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Imani S, Jabbarzadeh Kaboli P, Babaeizad A, Maghsoudloo M. Neoantigen mRNA vaccines and A 2A receptor antagonism: A strategy to enhance T cell immunity. Hum Vaccin Immunother 2025; 21:2458936. [PMID: 39882781 PMCID: PMC11784654 DOI: 10.1080/21645515.2025.2458936] [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: 12/05/2024] [Revised: 01/19/2025] [Accepted: 01/23/2025] [Indexed: 01/31/2025] Open
Abstract
Although neo-antigen mRNA vaccines are promising for personalized cancer therapy, their effectiveness is often limited by the immunosuppressive tumor microenvironment (TME). The adenosine A2A receptor (A2AR) inhibits dendritic cell (DC) function and weakens antitumor T cell responses through hypoxia-driven mechanisms within the TME. This review explores a novel strategy combining neo-antigen mRNA vaccines with A2AR antagonists (A2ARi). By targeting A2AR, this approach reduces TME-induced immunosuppression, enhances DC activation, and improves neo-antigen presentation. The review also discusses lipid nanoparticles (LNPs) to co-deliver A2ARi and mRNA vaccines, optimizing their effectiveness. The integration of neo-antigen mRNA-LNPs with A2ARi modulation offers a promising strategy to overcome immunosuppression, stimulate DC activation, and achieve precise anti-tumor responses with minimal off-target effects. This synergy represents significant progress in cancer immunotherapy, advancing the potential for personalized neoantigen therapies.
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Affiliation(s)
- Saber Imani
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang, China
| | | | - Ali Babaeizad
- Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Mazaher Maghsoudloo
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
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2
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Schiele P, Japp AS, Stark R, Sattelberg JJ, Nikolaou C, Kornhuber G, Abbasi P, Ding N, Rosnev S, Meinke S, Mühle K, Loyal L, Braun J, Dingeldey M, Durlanik S, Matzmohr N, Ponikwicka-Tyszko D, Wolczynski S, Rahman NA, Taniuchi I, Schlickeiser S, Giesecke-Thiel C, Blankenstein T, Na IK, Thiel A, Frentsch M. CD8 + T cell-derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells. SCIENCE ADVANCES 2025; 11:eadr9331. [PMID: 40397730 DOI: 10.1126/sciadv.adr9331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 04/17/2025] [Indexed: 05/23/2025]
Abstract
T cells and their effector functions, in particular the canonical cytotoxicity of CD8+ T cells involving perforin, granzymes, Fas ligand (FasL), and tumor necrosis factor related apoptosis inducing ligand (TRAIL), are crucial for tumor immunity. Here, we reveal a previously unidentified mechanism by which CD40L-expressing CD8+ T cells induce cytotoxicity in cancer cells. In murine models, up to 50% of tumor-specific CD8+ T cells expressed CD40L, and conditional CD40L ablation in CD8+ T cells alone led to tumor formation. Mechanistically, CD40L+CD8+ T cells can induce cell death in CD40-expressing cancer cells by triggering caspase-8 activation. We demonstrate that a gene signature for resistance to CD40 signaling-induced cell death strongly correlates with worse survival in different human cancer cohorts. Our results introduce CD40L as a rather counterintuitive, noncanonical cytotoxic factor that complements the capabilities of CD8+ T cells to combat cancers and has the potential to enhance the efficacy of immunotherapies.
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Affiliation(s)
- Phillip Schiele
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Alberto Sada Japp
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Captain T Cell GmbH, 12529 Berlin, Germany
| | - Regina Stark
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Tissue Immunology, BIH Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Joanna J Sattelberg
- Max-Delbrück-Center for Molecular Medicine and Institute for Immunology, Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany
| | - Christos Nikolaou
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Gereon Kornhuber
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Parya Abbasi
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Nina Ding
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Stanislav Rosnev
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Stefan Meinke
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Kerstin Mühle
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Lucie Loyal
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Julian Braun
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Manuela Dingeldey
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Sibel Durlanik
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Nadine Matzmohr
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Donata Ponikwicka-Tyszko
- Institute of Biomedicine, University of Turku, 20520 Turku, Finland
- Department of Biology and Pathology of Human Reproduction, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-748 Olsztyn, Poland
| | - Slawomir Wolczynski
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, 15-276 Bialystok, Poland
| | - Nafis A Rahman
- Institute of Biomedicine, University of Turku, 20520 Turku, Finland
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, 15-276 Bialystok, Poland
| | - Ichiro Taniuchi
- RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan
| | - Stephan Schlickeiser
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate members of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | | | - Thomas Blankenstein
- Max-Delbrück-Center for Molecular Medicine and Institute for Immunology, Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany
| | - Il-Kang Na
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Hematology, Oncology and Tumor Immunology, and ECRC Experimental and Clinical Research Center, both Charité-Universitätsmedizin Berlin, Corporate members of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Berlin, Germany
- ECRC Experimental and Clinical Research Center, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Thiel
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Marco Frentsch
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
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3
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Jimenez J, Amrute J, Ma P, Wang X, Das S, Dai R, Komaru Y, Herrlich A, Mack M, Lavine KJ. The immune checkpoint regulator CD40 potentiates myocardial inflammation. NATURE CARDIOVASCULAR RESEARCH 2025; 4:458-472. [PMID: 40217124 DOI: 10.1038/s44161-025-00633-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 03/05/2025] [Indexed: 04/15/2025]
Abstract
Immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here we leverage genetic mouse models, single-cell sequencing and cell depletion studies to show that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2+ macrophages and subsequent recruitment of effector memory CD8+ T cells. We identify a positive feedback loop between CCR2+ macrophages (positive for the chemokine receptor CCR2) and CD8+ T cells driven by IL-12b, TNF and IFNγ signaling that promotes myocardial inflammation and show that previous exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates left ventricular remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.
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Affiliation(s)
- Jesus Jimenez
- Center for Cardiovascular Research, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA
- Cardio-Oncology Center of Excellence, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA
| | - Junedh Amrute
- Center for Cardiovascular Research, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA
| | - Pan Ma
- Center for Cardiovascular Research, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA
| | - Xiaoran Wang
- Center for Cardiovascular Research, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA
| | - Shibali Das
- Center for Cardiovascular Research, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Yohei Komaru
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- John Cochran Division, VA Saint Louis Health Care System, St. Louis, MO, USA
| | - Andreas Herrlich
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- John Cochran Division, VA Saint Louis Health Care System, St. Louis, MO, USA
| | - Matthias Mack
- Division of Nephrology, Department of Medicine, University Hospital Regensburg, Regensburg, Germany
| | - Kory J Lavine
- Center for Cardiovascular Research, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
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4
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Szwed M, Jost T, Majka E, Gharibkandi NA, Majkowska-Pilip A, Frey B, Bilewicz A, Fietkau R, Gaipl U, Marczak A, Lubgan D. Pt-Au Nanoparticles in Combination with Near-Infrared-Based Hyperthermia Increase the Temperature and Impact on the Viability and Immune Phenotype of Human Hepatocellular Carcinoma Cells. Int J Mol Sci 2025; 26:1574. [PMID: 40004038 PMCID: PMC11855494 DOI: 10.3390/ijms26041574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/30/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Near-infrared light (NIR)-responsive metal-based nanoparticles (NPs) could be used for tumour therapy. We examined how platinum (Pt), gold (Au), and core-shell Pt-Au NPs affect the viability of human hepatocellular carcinoma (HCC) cell lines (Hep3B, HepG2, and Huh7D-12) alone and in combination with NIR exposure. In addition, the expression of immune checkpoint molecules (ICMs) on the tumour cells was analysed. We revealed that the cytotoxicity and programmed cell death induction of Au and Pt-Au NPs toward HCC cells could be enhanced by NIR with 960 nm in a different way. Pt-Au NPs were the only particles that resulted in an additional temperature increase of up to 2 °C after NIR. Regarding the tumour cell immune phenotype, not all of the cells experienced changes in immune phenotype. NIR itself was the trigger of the alterations, while the NPs did not significantly affect the expression of most of the examined ICMs, such as PD-L1, PD-L1, HVEM, CD70, ICOS-L, Ox40-L, and TNFRSF9. The combination of Pt-Au NPs with NIR resulted in the most prominent increase of ICMs in HepG2 cells. We conclude that the thermotherapeutic effect of Pt-Au NP application and NIR could be beneficial in multimodal therapy settings in liver cancer for selected patients.
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Affiliation(s)
- Marzena Szwed
- Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
| | - Tina Jost
- Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany; (T.J.); (B.F.); (U.G.); (D.L.)
- Comprehensive Cancer Center Erlangen-EMN, D-91054 Erlangen, Germany;
- Department of Radiation Oncology, Universitatsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Emilia Majka
- Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland; (E.M.); (N.A.G.); (A.M.-P.); (A.B.)
| | - Nasrin Abbasi Gharibkandi
- Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland; (E.M.); (N.A.G.); (A.M.-P.); (A.B.)
| | - Agnieszka Majkowska-Pilip
- Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland; (E.M.); (N.A.G.); (A.M.-P.); (A.B.)
| | - Benjamin Frey
- Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany; (T.J.); (B.F.); (U.G.); (D.L.)
- Comprehensive Cancer Center Erlangen-EMN, D-91054 Erlangen, Germany;
- Department of Radiation Oncology, Universitatsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie, D-91054 Erlangen, Germany
- FAU Profile Center Immunomedicine (FAU I-MED), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Aleksander Bilewicz
- Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland; (E.M.); (N.A.G.); (A.M.-P.); (A.B.)
| | - Rainer Fietkau
- Comprehensive Cancer Center Erlangen-EMN, D-91054 Erlangen, Germany;
- Department of Radiation Oncology, Universitatsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie, D-91054 Erlangen, Germany
- FAU Profile Center Immunomedicine (FAU I-MED), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Udo Gaipl
- Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany; (T.J.); (B.F.); (U.G.); (D.L.)
- Comprehensive Cancer Center Erlangen-EMN, D-91054 Erlangen, Germany;
- Department of Radiation Oncology, Universitatsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie, D-91054 Erlangen, Germany
- FAU Profile Center Immunomedicine (FAU I-MED), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Agnieszka Marczak
- Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
| | - Dorota Lubgan
- Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany; (T.J.); (B.F.); (U.G.); (D.L.)
- Comprehensive Cancer Center Erlangen-EMN, D-91054 Erlangen, Germany;
- Department of Radiation Oncology, Universitatsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie, D-91054 Erlangen, Germany
- FAU Profile Center Immunomedicine (FAU I-MED), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, D-91054 Erlangen, Germany
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5
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Ramadan E, Ahmed A, Naguib YW. Advances in mRNA LNP-Based Cancer Vaccines: Mechanisms, Formulation Aspects, Challenges, and Future Directions. J Pers Med 2024; 14:1092. [PMID: 39590584 PMCID: PMC11595619 DOI: 10.3390/jpm14111092] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 10/25/2024] [Accepted: 10/31/2024] [Indexed: 11/28/2024] Open
Abstract
After the COVID-19 pandemic, mRNA-based vaccines have emerged as a revolutionary technology in immunization and vaccination. These vaccines have shown remarkable efficacy against the virus and opened up avenues for their possible application in other diseases. This has renewed interest and investment in mRNA vaccine research and development, attracting the scientific community to explore all its other applications beyond infectious diseases. Recently, researchers have focused on the possibility of adapting this vaccination approach to cancer immunotherapy. While there is a huge potential, challenges still remain in the design and optimization of the synthetic mRNA molecules and the lipid nanoparticle delivery system required to ensure the adequate elicitation of the immune response and the successful eradication of tumors. This review points out the basic mechanisms of mRNA-LNP vaccines in cancer immunotherapy and recent approaches in mRNA vaccine design. This review displays the current mRNA modifications and lipid nanoparticle components and how these factors affect vaccine efficacy. Furthermore, this review discusses the future directions and clinical applications of mRNA-LNP vaccines in cancer treatment.
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Affiliation(s)
- Eslam Ramadan
- Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, H-6720 Szeged, Hungary;
- Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
| | - Ali Ahmed
- Department of Clinical Pharmacy, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;
| | - Youssef Wahib Naguib
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA
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Alam MS, Gaida MM, Witzel HR, Otsuka S, Abbasi A, Guerin T, Abdelmaksoud A, Wong N, Cam MC, Kozlov S, Ashwell JD. TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function. Cell Rep Med 2024; 5:101696. [PMID: 39178856 PMCID: PMC11528236 DOI: 10.1016/j.xcrm.2024.101696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/28/2024] [Accepted: 07/30/2024] [Indexed: 08/26/2024]
Abstract
Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DCs). Here, we find that genetic ablation or antibody blockade of tumor necrosis factor receptor 1 (TNFR1) enhanced intratumor T cell activation and slowed PDAC growth. While anti-PD-1 checkpoint inhibition alone had little effect, it further enhanced intratumor T cell activation in combination with anti-TNFR1. The major cellular alteration in the tumor microenvironment in the absence of TNFR1 signaling was a large increase in DC number and immunostimulatory phenotype. This may reflect a direct effect on DCs, because TNF induced TNFR1-dependent apoptosis of bone-marrow-derived DCs. The therapeutic response to anti-TNFR1 alone was superior to the combination of DC-activating agonistic anti-CD40 and Flt3 ligand (Flt3L). These observations suggest that targeting TNFR1, perhaps in concert with other strategies that promote DC generation and mobilization, may have therapeutic benefits.
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Affiliation(s)
- Muhammad S Alam
- Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Matthias M Gaida
- Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany; TRON, Translational Oncology at the University Medical Center, JGU-Mainz, 55131 Mainz, Germany; Research Center for Immunotherapy, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany
| | - Hagen R Witzel
- Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany
| | - Shizuka Otsuka
- Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Aamna Abbasi
- Department of Integrative Immunobiology, Duke University, Durham, NC 27708, USA
| | - Theresa Guerin
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21707, USA
| | - Abdalla Abdelmaksoud
- Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Nathan Wong
- Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Margaret C Cam
- Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Serguei Kozlov
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21707, USA
| | - Jonathan D Ashwell
- Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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7
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Cheng W, Huang Z, Hao Y, Hua H, Zhang B, Li X, Fu F, Yang J, Zheng K, Zhang X, Qi C. The engineered agonistic anti-CD40 antibody potentiates the antitumor effects of β-glucan by resetting TAMs. Immunol Lett 2024; 268:106882. [PMID: 38810887 DOI: 10.1016/j.imlet.2024.106882] [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: 12/12/2023] [Revised: 05/05/2024] [Accepted: 05/26/2024] [Indexed: 05/31/2024]
Abstract
Anti-CD40 antibodies (Abs) have been shown to induce antitumor T-cell responses. We reported that the engineered agonistic anti-CD40 Ab (5C11, IgG4 isotype) recognized human CD40 antigen expressed on a human B lymphoblastoid cell line as well as on splenic cells isolated from humanized CD40 mice. Of note, a single high dosage of 5C11 was able to prohibit tumor growth in parallel with an increase in the population of infiltrated CD8+ T cells. Furthermore, the antitumor effects of 5C11 were enhanced in the presence of β-glucan along with an increase in the population of infiltrated CD8+ T cells. In addition, the numbers of CD86+ TAMs and neutrophils were elevated in the combination of 5C11 and β-glucan compared with either 5C11 or β-glucan alone. Furthermore, the abundance of Faecalibaculum, one of the probiotics critical for tumor suppression, was obviously increased in the combination of 5C11 and β-glucan-treated mice. These data reveal a novel mechanism of tumor suppression upon the combination treatment of 5C11 and β-glucan and propose that the combination treatment of agonistic anti-human CD40 antibody 5C11 and β-glucan could be a promising therapeutic strategy for cancer patients.
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Affiliation(s)
- Wanpeng Cheng
- Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Ziyi Huang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China; Jiangsu Provincial Medical Key Discipline, Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Gastrointestinal tumor Immunology, The First Affiliated Hospital of Soochow University, 178 Ganjiang Road, Suzhou, China
| | - Yongzhe Hao
- Laboratory of Oncology, Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China
| | - Hui Hua
- Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Bo Zhang
- Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiangyang Li
- Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fengqing Fu
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China; Jiangsu Provincial Medical Key Discipline, Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Gastrointestinal tumor Immunology, The First Affiliated Hospital of Soochow University, 178 Ganjiang Road, Suzhou, China
| | - Jing Yang
- Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Kuiyang Zheng
- Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China; Jiangsu Provincial Medical Key Discipline, Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Gastrointestinal tumor Immunology, The First Affiliated Hospital of Soochow University, 178 Ganjiang Road, Suzhou, China.
| | - Chunjian Qi
- Laboratory of Oncology, Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China.
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8
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Rachayon M, Jirakran K, Sodsai P, Sughondhabirom A, Maes M. T cell activation and deficits in T regulatory cells are associated with major depressive disorder and severity of depression. Sci Rep 2024; 14:11177. [PMID: 38750122 PMCID: PMC11096341 DOI: 10.1038/s41598-024-61865-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 05/10/2024] [Indexed: 05/18/2024] Open
Abstract
Major depressive disorder (MDD) is associated with T cell activation, but no studies have examined the combined effects of T cell activation and deficits in T regulatory (Treg) cells on the severity of acute phase MDD. Using flow cytometry, we determined the percentage and median fluorescence intensity of CD69, CD71, CD40L, and HLADR-bearing CD3+, CD4+, and CD8+ cells, and cannabinoid type 1 receptor (CB1), CD152 and GARP (glycoprotein A repetitions predominant)-bearing CD25+ FoxP3 T regulatory (Treg) cells in 30 MDD patients and 20 healthy controls in unstimulated and stimulated (anti-CD3/CD28) conditions. Based on cytokine levels, we assessed M1 macrophage, T helper (Th)-1 cell, immune-inflammatory response system (IRS), T cell growth, and neurotoxicity immune profiles. We found that the immune profiles (including IRS and neurotoxicity) were significantly predicted by decreased numbers of CD152 or GARP-bearing CD25+ FoxP3 cells or CD152 and GARP expression in combination with increases in activated T cells (especially CD8+ CD40L+ percentage and expression). MDD patients showed significantly increased numbers of CD3+ CD71+, CD3+ CD40L+, CD4+ CD71+, CD4+ CD40L+, CD4+ HLADR+, and CD8+ HLADR+ T cells, increased CD3+ CD71+, CD4+ CD71+ and CD4+ HLADR+ expression, and lowered CD25+ FoxP3 expression and CD25+ FoxP+ CB1+ numbers as compared with controls. The Hamilton Depression Rating Scale score was strongly predicted (between 30 and 40% of its variance) by a lower number of CB1 or GARP-bearing Treg cells and one or more activated T cell subtypes (especially CD8+ CD40L+). In conclusion, increased T helper and cytotoxic cell activation along with decreased Treg homeostatic defenses are important parts of MDD that lead to enhanced immune responses and, as a result, neuroimmunotoxicity.
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Affiliation(s)
- Muanpetch Rachayon
- Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Ketsupar Jirakran
- Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Pediatrics, Faculty of Medicine, Center of Excellence for Maximizing Children's Developmental Potential, Chulalongkorn University, Bangkok, Thailand
| | - Pimpayao Sodsai
- Department of Microbiology, Faculty of Medicine, Center of Excellence in Immunology and Immune-Mediated Diseases, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand
| | - Atapol Sughondhabirom
- Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Chulalongkorn University, Bangkok, 10330, Thailand.
- Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
- Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, 610072, China.
- Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Korea.
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.
- Research Institute, Medical University Plovdiv, Plovdiv, Bulgaria.
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9
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Lim SH, Beers SA, Al-Shamkhani A, Cragg MS. Agonist Antibodies for Cancer Immunotherapy: History, Hopes, and Challenges. Clin Cancer Res 2024; 30:1712-1723. [PMID: 38153346 PMCID: PMC7615925 DOI: 10.1158/1078-0432.ccr-23-1014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/31/2023] [Accepted: 12/11/2023] [Indexed: 12/29/2023]
Abstract
Immunotherapy is among the most promising new treatment modalities to arise over the last two decades; antibody drugs are delivering immunotherapy to millions of patients with many different types of cancer. Initial success with antibody therapeutics came in the form of direct targeting or cytotoxic antibodies, such as rituximab and trastuzumab, which bind directly to tumor cells to elicit their destruction. These were followed by immunomodulatory antibodies that elicit antitumor responses by either stimulating immune cells or relieving tumor-mediated suppression. By far the most successful approach in the clinic to date has been relieving immune suppression, with immune checkpoint blockade now a standard approach in the treatment of many cancer types. Despite equivalent and sometimes even more impressive effects in preclinical models, agonist antibodies designed to stimulate the immune system have lagged behind in their clinical translation. In this review, we document the main receptors that have been targeted by agonist antibodies, consider the various approaches that have been evaluated to date, detail what we have learned, and consider how their anticancer potential can be unlocked.
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Affiliation(s)
- Sean H. Lim
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, SO16 6YD, UK
| | - Stephen A. Beers
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, SO16 6YD, UK
| | - Aymen Al-Shamkhani
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, SO16 6YD, UK
| | - Mark S. Cragg
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, SO16 6YD, UK
- Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
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10
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Jimenez J, Amrute J, Ma P, Wang X, Dai R, Lavine KJ. CD40 is an immune checkpoint regulator that potentiates myocardial inflammation through activation and expansion of CCR2 + macrophages and CD8 T-cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.14.584418. [PMID: 38559055 PMCID: PMC10980053 DOI: 10.1101/2024.03.14.584418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Novel immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here, we leveraged genetic mouse models, single cell sequencing, and cell depletion studies to demonstrate that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2 + macrophages and subsequent recruitment of effector memory CD8 T-cells. We identify a positive feedback loop between CCR2 + macrophages and CD8 T-cells driven by IL12b, TNF, and IFN-γ signaling that promotes myocardial inflammation and show that prior exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates LV remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.
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11
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Liu Y, Huang Y, Cui HW, Wang Y, Ma Z, Xiang Y, Xin HY, Liang JQ, Xin HW. Perspective view of allogeneic IgG tumor immunotherapy. Cancer Cell Int 2024; 24:100. [PMID: 38461238 PMCID: PMC10924995 DOI: 10.1186/s12935-024-03290-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 03/01/2024] [Indexed: 03/11/2024] Open
Abstract
Allogeneic tumors are eradicated by host immunity; however, it is unknown how it is initiated until the report in Nature by Yaron Carmi et al. in 2015. Currently, we know that allogeneic tumors are eradicated by allogeneic IgG via dendritic cells. AlloIgG combined with the dendritic cell stimuli tumor necrosis factor alpha and CD40L induced tumor eradication via the reported and our proposed potential signaling pathways. AlloIgG triggers systematic immune responses targeting multiple antigens, which is proposed to overcome current immunotherapy limitations. The promising perspectives of alloIgG immunotherapy would have advanced from mouse models to clinical trials; however, there are only 6 published articles thus far. Therefore, we hope this perspective view will provide an initiative to promote future discussion.
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Affiliation(s)
- Ying Liu
- Department of Radiology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, 434000, Hubei, China
- Laboratory of Oncology, School of Basic Medicine, Center for Molecular Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Yuanyi Huang
- Department of Radiology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, 434000, Hubei, China
| | - Hong-Wei Cui
- Center for Breast Cancer, Peking University Cancer Hospital at Inner Mongolia Campus and Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, 010021, Inner Mongolia, China
| | - YingYing Wang
- Division of Life Sciences and Medicine, Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China
| | - ZhaoWu Ma
- Laboratory of Oncology, School of Basic Medicine, Center for Molecular Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Ying Xiang
- Laboratory of Oncology, School of Basic Medicine, Center for Molecular Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Hong-Yi Xin
- The Doctoral Scientific Research Center, People's Hospital of Lianjiang, Guangdong, 524400, China.
- The Doctoral Scientific Research Center, People's Hospital of Lianjiang, Guangdong Medical University, Guangdong, 524400, China.
| | - Jun-Qing Liang
- Center for Breast Cancer, Peking University Cancer Hospital at Inner Mongolia Campus and Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, 010021, Inner Mongolia, China.
| | - Hong-Wu Xin
- Laboratory of Oncology, School of Basic Medicine, Center for Molecular Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China.
- Key Laboratory of Human Genetic Diseases Research of Inner Mongolia, Research Centre of Molecular Medicine, Medical College of Chifeng University, Chifeng, 024000, Inner Mongolian Autonomous Region, China.
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12
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Sasso J, Tenchov R, Bird R, Iyer KA, Ralhan K, Rodriguez Y, Zhou QA. The Evolving Landscape of Antibody-Drug Conjugates: In Depth Analysis of Recent Research Progress. Bioconjug Chem 2023; 34:1951-2000. [PMID: 37821099 PMCID: PMC10655051 DOI: 10.1021/acs.bioconjchem.3c00374] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/27/2023] [Indexed: 10/13/2023]
Abstract
Antibody-drug conjugates (ADCs) are targeted immunoconjugate constructs that integrate the potency of cytotoxic drugs with the selectivity of monoclonal antibodies, minimizing damage to healthy cells and reducing systemic toxicity. Their design allows for higher doses of the cytotoxic drug to be administered, potentially increasing efficacy. They are currently among the most promising drug classes in oncology, with efforts to expand their application for nononcological indications and in combination therapies. Here we provide a detailed overview of the recent advances in ADC research and consider future directions and challenges in promoting this promising platform to widespread therapeutic use. We examine data from the CAS Content Collection, the largest human-curated collection of published scientific information, and analyze the publication landscape of recent research to reveal the exploration trends in published documents and to provide insights into the scientific advances in the area. We also discuss the evolution of the key concepts in the field, the major technologies, and their development pipelines with company research focuses, disease targets, development stages, and publication and investment trends. A comprehensive concept map has been created based on the documents in the CAS Content Collection. We hope that this report can serve as a useful resource for understanding the current state of knowledge in the field of ADCs and the remaining challenges to fulfill their potential.
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Affiliation(s)
- Janet
M. Sasso
- CAS,
A Division of the American Chemical Society, Columbus, Ohio 43210, United States
| | - Rumiana Tenchov
- CAS,
A Division of the American Chemical Society, Columbus, Ohio 43210, United States
| | - Robert Bird
- CAS,
A Division of the American Chemical Society, Columbus, Ohio 43210, United States
| | | | | | - Yacidzohara Rodriguez
- CAS,
A Division of the American Chemical Society, Columbus, Ohio 43210, United States
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13
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Xie L, Fang J, Yu J, Zhang W, He Z, Ye L, Wang H. The role of CD4 + T cells in tumor and chronic viral immune responses. MedComm (Beijing) 2023; 4:e390. [PMID: 37829505 PMCID: PMC10565399 DOI: 10.1002/mco2.390] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 09/06/2023] [Accepted: 09/12/2023] [Indexed: 10/14/2023] Open
Abstract
Immunotherapies are mainly aimed to promote a CD8+ T cell response rather than a CD4+ T cell response as cytotoxic T lymphocytes (CTLs) can directly kill target cells. Recently, CD4+ T cells have received more attention due to their diverse roles in tumors and chronic viral infections. In antitumor and antichronic viral responses, CD4+ T cells relay help signals through dendritic cells to indirectly regulate CD8+ T cell response, interact with B cells or macrophages to indirectly modulate humoral immunity or macrophage polarization, and inhibit tumor blood vessel formation. Additionally, CD4+ T cells can also exhibit direct cytotoxicity toward target cells. However, regulatory T cells exhibit immunosuppression and CD4+ T cells become exhausted, which promote tumor progression and chronic viral persistence. Finally, we also outline immunotherapies based on CD4+ T cells, including adoptive cell transfer, vaccines, and immune checkpoint blockade. Overall, this review summarizes diverse roles of CD4+ T cells in the antitumor or protumor and chronic viral responses, and also highlights the immunotherapies based on CD4+ T cells, giving a better understanding of their roles in tumors and chronic viral infections.
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Affiliation(s)
- Luoyingzi Xie
- Institute of Hepatopancreatobiliary SurgeryChongqing General HospitalChongqingChina
- The Institute of ImmunologyThird Military Medical University (Army Medical University)ChongqingChina
| | - Jingyi Fang
- The Institute of ImmunologyThird Military Medical University (Army Medical University)ChongqingChina
| | - Juncheng Yu
- Department of Thoracic SurgeryXinqiao Hospital Third Military Medical University (Army Medical University)ChongqingChina
| | - Weinan Zhang
- Department of Plastic & Cosmetic SurgeryArmy Medical Center of PLAAmy Medical UniversityChongqingChina
| | - Zhiqiang He
- Department of Plastic & Cosmetic SurgeryArmy Medical Center of PLAAmy Medical UniversityChongqingChina
| | - Lilin Ye
- The Institute of ImmunologyThird Military Medical University (Army Medical University)ChongqingChina
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary SurgeryChongqing General HospitalChongqingChina
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14
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Lin HJ, Liu Y, Caroland K, Lin J. Polarization of Cancer-Associated Macrophages Maneuver Neoplastic Attributes of Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:3507. [PMID: 37444617 DOI: 10.3390/cancers15133507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/01/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Mounting evidence links the phenomenon of enhanced recruitment of tumor-associated macrophages towards cancer bulks to neoplastic growth, invasion, metastasis, immune escape, matrix remodeling, and therapeutic resistance. In the context of cancer progression, naïve macrophages are polarized into M1 or M2 subtypes according to their differentiation status, gene signatures, and functional roles. While the former render proinflammatory and anticancer effects, the latter subpopulation elicits an opposite impact on pancreatic ductal adenocarcinoma. M2 macrophages have gained increasing attention as they are largely responsible for molding an immune-suppressive landscape. Through positive feedback circuits involving a paracrine manner, M2 macrophages can be amplified by and synergized with neighboring neoplastic cells, fibroblasts, endothelial cells, and non-cell autonomous constituents in the microenvironmental niche to promote an advanced disease state. This review delineates the molecular cues expanding M2 populations that subsequently convey notorious clinical outcomes. Future therapeutic regimens shall comprise protocols attempting to abolish environmental niches favoring M2 polarization; weaken cancer growth typically assisted by M2; promote the recruitment of tumoricidal CD8+ T lymphocytes and dendritic cells; and boost susceptibility towards gemcitabine as well as other chemotherapeutic agents.
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Affiliation(s)
- Huey-Jen Lin
- Department of Medical & Molecular Sciences, University of Delaware, Willard Hall Education Building, 16 West Main Street, Newark, DE 19716, USA
| | - Yingguang Liu
- Department of Molecular and Cellular Sciences, College of Osteopathic Medicine, Liberty University, 306 Liberty View Lane, Lynchburg, VA 24502, USA
| | - Kailey Caroland
- Department of Biochemistry and Molecular Biology, Molecular Medicine Graduate Program, Greenebaum Comprehensive Cancer Center, School of Medicine, University of Maryland, 108 N. Greene Street, Baltimore, MD 21201, USA
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, Molecular Medicine Graduate Program, Greenebaum Comprehensive Cancer Center, School of Medicine, University of Maryland, 108 N. Greene Street, Baltimore, MD 21201, USA
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15
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Yan X, Ols S, Arcoverde Cerveira R, Lenart K, Hellgren F, Ye K, Cagigi A, Buggert M, Nimmerjahn F, Falkesgaard Højen J, Parera D, Pessara U, Fischer S, Loré K. Cell targeting and immunostimulatory properties of a novel Fcγ-receptor-independent agonistic anti-CD40 antibody in rhesus macaques. Cell Mol Life Sci 2023; 80:189. [PMID: 37353664 PMCID: PMC10289945 DOI: 10.1007/s00018-023-04828-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 05/11/2023] [Accepted: 06/01/2023] [Indexed: 06/25/2023]
Abstract
Targeting CD40 by agonistic antibodies used as vaccine adjuvants or for cancer immunotherapy is a strategy to stimulate immune responses. The majority of studied agonistic anti-human CD40 antibodies require crosslinking of their Fc region to inhibitory FcγRIIb to induce immune stimulation although this has been associated with toxicity in previous studies. Here we introduce an agonistic anti-human CD40 monoclonal IgG1 antibody (MAB273) unique in its specificity to the CD40L binding site of CD40 but devoid of Fcγ-receptor binding. We demonstrate rapid binding of MAB273 to B cells and dendritic cells resulting in activation in vitro on human cells and in vivo in rhesus macaques. Dissemination of fluorescently labeled MAB273 after subcutaneous administration was found predominantly at the site of injection and specific draining lymph nodes. Phenotypic cell differentiation and upregulation of genes associated with immune activation were found in the targeted tissues. Antigen-specific T cell responses were enhanced by MAB273 when given in a prime-boost regimen and for boosting low preexisting responses. MAB273 may therefore be a promising immunostimulatory adjuvant that warrants future testing for therapeutic and prophylactic vaccination strategies.
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Affiliation(s)
- Xianglei Yan
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Visionsgatan 4, BioClinicum J7:30, 171 64, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Sebastian Ols
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Visionsgatan 4, BioClinicum J7:30, 171 64, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Rodrigo Arcoverde Cerveira
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Visionsgatan 4, BioClinicum J7:30, 171 64, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Klara Lenart
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Visionsgatan 4, BioClinicum J7:30, 171 64, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Fredrika Hellgren
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Visionsgatan 4, BioClinicum J7:30, 171 64, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Kewei Ye
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Visionsgatan 4, BioClinicum J7:30, 171 64, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Alberto Cagigi
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Visionsgatan 4, BioClinicum J7:30, 171 64, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Marcus Buggert
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Falk Nimmerjahn
- Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Jesper Falkesgaard Højen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | | | | | | | - Karin Loré
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Visionsgatan 4, BioClinicum J7:30, 171 64, Stockholm, Sweden.
- Center of Molecular Medicine, Stockholm, Sweden.
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16
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Coveler AL, Smith DC, Phillips T, Curti BD, Goel S, Mehta AN, Kuzel TM, Markovic SN, Rixe O, Bajor DL, Gajewski TF, Gutierrez M, Lee HJ, Gopal AK, Caimi P, Heath EI, Thompson JA, Ansari S, Jacquemont C, Topletz-Erickson A, Zhou P, Schmitt MW, Grilley-Olson JE. Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas. J Immunother Cancer 2023; 11:e005584. [PMID: 37385724 PMCID: PMC10314623 DOI: 10.1136/jitc-2022-005584] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/26/2023] [Indexed: 07/01/2023] Open
Abstract
BACKGROUND SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. METHODS SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. RESULTS A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. CONCLUSIONS SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. TRIAL REGISTRATION NUMBER NCT02376699.
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Affiliation(s)
- Andrew L Coveler
- Fred Hutchinson Cancer Center, Seattle, Washington, USA
- University of Washington, Seattle, Washington, USA
| | | | | | | | - Sanjay Goel
- Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA
| | | | | | | | - Olivier Rixe
- The University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, USA
| | - David L Bajor
- Case Western Reserve University, Cleveland, Ohio, USA
- University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | | | - Martin Gutierrez
- Hackensack University Medical Center, Hackensack, New Jersey, USA
| | - Hun Ju Lee
- The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ajay K Gopal
- Fred Hutchinson Cancer Center, Seattle, Washington, USA
- University of Washington, Seattle, Washington, USA
| | - Paolo Caimi
- Case Western Reserve University, Cleveland, Ohio, USA
- University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | | | - John A Thompson
- Fred Hutchinson Cancer Center, Seattle, Washington, USA
- University of Washington, Seattle, Washington, USA
| | | | | | | | | | | | - Juneko E Grilley-Olson
- Duke Cancer Institute, Durham, North Carolina, USA
- Duke University, Durham, North Carolina, USA
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Parker S, McDowall C, Sanchez-Perez L, Osorio C, Duncker PC, Briley A, Swartz AM, Herndon JE, Yu YRA, McLendon RE, Tedder TF, Desjardins A, Ashley DM, Gunn MD, Enterline DS, Knorr DA, Pastan IH, Nair SK, Bigner DD, Chandramohan V. Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models. Sci Transl Med 2023; 15:eabn5649. [PMID: 36753564 PMCID: PMC10440725 DOI: 10.1126/scitranslmed.abn5649] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/17/2023] [Indexed: 02/10/2023]
Abstract
D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a single intratumoral injection of D2C7-IT+αCD40 treatment activated a proinflammatory phenotype in microglia and macrophages, promoted long-term tumor-specific CD8+ T cell immunity, and generated cures. D2C7-IT+αCD40 treatment increased intratumoral Slamf6+CD8+ T cells with a progenitor phenotype and decreased terminally exhausted CD8+ T cells. D2C7-IT+αCD40 treatment stimulated intratumoral CD8+ T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. Tumor transcriptome profiling established CD40 up-regulation, pattern recognition receptor, cell senescence, and immune response pathway activation as the drivers of D2C7-IT+αCD40 antitumor responses. To determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase 1 study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.
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Affiliation(s)
- Scott Parker
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Charlotte McDowall
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Luis Sanchez-Perez
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Cristina Osorio
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA
| | | | - Aaron Briley
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Adam M Swartz
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - James E Herndon
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA
| | - Yen-Rei A Yu
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Roger E McLendon
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA
- Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
| | - Thomas F Tedder
- Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
| | - Annick Desjardins
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA
| | - David M Ashley
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA
- Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
| | - Michael Dee Gunn
- Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
- Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
- Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
| | - David S Enterline
- Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA
| | - David A Knorr
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ira H Pastan
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Smita K Nair
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
- Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
| | - Darell D Bigner
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA
- Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
| | - Vidyalakshmi Chandramohan
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA
- Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
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18
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Pfefferlé M, Dubach IL, Buzzi RM, Dürst E, Schulthess-Lutz N, Baselgia L, Hansen K, Imhof L, Koernig S, Le Roy D, Roger T, Humar R, Schaer DJ, Vallelian F. Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity. J Immunother Cancer 2023; 11:e005718. [PMID: 36593065 PMCID: PMC9809320 DOI: 10.1136/jitc-2022-005718] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/01/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Agonistic anti-CD40 monoclonal antibodies (mAbs) have emerged as promising immunotherapeutic compounds with impressive antitumor effects in mouse models. However, preclinical and clinical studies faced dose-limiting toxicities mediated by necroinflammatory liver disease. An effective prophylactic treatment for liver immune-related adverse events that does not suppress specific antitumor immunity remains to be found. METHODS We used different mouse models and time-resolved single-cell RNA-sequencing to characterize the pathogenesis of anti-CD40 mAb induced liver toxicity. Subsequently, we developed an antibody-based treatment protocol to selectively target red blood cells (RBCs) for erythrophagocytosis in the liver, inducing an anti-inflammatory liver macrophage reprogramming. RESULTS We discovered that CD40 signaling in Clec4f+ Kupffer cells is the non-redundant trigger of anti-CD40 mAb-induced liver toxicity. Taking advantage of the highly specific functionality of liver macrophages to clear antibody-tagged RBCs from the blood, we hypothesized that controlled erythrophagocytosis and the linked anti-inflammatory signaling by the endogenous metabolite heme could be exploited to reprogram liver macrophages selectively. Repeated low-dose administration of a recombinant murine Ter119 antibody directed RBCs for selective phagocytosis in the liver and skewed the phenotype of liver macrophages into a Hmoxhigh/Marcohigh/MHCIIlow anti-inflammatory phenotype. This unique mode of action prevented necroinflammatory liver disease following high-dose administration of anti-CD40 mAbs. In contrast, extrahepatic inflammation, antigen-specific immunity, and antitumor activity remained unaffected in Ter119 treated animals. CONCLUSIONS Our study offers a targeted approach to uncouple CD40-augmented antitumor immunity in peripheral tissues from harmful inflammatoxicity in the liver.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Sandra Koernig
- CSL Ltd., Research, Bio21 Institute, Parkville, Victoria, Australia
| | | | | | - Rok Humar
- University of Zurich, Zurich, Switzerland
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19
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Mao C, Beiss V, Ho GW, Fields J, Steinmetz NF, Fiering S. In situ vaccination with cowpea mosaic virus elicits systemic antitumor immunity and potentiates immune checkpoint blockade. J Immunother Cancer 2022; 10:e005834. [PMID: 36460333 PMCID: PMC9723958 DOI: 10.1136/jitc-2022-005834] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND In situ vaccination (ISV) is a cancer immunotherapy strategy in which immunostimulatory reagents are introduced directly into a tumor to stimulate antitumor immunity both against the treated tumor and systemically against untreated tumors. Recently, we showed that cowpea mosaic virus (CPMV) is a potent multi-toll-like receptor (TLR) agonist with potent efficacy for treating tumors in mice and dogs by ISV. However, ISV with CPMV alone does not uniformly treat all mouse tumor models tested, however this can be overcome through strategic combinations. More insight is needed to delineate potency and mechanism of systemic antitumor immunity and abscopal effect. METHOD We investigated the systemic efficacy (abscopal effect) of CPMV ISV with a two-tumor mouse model using murine tumor lines B16F10, 4T1, CT26 and MC38. Flow cytometry identified changes in cell populations responsible for systemic efficacy of CPMV. Transgenic knockout mice and depleting antibodies validated the role of relevant candidate cell populations and cytokines. We evaluated these findings and engineered a multicomponent combination therapy to specifically target the candidate cell population and investigated its systemic efficacy, acquired resistance and immunological memory in mouse models. RESULTS ISV with CPMV induces systemic antitumor T-cell-mediated immunity that inhibits growth of untreated tumors and requires conventional type-1 dendritic cells (cDC1s). Furthermore, using multiple tumor mouse models resistant to anti-programmed death 1 (PD-1) therapy, we tested the hypothesis that CPMV along with local activation of antigen-presenting cells with agonistic anti-CD40 can synergize and strengthen antitumor efficacy. Indeed, this combination ISV strategy induces an influx of CD8+ T cells, triggers regression in both treated local and untreated distant tumors and potentiates tumor responses to anti-PD-1 therapy. Moreover, serial ISV overcomes resistance to anti-PD-1 therapy and establishes tumor-specific immunological memory. CONCLUSIONS These findings provide new insights into in situ TLR activation and cDC1 recruitment as effective strategies to overcome resistance to immunotherapy in treated and untreated tumors.
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Affiliation(s)
- Chenkai Mao
- Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USA
| | - Veronique Beiss
- Bioengineering, University of California San Diego, La Jolla, California, USA
| | - Gregory W Ho
- Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USA
| | - Jennifer Fields
- Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USA
| | - Nicole F Steinmetz
- Department of Biomedical Engineering, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Steven Fiering
- Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USA
- Geisel School of Medicine at Dartmouth, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire, USA
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20
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Melssen MM, Fisher CT, Slingluff CL, Melief CJM. Peptide emulsions in incomplete Freund's adjuvant create effective nurseries promoting egress of systemic CD4 + and CD8 + T cells for immunotherapy of cancer. J Immunother Cancer 2022; 10:jitc-2022-004709. [PMID: 36939214 PMCID: PMC9472143 DOI: 10.1136/jitc-2022-004709] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2022] [Indexed: 11/26/2022] Open
Abstract
Water-in-oil emulsion incomplete Freund's adjuvant (IFA) has been used as an adjuvant in preventive and therapeutic vaccines since its development. New generation, highly purified modulations of the adjuvant, Montanide incomplete seppic adjuvant (ISA)-51 and Montanide ISA-720, were developed to reduce toxicity. Montanide adjuvants are generally considered to be safe, with adverse events largely consisting of antigen and adjuvant dose-dependent injection site reactions (ISRs). Peptide vaccines in Montanide ISA-51 or ISA-720 are capable of inducing both high antibody titers and durable effector T cell responses. However, an efficient T cell response depends on the affinity of the peptide to the presenting major histocompatibility complex class I molecule, CD4+ T cell help and/or the level of co-stimulation. In fact, in the therapeutic cancer vaccine setting, presence of a CD4+ T cell epitope seems crucial to elicit a robust and durable systemic T cell response. Additional inclusion of a Toll-like receptor ligand can further increase the magnitude and durability of the response. Use of extended peptides that need a processing step only accomplished effectively by dendritic cells (DCs) can help to avoid antigen presentation by nucleated cells other than DC. Based on recent clinical trial results, therapeutic peptide-based cancer vaccines using emulsions in adjuvant Montanide ISA-51 can elicit robust antitumor immune responses, provided that sufficient tumor-specific CD4+ T cell help is given in addition to CD8+ T cell epitopes. Co-treatment with PD-1 T cell checkpoint inhibitor, chemotherapy or other immunomodulatory drugs may address local and systemic immunosuppressive mechanisms, and further enhance efficacy of therapeutic cancer peptide vaccines in IFA and its modern variants. Blinded randomized placebo-controlled trials are critical to definitively prove clinical efficacy. Mineral oil-based adjuvants for preventive vaccines, to tackle spread and severity of infectious disease, induce immune responses, but require more studies to reduce toxicity.
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Affiliation(s)
- Marit M Melssen
- Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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21
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Sellars MC, Wu CJ, Fritsch EF. Cancer vaccines: Building a bridge over troubled waters. Cell 2022; 185:2770-2788. [PMID: 35835100 PMCID: PMC9555301 DOI: 10.1016/j.cell.2022.06.035] [Citation(s) in RCA: 170] [Impact Index Per Article: 56.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/19/2022] [Accepted: 06/17/2022] [Indexed: 12/16/2022]
Abstract
Cancer vaccines aim to direct the immune system to eradicate cancer cells. Here we review the essential immunologic concepts underpinning natural immunity and highlight the multiple unique challenges faced by vaccines targeting cancer. Recent technological advances in mass spectrometry, neoantigen prediction, genetically and pharmacologically engineered mouse models, and single-cell omics have revealed new biology, which can help to bridge this divide. We particularly focus on translationally relevant aspects, such as antigen selection and delivery and the monitoring of human post-vaccination responses, and encourage more aggressive exploration of novel approaches.
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Affiliation(s)
- MacLean C Sellars
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
| | - Edward F Fritsch
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Salomon R, Dahan R. Next Generation CD40 Agonistic Antibodies for Cancer Immunotherapy. Front Immunol 2022; 13:940674. [PMID: 35911742 PMCID: PMC9326085 DOI: 10.3389/fimmu.2022.940674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/21/2022] [Indexed: 12/05/2022] Open
Abstract
The clinical use of anti-CD40 agonist monoclonal antibodies (mAbs) is aimed at recruiting the immune system to fight the tumor cells. This approach has been demonstrated to be effective in various preclinical models. However, human CD40 Abs displayed only modest antitumor activity in cancer patients, characterized by low efficacy and dose-limiting toxicity. While recent studies highlight the importance of engineering the Fc region of human CD40 mAbs to optimize their agonistic potency, toxicity remains the main limiting factor, restricting clinical application to suboptimal doses. Here, we discuss the current challenges in realizing the full potential of CD40 mAbs in clinical practice, and describe novel approaches designed to circumvent the systemic toxicity associated with CD40 agonism.
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23
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Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities. Nat Rev Drug Discov 2022; 21:529-540. [PMID: 35701637 DOI: 10.1038/s41573-022-00493-5] [Citation(s) in RCA: 207] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2022] [Indexed: 12/11/2022]
Abstract
Tumours employ various tactics to adapt and eventually resist immune attack. These mechanisms are collectively called adaptive immune resistance (AIR). The first defined and therapeutically validated AIR mechanism is the selective induction of programmed cell death 1 ligand 1 (PDL1) by interferon-γ in the tumour. Blockade of PDL1 binding to its receptor PD1 by antibodies (anti-PD therapy) has resulted in remission of a fraction of patients with advanced-stage cancer, especially in solid tumours. However, many clinical trials combining anti-PD therapy with other antitumour drugs conducted without a strong mechanistic rationale have failed to identify a synergistic or additive effect. In this Perspective article, we discuss why defining AIR mechanisms at the tumour site should be a key focus to direct future drug development as well as practical approaches to improve current cancer therapy.
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24
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Muik A, Adams 3rd HC, Gieseke F, Altintas I, Schoedel KB, Blum JM, Sänger B, Burm SM, Stanganello E, Verzijl D, Spires VM, Vascotto F, Toker A, Quinkhardt J, Fereshteh M, Diken M, Satijn DPE, Kreiter S, Ahmadi T, Breij ECW, Türeci Ö, Sasser K, Sahin U, Jure-Kunkel M. DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation through conditional CD40 and 4-1BB agonist activity. J Immunother Cancer 2022; 10:e004322. [PMID: 35688554 PMCID: PMC9189854 DOI: 10.1136/jitc-2021-004322] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Despite the preclinical promise of CD40 and 4-1BB as immuno-oncology targets, clinical efforts evaluating CD40 and 4-1BB agonists as monotherapy have found limited success. DuoBody-CD40×4-1BB (GEN1042/BNT312) is a novel investigational Fc-inert bispecific antibody for dual targeting and conditional stimulation of CD40 and 4-1BB to enhance priming and reactivation of tumor-specific immunity in patients with cancer. METHODS Characterization of DuoBody-CD40×4-1BB in vitro was performed in a broad range of functional immune cell assays, including cell-based reporter assays, T-cell proliferation assays, mixed-lymphocyte reactions and tumor-infiltrating lymphocyte assays, as well as live-cell imaging. The in vivo activity of DuoBody-CD40×4-1BB was assessed in blood samples from patients with advanced solid tumors that were treated with DuoBody-CD40×4-1BB in the dose-escalation phase of the first-in-human clinical trial (NCT04083599). RESULTS DuoBody-CD40×4-1BB exhibited conditional CD40 and 4-1BB agonist activity that was strictly dependent on crosslinking of both targets. Thereby, DuoBody-CD40×4-1BB strengthened the dendritic cell (DC)/T-cell immunological synapse, induced DC maturation, enhanced T-cell proliferation and effector functions in vitro and enhanced expansion of patient-derived tumor-infiltrating lymphocytes ex vivo. The addition of PD-1 blocking antibodies resulted in potentiation of T-cell activation and effector functions in vitro compared with either monotherapy, providing combination rationale. Furthermore, in a first-in-human clinical trial, DuoBody-CD40×4-1BB mediated clear immune modulation of peripheral antigen presenting cells and T cells in patients with advanced solid tumors. CONCLUSION DuoBody-CD40×4-1BB is capable of enhancing antitumor immunity by modulating DC and T-cell functions and shows biological activity in patients with advanced solid tumors. These findings demonstrate that targeting of these two pathways with an Fc-inert bispecific antibody may be an efficacious approach to (re)activate tumor-specific immunity and support the clinical investigation of DuoBody-CD40×4-1BB for the treatment of cancer.
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Affiliation(s)
| | | | | | - Isil Altintas
- Translational Research and Precision Medicine, Genmab BV, Utrecht, The Netherlands
| | | | | | | | - Saskia M Burm
- Translational Research and Precision Medicine, Genmab BV, Utrecht, The Netherlands
| | - Eliana Stanganello
- TRON-Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany
| | - Dennis Verzijl
- Translational Research and Precision Medicine, Genmab BV, Utrecht, The Netherlands
| | | | - Fulvia Vascotto
- TRON-Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany
| | | | | | | | | | | | | | - Tahamtan Ahmadi
- Experimental Medicine, Genmab US Inc, Plainsboro, New Jersey, USA
| | - Esther C W Breij
- Translational Research and Precision Medicine, Genmab BV, Utrecht, The Netherlands
| | | | | | - Ugur Sahin
- BioNTech SE, Mainz, Germany
- TRON-Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany
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25
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Gudd CLC, Possamai LA. The Role of Myeloid Cells in Hepatotoxicity Related to Cancer Immunotherapy. Cancers (Basel) 2022; 14:1913. [PMID: 35454819 PMCID: PMC9027811 DOI: 10.3390/cancers14081913] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/03/2022] [Accepted: 04/06/2022] [Indexed: 11/23/2022] Open
Abstract
Drug-related hepatotoxicity is an emerging clinical challenge with the widening use of immunotherapeutic agents in the field of oncology. This is an important complication to consider as more immune oncological targets are being identified to show promising results in clinical trials. The application of these therapeutics may be complicated by the development of immune-related adverse events (irAEs), a serious limitation often requiring high-dose immunosuppression and discontinuation of cancer therapy. Hepatoxicity presents one of the most frequently encountered irAEs and a better understanding of the underlying mechanism is crucial for the development of alternative therapeutic interventions. As a novel drug side effect, the immunopathogenesis of the condition is not completely understood. In the liver, myeloid cells play a central role in the maintenance of homeostasis and promotion of inflammation. Recent research has identified myeloid cells to be associated with hepatic adverse events of various immune modulatory monoclonal antibodies. In this review article, we provide an overview of the role of myeloid cells in the immune pathogenesis during hepatoxicity related to cancer immunotherapies and highlight potential treatment options.
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Affiliation(s)
- Cathrin L. C. Gudd
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK;
| | - Lucia A. Possamai
- Department of Metabolism, Digestion & Reproduction, Imperial College London, London SW7 2AZ, UK
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Meng Z, Zhang Y, Zhou X, Ji J, Liu Z. Nanovaccines with cell-derived components for cancer immunotherapy. Adv Drug Deliv Rev 2022; 182:114107. [PMID: 34995678 DOI: 10.1016/j.addr.2021.114107] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 10/16/2021] [Accepted: 12/29/2021] [Indexed: 12/13/2022]
Abstract
Cancer nanovaccines as one of immunotherapeutic approaches are able to attack tumors by stimulating tumor-specific immunological responses. However, there still exist multiple challenges to be tackled for cancer nanovaccines to evoke potent antitumor immunity. Particularly, the administration of exogenous materials may cause the off-target immunotherapy responses. In recent years, biomimetic nanovaccines by using cell lysates, cell-derived nanovesicles, or extracted cell membranes as the functional components have received extensive attention. Such nanovaccines based on cell-derived components would show many unique advantages including inherent biocompatibility and the ability to trigger immune responses against a range of tumor-associated antigens. In this review article, we will introduce the recent research progresses of those cell-derived biomimetic nanovaccines for cancer immunotherapy, and discuss the perspectives and challenges associated with the future clinical translation of these emerging vaccine platforms.
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Abstract
This review discusses peptide epitopes used as antigens in the development of vaccines in clinical trials as well as future vaccine candidates. It covers peptides used in potential immunotherapies for infectious diseases including SARS-CoV-2, influenza, hepatitis B and C, HIV, malaria, and others. In addition, peptides for cancer vaccines that target examples of overexpressed proteins are summarized, including human epidermal growth factor receptor 2 (HER-2), mucin 1 (MUC1), folate receptor, and others. The uses of peptides to target cancers caused by infective agents, for example, cervical cancer caused by human papilloma virus (HPV), are also discussed. This review also provides an overview of model peptide epitopes used to stimulate non-specific immune responses, and of self-adjuvanting peptides, as well as the influence of other adjuvants on peptide formulations. As highlighted in this review, several peptide immunotherapies are in advanced clinical trials as vaccines, and there is great potential for future therapies due the specificity of the response that can be achieved using peptide epitopes.
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Affiliation(s)
- Ian W Hamley
- Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, U.K
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28
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CD40 stimulation as a molecular adjuvant for cancer vaccines and other immunotherapies. Cell Mol Immunol 2022; 19:14-22. [PMID: 34282297 PMCID: PMC8752810 DOI: 10.1038/s41423-021-00734-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/31/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023] Open
Abstract
The substantial advances attained by checkpoint blockade immunotherapies have driven an expansion in the approaches used to promote T cell access to the tumor microenvironment to provide targets for checkpoint immunotherapy. Inherent in any T cell response to a tumor antigen is the capacity of dendritic cells to initiate and support such responses. Here, the rationale and early immunobiology of CD40 as a master regulator of dendritic cell activation is reviewed, with further contextualization and appreciation for the role of CD40 stimulation not only in cancer vaccines but also in other contemporary immune-oncology approaches.
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29
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Goodall CP, Schwarz B, Selivanovitch E, Avera J, Wang J, Miettinen H, Douglas T. Controlled Modular Multivalent Presentation of the CD40 Ligand on P22 Virus-like Particles Leads to Tunable Amplification of CD40 Signaling. ACS APPLIED BIO MATERIALS 2021; 4:8205-8214. [PMID: 35005938 DOI: 10.1021/acsabm.1c00718] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Ligands of the tumor necrosis factor superfamily (TNFSF) are appealing targets for immunotherapy research due to their integral involvement in stimulation or restriction of immune responses. TNFSF-targeted therapies are currently being developed to combat immunologically based diseases and cancer. A crucial determinant of effective TNFSF receptor binding and signaling is the trimeric quaternary structure of the ligand. Additionally, ligand multivalency is essential to propagate strong signaling in effector cells. Thus, designing a synthetic platform to display trimeric TNFSF ligands in a multivalent manner is necessary to further the understanding of ligand-receptor interactions. Viral nanocages have architectures that are amenable to genetic and chemical modifications of both their interior and exterior surfaces. Notably, the exterior surface of virus-like particles can be utilized as a platform for the modular multivalent presentation of target proteins. In this study, we build on previous efforts exploring the bacteriophage P22 virus-like particle for the exterior multivalent modular display of a potent immune-stimulating TNFSF protein, CD40 ligand (CD40L). Using a cell-based reporter system, we quantify the effects of tunable avidity on CD40 signaling by CD40L displayed on the surface of P22 nanocages. Multivalent presentation of CD40L resulted in a 53.6-fold decrease of the half maximal effective concentration (EC50) compared to free CD40L, indicating higher potency. Our results emphasize the power of using P22-based biomimetics to study ligand-receptor interactions within their proper structural context, which may contribute to the development of effective immune modulators.
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Affiliation(s)
- Cheri Peyton Goodall
- Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
| | - Benjamin Schwarz
- Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, 903 South 4th Street, Hamilton, Montana 59840, United States
| | - Ekaterina Selivanovitch
- Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
| | - John Avera
- Walden Biosciences, One Kendall Square, Suite 7102, Cambridge, Massachusetts 02139, United States
| | - Joseph Wang
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, 700 HMC Crescent Road, Hershey, Pennsylvania 17033, United States
| | - Heini Miettinen
- Department of Microbiology and Immunology, Montana State University, P.O. Box 173520, Bozeman, Montana 59717, United States
| | - Trevor Douglas
- Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
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Pretta A, Lai E, Persano M, Donisi C, Pinna G, Cimbro E, Parrino A, Spanu D, Mariani S, Liscia N, Dubois M, Migliari M, Impera V, Saba G, Pusceddu V, Puzzoni M, Ziranu P, Scartozzi M. Uncovering key targets of success for immunotherapy in pancreatic cancer. Expert Opin Ther Targets 2021; 25:987-1005. [PMID: 34806517 DOI: 10.1080/14728222.2021.2010044] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Despite available treatment options, pancreatic ductal adenocarcinoma (PDAC) is frequently lethal. Recent immunotherapy strategies have failed to yield any notable impact. Therefore, research is focussed on unearthing new drug targets and therapeutic strategies to tackle this malignancy and attain more positive outcomes for patients. AREAS COVERED In this perspective article, we evaluate the main resistance mechanisms to immune checkpoint inhibitors (ICIs) and the approaches to circumvent them. We also offer an assessment of concluded and ongoing trials of PDAC immunotherapy. Literature research was performed on Pubmed accessible through keywords such as: 'pancreatic ductal adenocarcinoma,' 'immunotherapy,' 'immunotherapy resistance,' 'immune escape,' 'biomarkers.' Papers published between 2000 and 2021 were selected. EXPERT OPINION The tumor microenvironment is a critical variable of treatment resistance because of its role as a physical barrier and inhibitory immune signaling. Promising therapeutic strategies appear to be a combination of immunotherapeutics with other targeted treatments. Going forward, predictive biomarkers are required to improve patient selection. Biomarker-driven trials could enhance approaches for assessing the role of immunotherapy in PDAC.
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Affiliation(s)
- Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome, Rome Italy.,Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Giovanna Pinna
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Erika Cimbro
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Alissa Parrino
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome, Rome Italy.,Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome, Rome Italy.,Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
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Schetters STT, Rodriguez E, Kruijssen LJW, Crommentuijn MHW, Boon L, Van den Bossche J, Den Haan JMM, Van Kooyk Y. Monocyte-derived APCs are central to the response of PD1 checkpoint blockade and provide a therapeutic target for combination therapy. J Immunother Cancer 2021; 8:jitc-2020-000588. [PMID: 32690667 PMCID: PMC7371367 DOI: 10.1136/jitc-2020-000588] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2020] [Indexed: 12/23/2022] Open
Abstract
Background PD1 immune checkpoint blockade (αPD1 ICB) has shown unparalleled success in treating many types of cancer. However, response to treatment does not always lead to tumor rejection. While αPD1 ICB relies on cytotoxic CD8+ T cells, antigen-presenting cells (APCs) at the tumor site are also needed for costimulation of tumor-infiltrating lymphocytes (TILs). It is still unclear how these APCs develop and function before and during αPD1 ICB or how they are associated with tumor rejection. Methods Here, we used B16 mouse melanoma and MC38 colorectal carcinoma tumor models, which show differential responses to αPD1 ICB. The immune composition of ICB insensitive B16 and sensitive MC38 were extensively investigated using multi-parameter flow cytometry and unsupervised clustering and trajectory analyses. We additionally analyzed existing single cell RNA sequencing data of the myeloid compartment of patients with melanoma undergoing αPD1 ICB. Lastly, we investigated the effect of CD40 agonistic antibody on the tumor-infiltrating monocyte-derived cells during αPD1 ICB. Results We show that monocyte-derived dendritic cells (moDCs) express high levels of costimulatory molecules and are correlated with effector TILs in the tumor microenvironment (TME) after αPD1 ICB only in responding mouse tumor models. Tumor-resident moDCs showed distinct differentiation from monocytes in both mouse and human tumors. We further confirmed significant enrichment of tumor-resident differentiated moDCs in patients with melanoma responding to αPD1 ICB therapy compared with non-responding patients. Moreover, moDCs could be targeted by agonistic anti-CD40 antibody, supporting moDC differentiation, effector T-cell expansion and anti-tumor immunity. Conclusion The combined analysis of myeloid and lymphoid populations in the TME during successful and non-successful PD1 ICB led to the discovery of monocyte-to-DC differentiation linked to expanding T-cell populations. This differentiation was found in patients during ICB, which was significantly higher during successful ICB. The finding of tumor-infiltrating monocytes and differentiating moDCs as druggable target for rational combination therapy opens new avenues of anti-tumor therapy design.
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Affiliation(s)
- Sjoerd T T Schetters
- Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands
| | - Ernesto Rodriguez
- Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands
| | - Laura J W Kruijssen
- Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands
| | - Matheus H W Crommentuijn
- Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands
| | - Louis Boon
- Polpharma Biologics, Utrecht, The Netherlands
| | - Jan Van den Bossche
- Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands
| | - Joke M M Den Haan
- Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands
| | - Yvette Van Kooyk
- Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands
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32
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Askmyr D, Abolhalaj M, Gomez Jimenez D, Greiff L, Lindstedt M, Lundberg K. Pattern recognition receptor expression and maturation profile of dendritic cell subtypes in human tonsils and lymph nodes. Hum Immunol 2021; 82:976-981. [PMID: 34511272 DOI: 10.1016/j.humimm.2021.08.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/18/2021] [Accepted: 08/10/2021] [Indexed: 01/02/2023]
Abstract
Dendritic cells (DCs) with capacity of antigen cross-presentation are of key interest for immunotherapy against cancer as they can induce antigen-specific cytotoxic T lymphocyte (CTL) responses. This study describes frequencies of DC subtypes in human tonsils and lymph nodes, and phenotypic aspects that may be targeted by adjuvant measures. From human tonsils and neck lymph nodes, DCs were identified through flow cytometry, and subsets of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were investigated. Maturity status was assessed and surface receptors with CTL-promoting potentials were studied. CD123+ pDCs as well as CD1c+, CD141+, and CD1c-CD141- mDCs were detected in tonsils and lymph nodes. Both sites featured a similar presence of DC subsets, with CD123+ pDC being dominant and CD141+ mDCs least frequent. Based on CD80/CD86 expression, all DC subtypes featured a low degree of maturation. Expression of pattern recognition receptors (PRRs) CD206, CD207, DC-SIGN, TLR2, and TLR4, as well as the chemokine receptor XCR1, indicated DC subset-specific receptor profiles. We conclude that tonsils and lymph nodes share common features in terms of DC subset frequency and maturation as well as PRR and XCR1 expression pattern. Our work suggests that both sites may be considered for vaccine deposition in DC-mediated immunotherapy.
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Affiliation(s)
- David Askmyr
- Department of ORL, Head & Neck Surgery, Skåne University Hospital, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden.
| | - Milad Abolhalaj
- Department of Immunotechnology, Lund University, Lund, Sweden.
| | | | - Lennart Greiff
- Department of ORL, Head & Neck Surgery, Skåne University Hospital, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden.
| | - Malin Lindstedt
- Department of Immunotechnology, Lund University, Lund, Sweden.
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Filbert EL, Björck PK, Srivastava MK, Bahjat FR, Yang X. APX005M, a CD40 agonist antibody with unique epitope specificity and Fc receptor binding profile for optimal therapeutic application. Cancer Immunol Immunother 2021; 70:1853-1865. [PMID: 33392713 PMCID: PMC8195934 DOI: 10.1007/s00262-020-02814-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 11/27/2020] [Indexed: 12/22/2022]
Abstract
Targeting CD40 with agonist antibodies is a promising approach to cancer immunotherapy. CD40 acts as a master regulator of immunity by mobilizing multiple arms of the immune system to initiate highly effective CD8 + T-cell-mediated responses against foreign pathogens and tumors. The clinical development of CD40 agonist antibodies requires careful optimization of the antibody to maximize therapeutic efficacy while minimizing adverse effects. Both epitope specificity and isotype are critical for CD40 agonist antibody mechanism of action and potency. We developed a novel antibody, APX005M, which binds with high affinity to the CD40 ligand-binding site on CD40 and is optimized for selective interaction with Fcγ receptors to enhance agonistic potency while limiting less desirable Fc-effector functions like antibody-dependent cellular cytotoxicity of CD40-expressing immune cells. APX005M is a highly potent inducer of innate and adaptive immune effector responses and represents a promising CD40 agonist antibody for induction of an effective anti-tumor immune response with a favorable safety profile.
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Affiliation(s)
- Erin L Filbert
- Apexigen, Inc, 75 Shoreway Road, Suite C, San Carlos, CA, 94070, USA
| | - Pia K Björck
- Apexigen, Inc, 75 Shoreway Road, Suite C, San Carlos, CA, 94070, USA
| | - Minu K Srivastava
- Apexigen, Inc, 75 Shoreway Road, Suite C, San Carlos, CA, 94070, USA
| | - Frances R Bahjat
- Apexigen, Inc, 75 Shoreway Road, Suite C, San Carlos, CA, 94070, USA
| | - Xiaodong Yang
- Apexigen, Inc, 75 Shoreway Road, Suite C, San Carlos, CA, 94070, USA.
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34
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Sasaki K, Takano S, Tomizawa S, Miyahara Y, Furukawa K, Takayashiki T, Kuboki S, Takada M, Ohtsuka M. C4b-binding protein α-chain enhances antitumor immunity by facilitating the accumulation of tumor-infiltrating lymphocytes in the tumor microenvironment in pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:212. [PMID: 34167573 PMCID: PMC8228942 DOI: 10.1186/s13046-021-02019-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 06/17/2021] [Indexed: 01/08/2023]
Abstract
Background Recent studies indicate that complement plays pivotal roles in promoting or suppressing cancer progression. We have previously identified C4b-binding protein α-chain (C4BPA) as a serum biomarker for the early detection of pancreatic ductal adenocarcinoma (PDAC). However, its mechanism of action remains unclear. Here, we elucidated the functional roles of C4BPA in PDAC cells and the tumor microenvironment. Methods We assessed stromal C4BPA, the C4BPA binding partner CD40, and the number of CD8+ tumor-infiltrating lymphocytes in resected human PDAC tissues via immunohistochemical staining. The biological functions of C4BPA were investigated in peripheral blood mononuclear cells (PBMCs) and human PDAC cell lines. Mouse C4BPA (mC4BPA) peptide, which is composed of 30 amino acids from the C-terminus and binds to CD40, was designed for further in vitro and in vivo experiments. In a preclinical experiment, we assessed the efficacy of gemcitabine plus nab-paclitaxel (GnP), dual immune checkpoint blockades (ICBs), and mC4BPA peptide in a mouse orthotopic transplantation model. Results Immunohistochemical analysis revealed that high stromal C4BPA and CD40 was associated with favorable PDAC prognosis (P=0.0005). Stromal C4BPA strongly correlated with the number of CD8+ tumor-infiltrating lymphocytes (P=0.001). In in vitro experiments, flow cytometry revealed that recombinant human C4BPA (rhC4BPA) stimulation increased CD4+ and CD8+ T cell numbers in PBMCs. rhC4BPA also promoted the proliferation of CD40-expressing PDAC cells. By contrast, combined treatment with gemcitabine and rhC4BPA increased PDAC cell apoptosis rate. mC4BPA peptide increased the number of murine T lymphocytes in vitro and the number of CD8+ tumor-infiltrating lymphocytes surrounding PDAC tumors in vivo. In a preclinical study, GnP/ICBs/mC4BPA peptide treatment, but not GnP treatment, led to the accumulation of a greater number of CD8+ T cells in the periphery of PDAC tumors and to greater tumor regression than did control treatment. Conclusions These findings demonstrate that the combination of GnP therapy with C4BPA inhibits PDAC progression by promoting antitumor T cell accumulation in the tumor microenvironment. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02019-0.
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Affiliation(s)
- Kosuke Sasaki
- Department of General Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba, 260-8677, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba, 260-8677, Japan.
| | - Satoshi Tomizawa
- Department of General Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba, 260-8677, Japan
| | - Yoji Miyahara
- Department of General Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba, 260-8677, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba, 260-8677, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba, 260-8677, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba, 260-8677, Japan
| | - Mamoru Takada
- Department of General Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba, 260-8677, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba, 260-8677, Japan
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35
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Enell Smith K, Deronic A, Hägerbrand K, Norlén P, Ellmark P. Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy. Expert Opin Biol Ther 2021; 21:1635-1646. [PMID: 34043482 DOI: 10.1080/14712598.2021.1934446] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Introduction: CD40 signaling activates dendritic cells leading to improved T cell priming against tumor antigens. CD40 agonism expands the tumor-specific T cell repertoire and has the potential to increase the fraction of patients that respond to established immunotherapies.Areas covered: This article reviews current as well as emerging CD40 agonist therapies with a focus on antibody-based therapies, including next generation bispecific CD40 agonists. The scientific rationale for different design criteria, binding epitopes, and formats are discussed.Expert opinion: The ability of CD40 agonists to activate dendritic cells and enhance antigen cross-presentation to CD8+ T cells provides an opportunity to elevate response rates of cancer immunotherapies. While there are many challenges left to address, including optimal dose regimen, CD40 agonist profile, combination partners and indications, we are confident that CD40 agonists will play an important role in the challenging task of reprogramming the immune system to fight cancer.
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Affiliation(s)
| | | | | | | | - Peter Ellmark
- Alligator Bioscience AB, Sweden.,Department of Immunotechnology, Lund University, Lund, Sweden
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36
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The human anti-CD40 agonist antibody mitazalimab (ADC-1013; JNJ-64457107) activates antigen-presenting cells, improves expansion of antigen-specific T cells, and enhances anti-tumor efficacy of a model cancer vaccine in vivo. Cancer Immunol Immunother 2021; 70:3629-3642. [PMID: 33948686 PMCID: PMC8571159 DOI: 10.1007/s00262-021-02932-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/27/2021] [Indexed: 01/10/2023]
Abstract
Non-responders to checkpoint inhibitors generally have low tumor T cell infiltration and could benefit from immunotherapy that activates dendritic cells, with priming of tumor-reactive T cells as a result. Such therapies may be augmented by providing tumor antigen in the form of cancer vaccines. Our aim was to study the effects of mitazalimab (ADC-1013; JNJ-64457107), a human anti-CD40 agonist IgG1 antibody, on activation of antigen-presenting cells, and how this influences the priming and anti-tumor potential of antigen-specific T cells, in mice transgenic for human CD40. Mitazalimab activated splenic CD11c+ MHCII+ dendritic cells and CD19+ MHCII+ B cells within 6 h, with a return to baseline within 1 week. This was associated with a dose-dependent release of proinflammatory cytokines in the blood, including IP-10, MIP-1α and TNF-α. Mitazalimab administered at different dose regimens with ovalbumin protein showed that repeated dosing expanded ovalbumin peptide (SIINFEKL)-specific CD8+ T cells and increased the frequency of activated ICOS+ T cells and CD44hi CD62L- effector memory T cells in the spleen. Mitazalimab prolonged survival of mice bearing MB49 bladder carcinoma tumors and increased the frequency of activated granzyme B+ CD8+ T cells in the tumor. In the ovalbumin-transfected tumor E.G7-OVA lymphoma, mitazalimab administered with either ovalbumin protein or SIINFEKL peptide prolonged the survival of E.G7-OVA tumor-bearing mice, as prophylactic and therapeutic treatment. Thus, mitazalimab activates antigen-presenting cells, which improves expansion and activation of antigen-specific T cells and enhances the anti-tumor efficacy of a model cancer vaccine.
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37
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Oba T, Makino K, Kajihara R, Yokoi T, Araki R, Abe M, Minderman H, Chang AE, Odunsi K, Ito F. In situ delivery of iPSC-derived dendritic cells with local radiotherapy generates systemic antitumor immunity and potentiates PD-L1 blockade in preclinical poorly immunogenic tumor models. J Immunother Cancer 2021; 9:e002432. [PMID: 34049930 PMCID: PMC8166607 DOI: 10.1136/jitc-2021-002432] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Dendritic cells (DCs) are a promising therapeutic target in cancer immunotherapy given their ability to prime antigen-specific T cells, and initiate antitumor immune response. A major obstacle for DC-based immunotherapy is the difficulty to obtain a sufficient number of functional DCs. Theoretically, this limitation can be overcome by using induced pluripotent stem cells (iPSCs); however, therapeutic strategies to engage iPSC-derived DCs (iPSC-DCs) into cancer immunotherapy remain to be elucidated. Accumulating evidence showing that induction of tumor-residing DCs enhances immunomodulatory effect of radiotherapy (RT) prompted us to investigate antitumor efficacy of combining intratumoral administration of iPSC-DCs with local RT. METHODS Mouse iPSCs were differentiated to iPSC-DCs on OP9 stromal cells expressing the notch ligand delta-like 1 in the presence of granulocyte macrophage colony-stimulating factor. Phenotype and the capacities of iPSC-DCs to traffic tumor-draining lymph nodes (TdLNs) and prime antigen-specific T cells were evaluated by flow cytometry and imaging flow cytometry. Antitumor efficacy of intratumoral injection of iPSC-DCs and RT was tested in syngeneic orthotopic mouse tumor models resistant to anti-PD-1 ligand 1 (PD-L1) therapy. RESULTS Mouse iPSC-DCs phenotypically resembled conventional type 2 DCs, and had a capacity to promote activation, proliferation and effector differentiation of antigen-specific CD8+ T cells in the presence of the cognate antigen in vitro. Combination of in situ administration of iPSC-DCs and RT facilitated the priming of tumor-specific CD8+ T cells, and synergistically delayed the growth of not only the treated tumor but also the distant non-irradiated tumors. Mechanistically, RT enhanced trafficking of intratumorally injected iPSC-DCs to the TdLN, upregulated CD40 expression, and increased the frequency of DC/CD8+ T cell aggregates. Phenotypic analysis of tumor-infiltrating CD8+ T cells and myeloid cells revealed an increase of stem-like Slamf6+ TIM3- CD8+ T cells and PD-L1 expression in tumor-associated macrophages and DCs. Consequently, combined therapy rendered poorly immunogenic tumors responsive to anti-PD-L1 therapy along with the development of tumor-specific immunological memory. CONCLUSIONS Our findings illustrate the translational potential of iPSC-DCs, and identify the therapeutic efficacy of a combinatorial platform to engage them for overcoming resistance to anti-PD-L1 therapy in poorly immunogenic tumors.
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MESH Headings
- Animals
- B7-H1 Antigen/antagonists & inhibitors
- B7-H1 Antigen/metabolism
- CD8-Positive T-Lymphocytes/drug effects
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- Cell Line, Tumor
- Coculture Techniques
- Dendritic Cells/immunology
- Dendritic Cells/metabolism
- Dendritic Cells/transplantation
- Immune Checkpoint Inhibitors/pharmacology
- Immunotherapy, Adoptive
- Induced Pluripotent Stem Cells/immunology
- Induced Pluripotent Stem Cells/metabolism
- Induced Pluripotent Stem Cells/transplantation
- Lymphocytes, Tumor-Infiltrating/drug effects
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Melanoma, Experimental/immunology
- Melanoma, Experimental/metabolism
- Melanoma, Experimental/pathology
- Melanoma, Experimental/therapy
- Mice, Inbred C57BL
- Mice, Transgenic
- Phenotype
- Radiotherapy, Adjuvant
- Signal Transduction
- Skin Neoplasms/immunology
- Skin Neoplasms/metabolism
- Skin Neoplasms/pathology
- Skin Neoplasms/therapy
- Tumor Burden/drug effects
- Tumor Microenvironment
- Mice
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Affiliation(s)
- Takaaki Oba
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University, Matsumoto, Nagano, Japan
| | - Kenichi Makino
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan
| | - Ryutaro Kajihara
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Toshihiro Yokoi
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Ryoko Araki
- Department of Basic Medical Sciences for Radiation Damages, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Masumi Abe
- Department of Basic Medical Sciences for Radiation Damages, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Hans Minderman
- Flow & Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Alfred E Chang
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Kunle Odunsi
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- University of Chicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA
| | - Fumito Ito
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, Nuew York, USA
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DeRogatis JM, Viramontes KM, Neubert EN, Tinoco R. PSGL-1 Immune Checkpoint Inhibition for CD4 + T Cell Cancer Immunotherapy. Front Immunol 2021; 12:636238. [PMID: 33708224 PMCID: PMC7940186 DOI: 10.3389/fimmu.2021.636238] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/04/2021] [Indexed: 01/15/2023] Open
Abstract
Immune checkpoint inhibition targeting T cells has shown tremendous promise in the treatment of many cancer types and are now standard therapies for patients. While standard therapies have focused on PD-1 and CTLA-4 blockade, additional immune checkpoints have shown promise in promoting anti-tumor immunity. PSGL-1, primarily known for its role in cellular migration, has also been shown to function as a negative regulator of CD4+ T cells in numerous disease settings including cancer. PSGL-1 is highly expressed on T cells and can engage numerous ligands that impact signaling pathways, which may modulate CD4+ T cell differentiation and function. PSGL-1 engagement in the tumor microenvironment may promote CD4+ T cell exhaustion pathways that favor tumor growth. Here we highlight that blocking the PSGL-1 pathway on CD4+ T cells may represent a new cancer therapy approach to eradicate tumors.
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Affiliation(s)
| | | | | | - Roberto Tinoco
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States
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39
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Kim SI, Cassella CR, Byrne KT. Tumor Burden and Immunotherapy: Impact on Immune Infiltration and Therapeutic Outcomes. Front Immunol 2021; 11:629722. [PMID: 33597954 PMCID: PMC7882695 DOI: 10.3389/fimmu.2020.629722] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 12/18/2020] [Indexed: 12/20/2022] Open
Abstract
Cancer immunotherapy has revolutionized the treatment landscape in medical oncology, but its efficacy has been variable across patients. Biomarkers to predict such differential response to immunotherapy include cytotoxic T lymphocyte infiltration, tumor mutational burden, and microsatellite instability. A growing number of studies also suggest that baseline tumor burden, or tumor size, predicts response to immunotherapy. In this review, we discuss the changes in immune profile and therapeutic responses that occur with increasing tumor size. We also overview therapeutic approaches to reduce tumor burden and favorably modulate the immune microenvironment of larger tumors.
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Affiliation(s)
- Samuel I Kim
- Program in Biochemistry, College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, United States
| | - Christopher R Cassella
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Katelyn T Byrne
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.,Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, United States
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40
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Schmiechen ZC, Stromnes IM. Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma. Front Immunol 2021; 11:613815. [PMID: 33584701 PMCID: PMC7876239 DOI: 10.3389/fimmu.2020.613815] [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: 10/03/2020] [Accepted: 12/10/2020] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with an overall 5-year survival rate of 10%. Disease lethality is due to late diagnosis, early metastasis and resistance to therapy, including immunotherapy. PDA creates a robust fibroinflammatory tumor microenvironment that contributes to immunotherapy resistance. While previously considered an immune privileged site, evidence demonstrates that in some cases tumor antigen-specific T cells infiltrate and preferentially accumulate in PDA and are central to tumor cell clearance and long-term remission. Nonetheless, PDA can rapidly evade an adaptive immune response using a myriad of mechanisms. Mounting evidence indicates PDA interferes with T cell differentiation into potent cytolytic effector T cells via deficiencies in naive T cell priming, inducing T cell suppression or promoting T cell exhaustion. Mechanistic research indicates that immunotherapy combinations that change the suppressive tumor microenvironment while engaging antigen-specific T cells is required for treatment of advanced disease. This review focuses on recent advances in understanding mechanisms limiting T cell function and current strategies to overcome immunotherapy resistance in PDA.
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Affiliation(s)
- Zoe C. Schmiechen
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Ingunn M. Stromnes
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
- Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, United States
- Center for Genome Engineering, University of Minnesota Medical School, Minneapolis, MN, United States
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41
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Oba T, Long MD, Keler T, Marsh HC, Minderman H, Abrams SI, Liu S, Ito F. Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s. Nat Commun 2020; 11:5415. [PMID: 33110069 PMCID: PMC7592056 DOI: 10.1038/s41467-020-19192-z] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 10/02/2020] [Indexed: 01/01/2023] Open
Abstract
The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-PD-1/PD-L1 therapy. Evidence indicates crucial roles of Batf3-dependent conventional type-1 dendritic cells (cDC1s) for inducing antitumor T-cell immunity; however, strategies to maximize cDC1 engagement remain elusive. Here, using multiple orthotopic tumor mouse models resistant to anti-PD-L1-therapy, we are testing the hypothesis that in situ induction and activation of tumor-residing cDC1s overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1+ Slamf6+ CD8+ T cells, triggers regression not only of primary, but also untreated distant tumors, and renders tumors responsive to anti-PD-L1 therapy. Furthermore, serial in situ immunomodulation (ISIM) reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, and establishes tumor-specific immunological memory. These findings provide new insights into cDC1 biology as a critical determinant to overcome mechanisms of intratumoral T-cell exclusion.
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Affiliation(s)
- Takaaki Oba
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Mark D Long
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Tibor Keler
- Celldex Therapeutics, Inc., Hampton, NJ, USA
| | | | - Hans Minderman
- Flow & Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Scott I Abrams
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Song Liu
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Fumito Ito
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. .,Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. .,Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. .,Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA.
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42
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Hübbe ML, Jæhger DE, Andresen TL, Andersen MH. Leveraging Endogenous Dendritic Cells to Enhance the Therapeutic Efficacy of Adoptive T-Cell Therapy and Checkpoint Blockade. Front Immunol 2020; 11:578349. [PMID: 33101304 PMCID: PMC7546347 DOI: 10.3389/fimmu.2020.578349] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/26/2020] [Indexed: 01/15/2023] Open
Abstract
Adoptive cell therapy (ACT), based on treatment with autologous tumor infiltrating lymphocyte (TIL)-derived or genetically modified chimeric antigen receptor (CAR) T cells, has become a potentially curative therapy for subgroups of patients with melanoma and hematological malignancies. To further improve response rates, and to broaden the applicability of ACT to more types of solid malignancies, it is necessary to explore and define strategies that can be used as adjuvant treatments to ACT. Stimulation of endogenous dendritic cells (DCs) alongside ACT can be used to promote epitope spreading and thereby decrease the risk of tumor escape due to target antigen downregulation, which is a common cause of disease relapse in initially responsive ACT treated patients. Addition of checkpoint blockade to ACT and DC stimulation might further enhance response rates by counteracting an eventual inactivation of infused and endogenously primed tumor-reactive T cells. This review will outline and discuss therapeutic strategies that can be utilized to engage endogenous DCs alongside ACT and checkpoint blockade, to strengthen the anti-tumor immune response.
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Affiliation(s)
- Mie Linder Hübbe
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital Herlev, Copenhagen, Denmark
| | - Ditte Elisabeth Jæhger
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Thomas Lars Andresen
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital Herlev, Copenhagen, Denmark
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43
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Schetters STT, Li RJE, Kruijssen LJW, Engels S, Ambrosini M, Garcia-Vallejo JJ, Kalay H, Unger WWJ, van Kooyk Y. Adaptable antigen matrix platforms for peptide vaccination strategies and T cell-mediated anti-tumor immunity. Biomaterials 2020; 262:120342. [PMID: 32905903 DOI: 10.1016/j.biomaterials.2020.120342] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/17/2020] [Accepted: 08/21/2020] [Indexed: 12/30/2022]
Abstract
Injection of antigenic peptides has been widely used as a vaccine strategy to boost T cell immunity. However, the poor immunogenicity of single peptides can potentially be strengthened through modification of the tertiary structure and the selection of the accompanying adjuvant. Here, we generated antigenic peptides into non-linear trimers by solid phase peptide synthesis, thereby enhancing antigen presentation by dendritic cells to CD8+ T cells in vitro and in vivo. CD8+ T cells from mice vaccinated with trimers showed an KLRG1+ effector phenotype and were able to recognize and kill antigen-expressing tumor cells ex vivo. Importantly, trimers outperformed synthetic long peptide in terms of T cell response even when equal number of epitopes were used for immunization. To improve the synthesis of trimers containing difficult peptide sequences, we developed a novel small molecule that functions as conjugation platform for synthetic long peptides. This platform , termed Antigen MAtriX (AMAX) improved yield, purity and solubility of trimers over conventional solid phase synthesis strategies. AMAX outperformed synthetic long peptides in terms of both CD8+ and CD4+ T cell responses and allowed functionalization with DC-SIGN-binding carbohydrates for in vivo dendritic cell targeting strategies, boosting T cell responses even further. Moreover, we show that agonistic CD40 antibody combined with MF59 (AddaVax) emulsion synergistically improves the antigen-specific T cell response of the AMAX in vivo. Also, tumor-associated antigens and neo-antigens could be incorporated in AMAX for tumor-specific CD8+ T cell responses. Importantly, immunization with a mix of neoantigen AMAX could reduce tumor growth in a pre-clinical syngeneic mouse model. Hence, we provide pre-clinical support for the induction of effector CD8+ T cells through the adaptable AMAX platform as easy implementable peptidic vaccination strategy against any antigen of choice, including neoantigens for anti-tumor immunity.
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Affiliation(s)
- Sjoerd T T Schetters
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands.
| | - R J Eveline Li
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands
| | - Laura J W Kruijssen
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands
| | - Steef Engels
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands
| | - Martino Ambrosini
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands
| | - Juan J Garcia-Vallejo
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands
| | - Hakan Kalay
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands
| | - Wendy W J Unger
- Laboratory of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands
| | - Yvette van Kooyk
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands.
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Oba T, Hoki T, Yamauchi T, Keler T, Marsh HC, Cao X, Ito F. A Critical Role of CD40 and CD70 Signaling in Conventional Type 1 Dendritic Cells in Expansion and Antitumor Efficacy of Adoptively Transferred Tumor-Specific T Cells. THE JOURNAL OF IMMUNOLOGY 2020; 205:1867-1877. [PMID: 32848036 DOI: 10.4049/jimmunol.2000347] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 07/29/2020] [Indexed: 12/29/2022]
Abstract
In vivo expansion of adoptively transferred CD8+ T cells is a critical determinant of successful adoptive T cell therapy. Emerging evidence indicates Batf3-dependent conventional type 1 dendritic cells (cDC1s) rarely found within the tumor myeloid compartment are crucial for effector T cell recruitment to the tumor microenvironment. However, the role of cDC1s in expansion of tumor-specific CD8+ T cells remains unclear. In this article, we addressed the role of cDC1s and their costimulatory molecules, CD40, CD70, and CD80/CD86, in expansion and antitumor efficacy of adoptively transferred in vitro-primed CD8+ T cells recognizing nonmutated tumor-associated self-antigens. We found that TLR/CD40-mediated expansion and antitumor efficacy of adoptively transferred tumor-specific CD8+ T cells were abrogated in Batf3-/- mice. Further mechanistic studies using mixed bone marrow chimeric mice identified that CD40 and CD70 but not CD80/CD86 signaling in cDC1s played a critical role in expansion and antitumor efficacy of adoptively transferred CD8+ T cells. Moreover, induction and activation of cDC1s by administration of FMS-like tyrosine kinase 3 ligand (Flt3L) and TLR/CD40 agonists augmented expansion of adoptively transferred CD8+ T cells, delayed tumor growth, and improved survival. These findings reveal a key role for CD40 and CD70 signaling in cDC1s and have major implications for the design of new vaccination strategies with adoptive T cell therapy.
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Affiliation(s)
- Takaaki Oba
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263
| | - Toshifumi Hoki
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263
| | - Takayoshi Yamauchi
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263
| | - Tibor Keler
- Celldex Therapeutics, Inc., Hampton, NJ 08827
| | | | - Xuefang Cao
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Fumito Ito
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263; .,Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263; and.,Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14263
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Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy. Pharmaceutics 2020; 12:pharmaceutics12070663. [PMID: 32674488 PMCID: PMC7408110 DOI: 10.3390/pharmaceutics12070663] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 06/29/2020] [Accepted: 07/04/2020] [Indexed: 02/07/2023] Open
Abstract
The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the innate immune system, but also generals of adaptive immunity and they orchestrate the de novo induction of tolerogenic and immunogenic T cell responses. Thus, combinatorial approaches addressing DCs and T cells in parallel represent an attractive strategy to achieve higher response rates across patients. However, this requires profound knowledge about the dynamic interplay of DCs, T cells, other immune and tumor cells. Here, we summarize the DC subsets present in mice and men and highlight conserved and divergent characteristics between different subsets and species. Thereby, we supply a resource of the molecular players involved in key functional features of DCs ranging from their sentinel function, the translation of the sensed environment at the DC:T cell interface to the resulting specialized T cell effector modules, as well as the influence of the tumor microenvironment on the DC function. As of today, mostly monocyte derived dendritic cells (moDCs) are used in autologous cell therapies after tumor antigen loading. While showing encouraging results in a fraction of patients, the overall clinical response rate is still not optimal. By disentangling the general aspects of DC biology, we provide rationales for the design of next generation DC vaccines enabling to exploit and manipulate the described pathways for the purpose of cancer immunotherapy in vivo. Finally, we discuss how DC-based vaccines might synergize with checkpoint inhibition in the treatment of malignant diseases.
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Morales Del Valle C, Maxwell JR, Xu MM, Menoret A, Mittal P, Tsurutani N, Adler AJ, Vella AT. Costimulation Induces CD4 T Cell Antitumor Immunity via an Innate-like Mechanism. Cell Rep 2020; 27:1434-1445.e3. [PMID: 31042471 DOI: 10.1016/j.celrep.2019.04.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 12/12/2018] [Accepted: 04/02/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic exposure to tumor-associated antigens inactivates cognate T cells, restricting the repertoire of tumor-specific effector T cells. This problem was studied here by transferring TCR transgenic CD4 T cells into recipient mice that constitutively express a cognate self-antigen linked to MHC II on CD11c-bearing cells. Immunotherapeutic agonists to CD134 plus CD137, "dual costimulation," induces specific CD4 T cell expansion and expression of the receptor for the Th2-associated IL-1 family cytokine IL-33. Rather than producing IL-4, however, they express the tumoricidal Th1 cytokine IFNγ when stimulated with IL-33 or IL-36 (a related IL-1 family member) plus IL-12 or IL-2. IL-36, which is induced within B16-F10 melanomas by dual costimulation, reduces tumor growth when injected intratumorally as a monotherapy and boosts the efficacy of tumor-nonspecific dual costimulated CD4 T cells. Dual costimulation thus enables chronic antigen-exposed CD4 T cells, regardless of tumor specificity, to elaborate tumoricidal function in response to tumor-associated cytokines.
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Affiliation(s)
| | - Joseph R Maxwell
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA
| | - Maria M Xu
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA
| | - Antoine Menoret
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA
| | - Payal Mittal
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA
| | - Naomi Tsurutani
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA
| | - Adam J Adler
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA.
| | - Anthony T Vella
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA.
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Mehta A, Hwang WL, Weekes C. The present and future of systemic and microenvironment-targeted therapy for pancreatic adenocarcinoma. ANNALS OF PANCREATIC CANCER 2020; 3:3. [PMID: 33294843 PMCID: PMC7720884 DOI: 10.21037/apc-2020-pda-05] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Metastatic pancreatic adenocarcinoma remains one of the deadliest cancer diagnoses with 5-year survival rates as low as 3%. For decades, gemcitabine remained the mainstay of systemic therapy before the approvals of FOLFIRINOX and gemcitabine with nab-paclitaxel. Despite these advances in the early 2010s, almost all patients progress on systemic chemotherapy and significant effort is needed to identify novel therapeutic targets. A promising array of approaches is currently under investigation, enabled by deeper understanding of the immune system within the tumor microenvironment (TME) and of the key vulnerabilities in pathways essential for tumor survival. In this review, we will explore the different approaches to boost tumor immunity and to target tumor metabolic pathways that are currently under clinical investigation for systemic treatment, and highlight the promising therapeutic areas that may give rise to the next generation of therapies for pancreatic cancer.
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Affiliation(s)
- Arnav Mehta
- Department of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA
- Dana Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - William L. Hwang
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
- Koch Institute for Integrative Cancer Research, Cambridge, MA, USA
| | - Colin Weekes
- Department of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA
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48
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Sufficiency of CD40 activation and immune checkpoint blockade for T cell priming and tumor immunity. Proc Natl Acad Sci U S A 2020; 117:8022-8031. [PMID: 32213589 DOI: 10.1073/pnas.1918971117] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Innate immune receptors such as toll-like receptors (TLRs) provide critical molecular links between innate cells and adaptive immune responses. Here, we studied the CD40 pathway as an alternative bridge between dendritic cells (DCs) and adaptive immunity in cancer. Using an experimental design free of chemo- or radiotherapy, we found CD40 activation with agonistic antibodies (⍺CD40) produced complete tumor regressions in a therapy-resistant pancreas cancer model, but only when combined with immune checkpoint blockade (ICB). This effect, unachievable with ICB alone, was independent of TLR, STING, or IFNAR pathways. Mechanistically, αCD40/ICB primed durable T cell responses, and efficacy required DCs and host expression of CD40. Moreover, ICB drove optimal generation of polyfunctional T cells in this "cold" tumor model, instead of rescuing T cell exhaustion. Thus, immunostimulation via αCD40 is sufficient to synergize with ICB for priming. Clinically, combination αCD40/ICB may extend efficacy in patients with "cold" and checkpoint-refractory tumors.
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49
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Wattenberg MM, Beatty GL. Overcoming immunotherapeutic resistance by targeting the cancer inflammation cycle. Semin Cancer Biol 2020; 65:38-50. [PMID: 31954172 DOI: 10.1016/j.semcancer.2020.01.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 01/05/2020] [Accepted: 01/07/2020] [Indexed: 02/07/2023]
Abstract
Inflammation is a hallmark of cancer and supports tumor growth, proliferation, and metastasis, but also inhibits T cell immunosurveillance and the efficacy of immunotherapy. The biology of cancer inflammation is defined by a cycle of distinct immunological steps that begins during disease conception with the release of inflammatory soluble factors. These factors communicate with host organs to trigger bone marrow mobilization of myeloid cells, trafficking of myeloid cells to the tumor, and differentiation of myeloid cells within the tumor bed. Tumor-infiltrating myeloid cells then orchestrate an immunosuppressive microenvironment and assist in sustaining a vicious cycle of inflammation that co-evolves with tumor cells. This Cancer-Inflammation Cycle acts as a rheostat or "inflammostat" that impinges upon T cell immunosurveillance and prevents the development of productive anti-tumor immunity. Here, we define the major nodes of the Cancer-Inflammation Cycle and describe their impact on T cell immunosurveillance in cancer. Additionally, we discuss emerging pre-clinical and clinical data suggesting that intervening upon the Cancer-Inflammation Cycle will be a necessary step for broadening the potential of immunotherapy in cancer.
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Affiliation(s)
- Max M Wattenberg
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Gregory L Beatty
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
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50
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Abstract
The adaptive immune response is a 500-million-year-old (the "Big Bang" of Immunology) collective set of rearranged and/or selected receptors capable of recognizing soluble and cell surface molecules or shape (B cells, antibody), endogenous and extracellular peptides presented by Major Histocompatibility (MHC) molecules including Class I and Class II (conventional αβ T cells), lipid in the context of MHC-like molecules of the CD1 family (NKT cells), metabolites and B7 family molecules/butyrophilins with stress factors (γδT cells), and stress ligands and absence of MHC molecules (natural killer, NK cells). What makes tumor immunogenic is the recruitment of initially innate immune cells to sites of stress or tissue damage with release of Damage-Associated Molecular Pattern (DAMP) molecules. Subsequent maintenance of a chronic inflammatory state, representing a balance between mature, normalized blood vessels, innate and adaptive immune cells and the tumor provides a complex tumor microenvironment serving as the backdrop for Darwinian selection, tumor elimination, tumor equilibrium, and ultimately tumor escape. Effective immunotherapies are still limited, given the complexities of this highly evolved and selected tumor microenvironment. Cytokine therapies and Immune Checkpoint Blockade (ICB) enable immune effector function and are largely dependent on the shape and size of the B and T cell repertoires (the "adaptome"), now accessible by Next-Generation Sequencing (NGS) and dimer-avoidance multiplexed PCR. How immune effectors access the tumor (infiltrated, immune sequestered, and immune desserts), egress and are organized within the tumor are of contemporary interest and substantial investigation.
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