, Ruas LP, Fogagnolo CT, Lima GC, Bajgelman MC. Boosting Antitumor Response by Costimulatory Strategies Driven to 4-1BB and OX40 T-cell Receptors. Front Cell Dev Biol 2021; 9:692982. [PMID: 34277638 PMCID: PMC8277962 DOI: 10.3389/fcell.2021.692982] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 05/27/2021] [Indexed: 01/01/2023] Open
Abstract
Immunotherapy explores several strategies to enhance the host immune system’s ability to detect and eliminate cancer cells. The use of antibodies that block immunological checkpoints, such as anti–programed death 1/programed death 1 ligand and cytotoxic T-lymphocyte–associated protein 4, is widely recognized to generate a long-lasting antitumor immune response in several types of cancer. Evidence indicates that the elimination of tumors by T cells is the key for tumor control. It is well known that costimulatory and coinhibitory pathways are critical regulators in the activation of T cells. Besides blocking checkpoints inhibitors, the agonistic signaling on costimulatory molecules also plays an important role in T-cell activation and antitumor response. Therefore, molecules driven to costimulatory pathways constitute promising targets in cancer therapy. The costimulation of tumor necrosis factor superfamily receptors on lymphocytes surface may transduce signals that control the survival, proliferation, differentiation, and effector functions of these immune cells. Among the members of the tumor necrosis factor receptor superfamily, there are 4-1BB and OX40. Several clinical studies have been carried out targeting these molecules, with agonist monoclonal antibodies, and preclinical studies exploring their ligands and other experimental approaches. In this review, we discuss functional aspects of 4-1BB and OX40 costimulation, as well as the progress of its application in immunotherapies.
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Affiliation(s)
- Daniele E Mascarelli
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil.,Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil
| | - Rhubia S M Rosa
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil.,Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil
| | - Jessica M Toscaro
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil.,Medical School, University of Campinas (UNICAMP), Campinas, Brazil
| | - Isadora F Semionatto
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil.,Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil
| | - Luciana P Ruas
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil
| | - Carolinne T Fogagnolo
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil.,Medical School of Ribeirão Preto (FMRP), University of São Paulo, Ribeirão Preto, Brazil
| | - Gabriel C Lima
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil.,Pro Rectory of Graduation, University of São Paulo, São Paulo, Brazil
| | - Marcio C Bajgelman
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil.,Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil.,Medical School, University of Campinas (UNICAMP), Campinas, Brazil
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35
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Pourakbari R, Hajizadeh F, Parhizkar F, Aghebati-Maleki A, Mansouri S, Aghebati-Maleki L. Co-stimulatory agonists: An insight into the immunotherapy of cancer. EXCLI JOURNAL 2021; 20:1055-1085. [PMID: 34267616 PMCID: PMC8278219 DOI: 10.17179/excli2021-3522] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/17/2021] [Indexed: 12/14/2022]
Abstract
Immune checkpoint pathways consist of stimulatory pathways, which can function like a strong impulse to promote T helper cells or killer CD8+ cells activation and proliferation. On the other hand, inhibitory pathways keep self-tolerance of the immune response. Increasing immunological activity by stimulating and blocking these signaling pathways are recognized as immune checkpoint therapies. Providing the best responses of CD8+ T cell needs the activation of T cell receptor along with the co-stimulation that is generated via stimulatory checkpoint pathways ligation including Inducible Co-Stimulator (ICOS), CD40, 4-1BB, GITR, and OX40. In cancer, programmed cell death receptor-1 (PD-1), Programmed cell death ligand-1(PD-L1) and Cytotoxic T Lymphocyte-Associated molecule-4 (CTLA-4) are the most known inhibitory checkpoint pathways, which can hinder the immune responses which have specifically anti-tumor characteristics and attenuate T cell activation and also cytokine production. The use of antagonistic monoclonal antibodies (mAbs) that block CTLA-4 or PD-1 activation is used in a variety of malignancies. It has been reported that they can lead to an increase in T cells and thereby strengthen anti-tumor immunity. Agonists of stimulatory checkpoint pathways can induce strong immunologic responses in metastatic patients; however, for achieving long-lasting benefits for the wide range of patients, efficient combinatorial therapies are required. In the present review, we focus on the preclinical and basic research on the molecular and cellular mechanisms by which immune checkpoint inhibitor blockade or other approaches with co-stimulatory agonists work together to improve T-cell antitumor immunity.
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Affiliation(s)
- Ramin Pourakbari
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farnaz Hajizadeh
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Forough Parhizkar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Aghebati-Maleki
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanaz Mansouri
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Liu E, Ang SOT, Kerbauy L, Basar R, Kaur I, Kaplan M, Li L, Tong Y, Daher M, Ensley EL, Uprety N, Nunez Cortes AK, Yang RZ, Li Y, Shaim H, Reyes Silva F, Lin P, Mohanty V, Acharya S, Shanley M, Muniz-Feliciano L, Banerjee PP, Chen K, Champlin RE, Shpall EJ, Rezvani K. GMP-Compliant Universal Antigen Presenting Cells (uAPC) Promote the Metabolic Fitness and Antitumor Activity of Armored Cord Blood CAR-NK Cells. Front Immunol 2021; 12:626098. [PMID: 33717142 PMCID: PMC7952299 DOI: 10.3389/fimmu.2021.626098] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Natural killer (NK) cells are innate lymphocytes recognized for their important role against tumor cells. NK cells expressing chimeric antigen receptors (CARs) have enhanced effector function against various type of cancer and are attractive contenders for the next generation of cancer immunotherapies. However, a number of factors have hindered the application of NK cells for cellular therapy, including their poor in vitro growth kinetics and relatively low starting percentages within the mononuclear cell fraction of peripheral blood or cord blood (CB). To overcome these limitations, we genetically-engineered human leukocyte antigen (HLA)-A- and HLA-B- K562 cells to enforce the expression of CD48, 4-1BBL, and membrane-bound IL-21 (mbIL21), creating a universal antigen presenting cell (uAPC) capable of stimulating their cognate receptors on NK cells. We have shown that uAPC can drive the expansion of both non-transduced (NT) and CAR-transduced CB derived NK cells by >900-fold in 2 weeks of co-culture with excellent purity (>99.9%) and without indications of senescence/exhaustion. We confirmed that uAPC-expanded research- and clinical-grade NT and CAR-transduced NK cells have higher metabolic fitness and display enhanced effector function against tumor targets compared to the corresponding cell fractions cultured without uAPCs. This novel approach allowed the expansion of highly pure GMP-grade CAR NK cells at optimal cell numbers to be used for adoptive CAR NK cell-based cancer immunotherapy.
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Affiliation(s)
- Enli Liu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sonny O. T. Ang
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Lucila Kerbauy
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Departments of Stem Cell Transplantation and Hemotherapy/Cellular Therapy, Hospital Israelita Albert Einstein, Saõ Paulo, Brazil
- Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Biosciences Institute, University of Saõ Paulo, Saõ Paulo, Brazil
| | - Rafet Basar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Indreshpal Kaur
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mecit Kaplan
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Li Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Yijiu Tong
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - May Daher
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Emily L. Ensley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nadima Uprety
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ana Karen Nunez Cortes
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ryan Z. Yang
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ye Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Hila Shaim
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Francia Reyes Silva
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Paul Lin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Vakul Mohanty
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sunil Acharya
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mayra Shanley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Luis Muniz-Feliciano
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Pinaki P. Banerjee
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ken Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Richard E. Champlin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elizabeth J. Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Lee KY, Wong HY, Zeng Q, Le Lin J, Cheng MS, Kuick CH, Chang KTE, Loh AHP, Schwarz H. Ectopic CD137 expression by rhabdomyosarcoma provides selection advantages but allows immunotherapeutic targeting. Oncoimmunology 2021; 10:1877459. [PMID: 33643694 PMCID: PMC7872024 DOI: 10.1080/2162402x.2021.1877459] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 01/11/2021] [Accepted: 01/13/2021] [Indexed: 11/29/2022] Open
Abstract
Rhabdomyosarcoma (RMS) is a heterogeneous soft tissue neoplasm most frequently found in children and adolescents. As the prognosis for recurrent and metastatic RMS remains poor, immunotherapies are hoped to improve quality of life and survival. CD137 is a member of tumor necrosis factor receptor family and a T cell costimulatory molecule which induces potent cellular immune responses that are able to eliminate malignant cells. Therefore, it was puzzling to find expression of CD137 on an RMS tissue microarray by multiplex staining. CD137 is not only expressed by infiltrating T cells but also by malignant RMS cells. Functional in vitro experiments demonstrate that CD137 on RMS cells is being transferred to adjacent antigen-presenting cells by trogocytosis, where it downregulates CD137 ligand, and thereby reduces T cell costimulation which results in reduced killing of RMS cells. The transfer of CD137 and the subsequent downregulation of CD137 ligand is a physiological negative feedback mechanism that is likely usurped by RMS, and may facilitate its escape from immune surveillance. In addition, CD137 signals into RMS cells and induces IL-6 and IL-8 secretion, which are linked to RMS metastasis and poor prognosis. However, the ectopic expression of CD137 on RMS cells is an Achilles' heel that may be utilized for immunotherapy. Natural killer cells expressing an anti-CD137 chimeric antigen receptor specifically kill CD137-expressing RMS cells. Our study implicates ectopic CD137 expression as a pathogenesis mechanism in RMS, and it demonstrates that CD137 may be a novel target for immunotherapy of RMS.
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Affiliation(s)
- Kang Yi Lee
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore
| | - Hiu Yi Wong
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore
| | - Qun Zeng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore
| | - Jia Le Lin
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore
| | - Man Si Cheng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore
| | | | | | | | - Herbert Schwarz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore
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Mock J, Stringhini M, Villa A, Weller M, Weiss T, Neri D. An engineered 4-1BBL fusion protein with "activity on demand". Proc Natl Acad Sci U S A 2020; 117:31780-31788. [PMID: 33239441 PMCID: PMC7749310 DOI: 10.1073/pnas.2013615117] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Engineered cytokines are gaining importance in cancer therapy, but these products are often limited by toxicity, especially at early time points after intravenous administration. 4-1BB is a member of the tumor necrosis factor receptor superfamily, which has been considered as a target for therapeutic strategies with agonistic antibodies or using its cognate cytokine ligand, 4-1BBL. Here we describe the engineering of an antibody fusion protein, termed F8-4-1BBL, that does not exhibit cytokine activity in solution but regains biological activity on antigen binding. F8-4-1BBL bound specifically to its cognate antigen, the alternatively spliced EDA domain of fibronectin, and selectively localized to tumors in vivo, as evidenced by quantitative biodistribution experiments. The product promoted a potent antitumor activity in various mouse models of cancer without apparent toxicity at the doses used. F8-4-1BBL represents a prototype for antibody-cytokine fusion proteins, which conditionally display "activity on demand" properties at the site of disease on antigen binding and reduce toxicity to normal tissues.
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Affiliation(s)
- Jacqueline Mock
- Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), CH-8093 Zürich, Switzerland
| | - Marco Stringhini
- Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), CH-8093 Zürich, Switzerland
| | - Alessandra Villa
- Antibody Research, Philochem AG, CH-8112 Otelfingen, Switzerland
| | - Michael Weller
- Department of Neurology, University Hospital Zurich, University of Zurich, CH-8091 Zürich, Switzerland
| | - Tobias Weiss
- Department of Neurology, University Hospital Zurich, University of Zurich, CH-8091 Zürich, Switzerland
| | - Dario Neri
- Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), CH-8093 Zürich, Switzerland;
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Choi BK, Lee HW. The Murine CD137/CD137 Ligand Signalosome: A Signal Platform Generating Signal Complexity. Front Immunol 2020; 11:553715. [PMID: 33362756 PMCID: PMC7758191 DOI: 10.3389/fimmu.2020.553715] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 11/06/2020] [Indexed: 12/21/2022] Open
Abstract
CD137, a member of the TNFR family, is a costimulatory receptor, and CD137L, a member of the TNF family, is its ligand. Studies using CD137- and CD137L-deficient mice and antibodies against CD137 and CD137L have revealed the diverse and paradoxical effects of these two proteins in various cancers, autoimmunity, infections, and inflammation. Both their cellular diversity and their spatiotemporal expression patterns indicate that they mediate complex immune responses. This intricacy is further enhanced by the bidirectional signal transduction events that occur when these two proteins interact in various types of immune cells. Here, we review the biology of murine CD137/CD137L, particularly, the complexity of their proximal signaling pathways, and speculate on their roles in immune responses.
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Affiliation(s)
- Beom K Choi
- Biomedicine Production Branch, Program for Immunotherapy Research, National Cancer Center, Goyang, South Korea
| | - Hyeon-Woo Lee
- Department of Pharmacology, School of Dentistry, Graduate School, Institute of Oral Biology, Kyung Hee University, Seoul, South Korea
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Wong HY, Prasad A, Gan SU, Chua JJE, Schwarz H. Identification of CD137-Expressing B Cells in Multiple Sclerosis Which Secrete IL-6 Upon Engagement by CD137 Ligand. Front Immunol 2020; 11:571964. [PMID: 33240262 PMCID: PMC7677239 DOI: 10.3389/fimmu.2020.571964] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 10/12/2020] [Indexed: 12/21/2022] Open
Abstract
The potent costimulatory effect of CD137 has been implicated in several murine autoimmune disease models. CD137 costimulates and polarizes antigen-specific T cells toward a potent Th1/Tc1 response, and is essential for the development of experimental autoimmune encephalomyelitis (EAE), a murine model of Multiple Sclerosis (MS). This study aimed to investigate a role of CD137 in MS. Immunohistochemical and immunofluorescence staining of MS brain tissues was used to identify expression of CD137. CD137+ cells were identified in MS brain samples, with active lesions having the highest frequency of CD137+ cells. CD137 expression was found on several leukocyte subsets, including T cells, B cells and endothelial cells. In particular, CD137+ B cells were found in meningeal infiltrates. In vitro experiments showed that CD137 engagement on activated B cells increased early TNF and persistent IL-6 secretion with increased cell proliferation. These CD137+ B cells could interact with CD137L-expressing cells, secrete pro-inflammatory cytokines and accumulate in the meningeal infiltrate. This study demonstrates CD137 expression by activated B cells, enhancement of the inflammatory activity of B cells upon CD137 engagement, and provides evidence for a pathogenic role of CD137+ B cells in MS.
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Affiliation(s)
- Hiu Yi Wong
- Department of Physiology, National University of Singapore, Singapore, Singapore
- Immunology Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ankshita Prasad
- Institute for Health Innovation and Technology, National University of Singapore, Singapore, Singapore
| | - Shu Uin Gan
- Department of Surgery, National University of Singapore, Singapore, Singapore
| | - John Jia En Chua
- Department of Physiology, National University of Singapore, Singapore, Singapore
- Institute for Health Innovation and Technology, National University of Singapore, Singapore, Singapore
- LSI Neurobiology Programme, National University of Singapore, Singapore, Singapore
| | - Herbert Schwarz
- Department of Physiology, National University of Singapore, Singapore, Singapore
- Immunology Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Chauhan SKS, Koehl U, Kloess S. Harnessing NK Cell Checkpoint-Modulating Immunotherapies. Cancers (Basel) 2020; 12:E1807. [PMID: 32640575 PMCID: PMC7408278 DOI: 10.3390/cancers12071807] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 12/11/2022] Open
Abstract
During the host immune response, the precise balance of the immune system, regulated by immune checkpoint, is required to avoid infection and cancer. These immune checkpoints are the mainstream regulator of the immune response and are crucial for self-tolerance. During the last decade, various new immune checkpoint molecules have been studied, providing an attractive path to evaluate their potential role as targets for effective therapeutic interventions. Checkpoint inhibitors have mainly been explored in T cells until now, but natural killer (NK) cells are a newly emerging target for the determination of checkpoint molecules. Simultaneously, an increasing number of therapeutic dimensions have been explored, including modulatory and inhibitory checkpoint molecules, either causing dysfunction or promoting effector functions. Furthermore, the combination of the immune checkpoint with other NK cell-based therapeutic strategies could also strengthen its efficacy as an antitumor therapy. In this review, we have undertaken a comprehensive review of the literature to date regarding underlying mechanisms of modulatory and inhibitory checkpoint molecules.
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Affiliation(s)
| | - Ulrike Koehl
- Institute of cellular therapeutics, Hannover Medical School, 30625 Hannover, Germany; (U.K.); (S.K.)
- Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
- Institute of Clinical Immunology, University of Leipzig, 04103 Leipzig, Germany
| | - Stephan Kloess
- Institute of cellular therapeutics, Hannover Medical School, 30625 Hannover, Germany; (U.K.); (S.K.)
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Trüb M, Uhlenbrock F, Claus C, Herzig P, Thelen M, Karanikas V, Bacac M, Amann M, Albrecht R, Ferrara-Koller C, Thommen D, Rothschield S, Savic Prince S, Mertz KD, Cathomas G, Rosenberg R, Heinzelmann-Schwarz V, Wiese M, Lardinois D, Umana P, Klein C, Laubli H, Kashyap AS, Zippelius A. Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer. J Immunother Cancer 2020; 8:e000238. [PMID: 32616554 PMCID: PMC7333869 DOI: 10.1136/jitc-2019-000238] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The costimulatory receptor 4-1BB (CD137, TNFRSF9) plays an important role in sustaining effective T cell immune responses and is investigated as target for cancer therapy. Systemic 4-1BB directed therapies elicit toxicity or low efficacy, which significantly hampered advancement of 4-1BB-based immunotherapy. Therefore, targeted delivery of 4-1BB agonist to the tumor side is needed for eliciting antitumor efficacy while avoiding systemic toxicity. METHODS We analyzed the immunostimulatory properties of a fibroblast activation protein (FAP)-targeted 4-1BB agonist (FAP-4-1BBL) by assessing tumor-infiltrating lymphocytes' (TIL) activity from patients with non-small cell lung cancer and epithelial ovarian cancer. RESULTS Combination treatment with FAP-4-1BBL and T cell receptor stimulation by either anti-CD3 or T cell bispecific antibodies significantly enhanced TIL activation and effector functions, including T cell proliferation, secretion of proinflammatory cytokines and cytotoxicity. Notably, costimulation with FAP-4-1BBL led to de novo secretion of interleukin (IL)-13. This was associated with cytokine-mediated tumor cell apoptosis, which was partially dependent on IL-13 alpha 1/2 receptors and STAT6 phosphorylation. CONCLUSIONS Our study provides mechanistic insights into T cell stimulation induced by FAP-4-1BBL in primary human tumors and supports the investigation of FAP-4-1BBL compound in early clinical trials.
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Affiliation(s)
- Marta Trüb
- Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Franziska Uhlenbrock
- Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | | | - Petra Herzig
- Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Martin Thelen
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | | | - Marina Bacac
- Roche Innovation Center Zurich, Schlieren, Switzerland
| | - Maria Amann
- Roche Innovation Center Zurich, Schlieren, Switzerland
| | | | | | - Daniela Thommen
- Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | | | - Kirsten D Mertz
- Institute of Pathology, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland
| | - Gieri Cathomas
- Institute of Pathology, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland
| | - Robert Rosenberg
- Department of Surgery, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland
| | | | - Mark Wiese
- Division of Thoracic Surgery, University Hospital Basel, Basel, Switzerland
| | - Didier Lardinois
- Division of Thoracic Surgery, University Hospital Basel, Basel, Switzerland
| | - Pablo Umana
- Roche Innovation Center Zurich, Schlieren, Switzerland
| | | | - Heinz Laubli
- Medical Oncology, University Hospital Basel, Basel, Switzerland
| | - Abhishek S Kashyap
- Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
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Sievers NM, Dörrie J, Schaft N. CARs: Beyond T Cells and T Cell-Derived Signaling Domains. Int J Mol Sci 2020; 21:E3525. [PMID: 32429316 PMCID: PMC7279007 DOI: 10.3390/ijms21103525] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/08/2020] [Accepted: 05/13/2020] [Indexed: 02/06/2023] Open
Abstract
When optimizing chimeric antigen receptor (CAR) therapy in terms of efficacy, safety, and broadening its application to new malignancies, there are two main clusters of topics to be addressed: the CAR design and the choice of transfected cells. The former focuses on the CAR construct itself. The utilized transmembrane and intracellular domains determine the signaling pathways induced by antigen binding and thereby the cell-specific effector functions triggered. The main part of this review summarizes our understanding of common signaling domains employed in CARs, their interactions among another, and their effects on different cell types. It will, moreover, highlight several less common extracellular and intracellular domains that might permit unique new opportunities. Different antibody-based extracellular antigen-binding domains have been pursued and optimized to strike a balance between specificity, affinity, and toxicity, but these have been reviewed elsewhere. The second cluster of topics is about the cellular vessels expressing the CAR. It is essential to understand the specific attributes of each cell type influencing anti-tumor efficacy, persistence, and safety, and how CAR cells crosstalk with each other and bystander cells. The first part of this review focuses on the progress achieved in adopting different leukocytes for CAR therapy.
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Affiliation(s)
- Nico M. Sievers
- Department of Dermatology, Universtitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Hartmannstraße 14, 91052 Erlangen, Germany; (N.M.S.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Ulmenweg 18, 91054 Erlangen, Germany
| | - Jan Dörrie
- Department of Dermatology, Universtitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Hartmannstraße 14, 91052 Erlangen, Germany; (N.M.S.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Ulmenweg 18, 91054 Erlangen, Germany
| | - Niels Schaft
- Department of Dermatology, Universtitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Hartmannstraße 14, 91052 Erlangen, Germany; (N.M.S.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Ulmenweg 18, 91054 Erlangen, Germany
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Harvey JB, Phan LH, Villarreal OE, Bowser JL. CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers. Front Immunol 2020; 11:508. [PMID: 32351498 PMCID: PMC7174602 DOI: 10.3389/fimmu.2020.00508] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
CD73, a cell surface 5'nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.
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Affiliation(s)
- Jerry B. Harvey
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Luan H. Phan
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Oscar E. Villarreal
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jessica L. Bowser
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
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Comprehensive analysis of tumor necrosis factor receptor TNFRSF9 (4-1BB) DNA methylation with regard to molecular and clinicopathological features, immune infiltrates, and response prediction to immunotherapy in melanoma. EBioMedicine 2020; 52:102647. [PMID: 32028068 PMCID: PMC6997575 DOI: 10.1016/j.ebiom.2020.102647] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 01/16/2020] [Accepted: 01/16/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Immunotherapy, including checkpoint inhibition, has remarkably improved prognosis in advanced melanoma. Despite this success, acquired resistance is still a major challenge. The T cell costimulatory receptor TNFRSF9 (also known as 4-1BB and CD137) is a promising new target for immunotherapy and two agonistic antibodies are currently tested in clinical trials. However, little is known about epigenetic regulation of the encoding gene. In this study we investigate a possible correlation of TNFRSF9 DNA methylation with gene expression, clinicopathological parameters, molecular and immune correlates, and response to anti-PD-1 immunotherapy to assess the validity of TNFRSF9 methylation to serve as a biomarker. METHODS We performed a correlation analyses of methylation at twelve CpG sites within TNFRSF9 with regard to transcriptional activity, immune cell infiltration, mutation status, and survival in a cohort of N = 470 melanoma patients obtained from The Cancer Genome Atlas. Furthermore, we used quantitative methylation-specific PCR to confirm correlations in a cohort of N = 115 melanoma patients' samples (UHB validation cohort). Finally, we tested the ability of TNFRSF9 methylation and expression to predict progression-free survival (PFS) and response to anti-PD-1 immunotherapy in a cohort comprised of N = 121 patients (mRNA transcription), (mRNA ICB cohort) and a case-control study including N = 48 patients (DNA methylation, UHB ICB cohort). FINDINGS We found a significant inverse correlation between TNFRSF9 DNA methylation and mRNA expression levels at six of twelve analyzed CpG sites (P ≤ 0.005), predominately located in the promoter flank region. Consistent with its role as costimulatory receptor in immune cells, TNFRSF9 mRNA expression and hypomethylation positively correlated with immune cell infiltrates and an interferon-γ signature. Furthermore, elevated TNFRSF9 mRNA expression and TNFRSF9 hypomethylation correlated with superior overall survival. In patients receiving anti-PD-1 immunotherapy (mRNA ICB cohort), we found that TNFRSF9 hypermethylation and reduced mRNA expression correlated with poor PFS and response. INTERPRETATION Our study suggests that TNFRSF9 mRNA expression is regulated via DNA methylation. The observed correlations between TNFRSF9 DNA methylation or mRNA expression with known features of response to immune checkpoint blockage suggest TNFRSF9 methylation could serve as a biomarker in the context of immunotherapies. Concordantly, we identified a correlation between TNFRSF9 DNA methylation and mRNA expression with disease progression in patients under immunotherapy. Our study provides rationale for further investigating TNFRSF9 DNA methylation as a predictive biomarker for response to immunotherapy. FUNDING AF was partly funded by the Mildred Scheel Foundation. SF received funding from the University Hospital Bonn BONFOR program (O-105.0069). DN was funded in part by DFG Cluster of Excellence ImmunoSensation (EXC 1023). The funders had no role in study design, data collection and analysis, interpretation, decision to publish, or preparation of the manuscript; or any aspect pertinent to the study.
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Liao P, Wang H, Tang YL, Tang YJ, Liang XH. The Common Costimulatory and Coinhibitory Signaling Molecules in Head and Neck Squamous Cell Carcinoma. Front Immunol 2019; 10:2457. [PMID: 31708918 PMCID: PMC6819372 DOI: 10.3389/fimmu.2019.02457] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 10/01/2019] [Indexed: 02/05/2023] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are closely linked with immunosuppression, accompanied by complex immune cell functional activities. The abnormal competition between costimulatory and coinhibitory signal molecules plays an important role in the malignant progression of HNSCC. This review will summarize the features of costimulatory molecules (including CD137, OX40 as well as CD40) and coinhibitory molecules (including CTLA-4, PD-1, LAG3, and TIM3), analyze the underlying mechanism behind these molecules' regulation of the progression of HNSCC, and introduce the clinic application. Vaccines, such as those targeting STING while working synergistically with monoclonal antibodies, are also discussed. A deep understanding of the tumor immune landscape will help find new and improved tumor immunotherapy for HNSCC.
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Affiliation(s)
- Peng Liao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Haofan Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Jie Tang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Zeng Q, Zhou Y, Schwarz H. CD137L-DCs, Potent Immune-Stimulators-History, Characteristics, and Perspectives. Front Immunol 2019; 10:2216. [PMID: 31632390 PMCID: PMC6783506 DOI: 10.3389/fimmu.2019.02216] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 09/02/2019] [Indexed: 12/31/2022] Open
Abstract
Dendritic cell (DC)-based immunotherapies are being explored for over 20 years and found to be very safe. Most often, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4)-induced monocyte-derived DCs (moDCs) are being used, which have demonstrated some life-prolonging benefit to patients of multiple tumors. However, the limited clinical response and efficacy call for the development of more potent DCs. CD137L-DC may meet this demand. CD137L-DCs are a novel type of monocyte-derived inflammatory DCs that are induced by CD137 ligand (CD137L) agonists. CD137L is expressed on the surface of antigen-presenting cells, including monocytes, and signaling of CD137L into monocytes induces their differentiation to CD137L-DCs. CD137L-DCs preferentially induce type 1 T helper (Th1) cell polarization and strong type 1 CD8+ T cell (Tc1) responses against tumor-associated viral antigens. The in vitro T cell-stimulatory capacity of CD137L-DCs is superior to that of conventional moDCs. The transcriptomic profile of CD137L-DC is highly similar to that of in vivo DCs at sites of inflammation. The strict activation dependence of CD137 expression and its restricted expression on activated T cells, NK cells, and vascular endothelial cells at inflammatory sites make CD137 an ideally suited signal for the induction of monocyte-derived inflammatory DCs in vivo. These findings and their potency encouraged a phase I clinical trial of CD137L-DCs against Epstein-Barr virus-associated nasopharyngeal carcinoma. In this review, we introduce and summarize the history, the characteristics, and the transcriptional profile of CD137L-DC, and discuss the potential development and applications of CD137L-DC.
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Affiliation(s)
- Qun Zeng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Yubin Zhou
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Herbert Schwarz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
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Vidard L, Dureuil C, Baudhuin J, Vescovi L, Durand L, Sierra V, Parmantier E. CD137 (4-1BB) Engagement Fine-Tunes Synergistic IL-15- and IL-21-Driven NK Cell Proliferation. THE JOURNAL OF IMMUNOLOGY 2019; 203:676-685. [PMID: 31201235 DOI: 10.4049/jimmunol.1801137] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 05/27/2019] [Indexed: 12/22/2022]
Abstract
To understand and dissect the mechanisms driving human NK cell proliferation, we exploited the methodology used in cell therapy to numerically expand NK cells in the presence of K562-derived artificial APC (aAPCs) and cytokines. For four consecutive weeks, high expression of CD137L by a K562-derived aAPC cell line could sustain NK cell expansion by 3 × 105-fold, whereas low expression of CD137L by the parental K562 cell line only supported the expansion by 2 × 103-fold. The level of expression of CD137L, however, did not modulate the sensitivity of K562 cells to the intrinsic cytotoxicity of NK cells. Similarly, the low NK cell proliferation in the presence of the parental K562 cell line and cytokines was increased by adding agonistic anti-CD137 Abs to levels similar to CD137L-expressing K562-derived aAPCs. Finally, synergy between IL-15 and IL-21 was observed only upon CD137 engagement and the presence of aAPCs. Therefore, we conclude that NK cell proliferation requires cell-to-cell contact, activation of the CD137 axis, and presence of IL-15 (or its membranous form) and IL-21. By analogy with the three-signal model required to activate T cells, we speculate that the cell-to-cell contact represents "signal 1," CD137 represents "signal 2," and cytokines represent "signal 3." The precise nature of signal 1 remains to be defined.
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Affiliation(s)
- Laurent Vidard
- Department of Immuno-Oncology, Sanofi, 94403 Vitry-sur-Seine, France
| | - Christine Dureuil
- Department of Immuno-Oncology, Sanofi, 94403 Vitry-sur-Seine, France
| | - Jérémy Baudhuin
- Department of Immuno-Oncology, Sanofi, 94403 Vitry-sur-Seine, France
| | - Lionel Vescovi
- Department of Immuno-Oncology, Sanofi, 94403 Vitry-sur-Seine, France
| | - Laurence Durand
- Department of Immuno-Oncology, Sanofi, 94403 Vitry-sur-Seine, France
| | - Véronique Sierra
- Department of Immuno-Oncology, Sanofi, 94403 Vitry-sur-Seine, France
| | - Eric Parmantier
- Department of Immuno-Oncology, Sanofi, 94403 Vitry-sur-Seine, France
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Hinner MJ, Aiba RSB, Jaquin TJ, Berger S, Dürr MC, Schlosser C, Allersdorfer A, Wiedenmann A, Matschiner G, Schüler J, Moebius U, Rothe C, Matis L, Olwill SA. Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343. Clin Cancer Res 2019; 25:5878-5889. [DOI: 10.1158/1078-0432.ccr-18-3654] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 03/14/2019] [Accepted: 05/22/2019] [Indexed: 11/16/2022]
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Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity. Nat Commun 2019; 10:2141. [PMID: 31105267 PMCID: PMC6526162 DOI: 10.1038/s41467-019-10088-1] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 04/15/2019] [Indexed: 11/09/2022] Open
Abstract
Costimulation of T cell responses with monoclonal antibody agonists (mAb-AG) targeting 4-1BB showed robust anti-tumor activity in preclinical models, but their clinical development was hampered by low efficacy (Utomilumab) or severe liver toxicity (Urelumab). Here we show that isotype and intrinsic agonistic strength co-determine the efficacy and toxicity of anti-4-1BB mAb-AG. While intrinsically strong agonistic anti-4-1BB can activate 4-1BB in the absence of FcγRs, weak agonistic antibodies rely on FcγRs to activate 4-1BB. All FcγRs can crosslink anti-41BB antibodies to strengthen co-stimulation, but activating FcγR-induced antibody-dependent cell-mediated cytotoxicity compromises anti-tumor immunity by deleting 4-1BB+ cells. This suggests balancing agonistic activity with the strength of FcγR interaction as a strategy to engineer 4-1BB mAb-AG with optimal therapeutic performance. As a proof of this concept, we have developed LVGN6051, a humanized 4-1BB mAb-AG that shows high anti-tumor efficacy in the absence of liver toxicity in a mouse model of cancer immunotherapy. Agonistic 4-1BB antibodies developed for cancer immunotherapy have suffered from either hepatotoxicity or insufficient anti-cancer activity. Here the authors determine the contribution of FcγR binding and agonistic strength to these outcomes, and engineer a 4-1BB antibody with potent anti-tumor effect and no liver toxicity in mice.
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