1. Neospora caninum: a new class of biopharmaceuticals in the therapeutic arsenal against cancer
- Author
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Lantier, Louis, Poupée-Beaugé, Agathe, di Tommaso, Anne, Ducournau, Céline, Epardaud, Mathieu, Lakhrif, Zineb, Germon, Stéphanie, Debierre-Grockiego, Françoise, Mévélec, Marie-Noëlle, Battistoni, Arthur, Coënon, Loïs, Deluce-Kakwata-Nkor, Nora, Velge-Roussel, Florence, Beauvillain, Céline, Baranek, Thomas, Lee, Gordon Scott, Kervarrec, Thibault, Touzé, Antoine, Moiré, Nathalie, Dimier-Poisson, Isabelle, Chanteloup, Nathalie Katy, Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Kymeris Santé, Département de Pathologie [CHRU Tours], Université Francois Rabelais [Tours], ARD2020 Biomedicaments program (2017 00118200), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Tours, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Université Francois Rabelais [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Université Francois Rabelais [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
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[SDV.IMM] Life Sciences [q-bio]/Immunology ,[SDV]Life Sciences [q-bio] ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,immunity ,[SDV] Life Sciences [q-bio] ,Oncolytic and Local Immunotherapy ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,parasitic diseases ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,immunotherapy ,cellular ,RC254-282 - Abstract
International audience; Background Microorganisms that can be used for their lytic activity against tumor cells as well as inducing or reactivating antitumor immune responses are a relevant part of the available immunotherapy strategies. Viruses, bacteria and even protozoa have been largely explored with success as effective human antitumor agents. To date, only one oncolytic virus-T-VEC-has been approved by the US Food and Drug Administration for use in biological cancer therapy in clinical trials. The goal of our study is to evaluate the potential of a livestock pathogen, the protozoan Neospora caninum, non-pathogenic in humans, as an effective and safe antitumorous agent.Methods/Results We demonstrated that the treatment of murine thymoma EG7 by subcutaneous injection of N. caninum tachyzoites either in or remotely from the tumor strongly inhibits tumor development, and often causes their complete eradication. Analysis of immune responses showed that N. caninum had the ability to 1) lyze infected cancer cells, 2) reactivate the immunosuppressed immune cells and 3) activate the systemic immune system by generating a protective antitumor response dependent on natural killer cells, CD8-T cells and associated with a strong interferon (IFN)-gamma secretion in the tumor microenvironment. Most importantly, we observed a total clearance of the injected agent in the treated animals: N. caninum exhibited strong anticancer effects without persisting in the organism of treated mice. We also established in vitro and an in vivo non-obese diabetic/severe combined immunodeficiency mouse model that N. caninum infected and induced a strong regression of human Merkel cell carcinoma. Finally, we engineered a N. caninum strain to secrete human interleukin (IL)-15, associated with the alpha-subunit of the IL-15 receptor thus strengthening the immuno-stimulatory properties of N. caninum. Indeed, this NC1-IL15hRec strain induced both proliferation of and IFN-gamma secretion by human peripheral blood mononuclear cells, as well as improved efficacy in vivo in the EG7 tumor model.Conclusion These results highlight N. caninum as a potential, extremely effective and non-toxic anticancer agent, capable of being engineered to either express at its surface or to secrete biodrugs. Our work has identified the broad clinical possibilities of using N. caninum as an oncolytic protozoan in human medicine.
- Published
- 2020
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