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New dawn of cellular therapies in autoimmune diseases

2023; Cell Press; Volume: 31; Linguagem: Inglês

10.1016/j.omtm.2023.101141

2329-0501

Dimitrios L. Wagner, Lennard Ostendorf,

T-cell and B-cell Immunology

In many autoimmune diseases, autoreactive antibodies contribute to the pathogenesis or directly induce organ dysfunction. These antibodies are secreted by B and plasma cells, which have thus been identified as important treatment targets. However, some antibody-secreting cells, such as long-lived plasma cells (LLPCs), have remained elusive targets. Their proliferative senescence precludes antiproliferative approaches and their negativity for CD20 precludes an attack with rituximab or other αCD20 monoclonal antibodies.1Maschmeyer P. Chang H.-D. Cheng Q. Mashreghi M.-F. Hiepe F. Alexander T. Radbruch A. Immunological memory in rheumatic inflammation - a roadblock to tolerance induction.Nat. Rev. Rheumatol. 2021; 17: 291-305https://doi.org/10.1038/s41584-021-00601-6Crossref PubMed Scopus (14) Google Scholar Other B cells escape targeting by transiently downregulating CD20 or hiding in tissue niches.2Crickx E. Chappert P. Sokal A. Weller S. Azzaoui I. Vandenberghe A. Bonnard G. Rossi G. Fadeev T. Storck S. et al.Rituximab-resistant splenic memory B cells and newly engaged naive B cells fuel relapses in patients with immune thrombocytopenia.Sci. Transl. Med. 2021; 13eabc3961https://doi.org/10.1126/scitranslmed.abc3961Crossref PubMed Scopus (26) Google Scholar CD19-targeting chimeric antigen receptor (CAR) T cells now have shown remarkable short-term efficacy in a case series of patients with the autoimmune disease systemic lupus erythematosus (SLE) by depleting most autoantibody-secreting cells.3Mougiakakos D. Krönke G. Völkl S. Kretschmann S. Aigner M. Kharboutli S. Böltz S. Manger B. Mackensen A. Schett G. CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus.N. Engl. J. Med. 2021; 385: 567-569https://doi.org/10.1056/NEJMc2107725Crossref PubMed Scopus (116) Google Scholar,4Mackensen A. Müller F. Mougiakakos D. Böltz S. Wilhelm A. Aigner M. Völkl S. Simon D. Kleyer A. Munoz L. et al.Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus.Nat. Med. 2022; 28: 2124-2132https://doi.org/10.1038/s41591-022-02017-5Crossref PubMed Scopus (121) Google Scholar The ability of this "living drug" to invade tissues likely leads to an increased treatment effect compared with monoclonal antibodies. In this issue of Molecular Therapy: Methods & Clinical Development, Nunez et al.5Nunez D. Patel D. Volkov J. Wong S. Vorndran Z. Müller F. Aigner M. Völkl S. Mackensen A. Schett G. et al.Cytokine and reactivity profiles SLE patients following anti-CD19 CART therapy.Mol. Ther. Methods Clin. Dev. 2023; : 31https://doi.org/10.1016/j.omtm.2023.08.023Abstract Full Text Full Text PDF Scopus (0) Google Scholar present data on proinflammatory cytokines, autoantibodies, and vaccine-induced protective antibodies before and 3 months after CD19-CAR T cell therapy, thereby expanding our understanding of the biological mode of action of CAR T cells in SLE. Although this approach has undoubtedly been very successful in the reported cases, a controlled trial and long-term outcome data are still pending. The adaptation of CD19-CAR T cell-based therapies to target B and plasma cells is only the next step in a long history of treatment approaches of malignant diseases translated to autoimmune diseases. Previous examples include the depletion of pathogenic autoimmune B cells with the anti-CD20 antibody rituximab, targeting of LLPCs with the anti-CD38 antibody daratumumab,6Ostendorf L. Burns M. Durek P. Heinz G.A. Heinrich F. Garantziotis P. Enghard P. Richter U. Biesen R. Schneider U. et al.Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus.N. Engl. J. Med. 2020; 383: 1149-1155https://doi.org/10.1056/NEJMoa2023325Crossref PubMed Scopus (141) Google Scholar and autologous hematopoietic stem cell transplantation to "reset" the immune memory of both B and T cells.1Maschmeyer P. Chang H.-D. Cheng Q. Mashreghi M.-F. Hiepe F. Alexander T. Radbruch A. Immunological memory in rheumatic inflammation - a roadblock to tolerance induction.Nat. Rev. Rheumatol. 2021; 17: 291-305https://doi.org/10.1038/s41584-021-00601-6Crossref PubMed Scopus (14) Google Scholar Anti-CD19 CAR T cells are likely only the beginning of wider and more targeted use of cellular therapies in autoimmune diseases: regulatory T cell products have been successfully used in early-stage clinical trials for organ transplantation and are especially interesting for diseases in which T-cell-mediated organ damage plays an important role.7Roemhild A. Otto N.M. Moll G. Abou-El-Enein M. Kaiser D. Bold G. Schachtner T. Choi M. Oellinger R. Landwehr-Kenzel S. et al.Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial.BMJ. 2020; 371: m3734https://doi.org/10.1136/bmj.m3734Crossref PubMed Scopus (88) Google Scholar,8Landwehr-Kenzel S. Müller-Jensen L. Kuehl J.-S. Abou-El-Enein M. Hoffmann H. Muench S. Kaiser D. Roemhild A. von Bernuth H. Voeller M. et al.Adoptive transfer of ex vivo expanded regulatory T cells improves immune cell engraftment and therapy-refractory chronic GvHD.Mol. Ther. 2022; 30: 2298-2314https://doi.org/10.1016/j.ymthe.2022.02.025Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar For autoantibody-mediated autoimmune diseases, CAR T cells targeting more specific plasma cell antigens (such as BCMA) are currently in clinical trials for autoimmune diseases. A recent census counted 14 ongoing trials using CD19 and/or BCMA-targeted CAR T cells in SLE alone.9Mullard A. CAR T cell therapies raise hopes — and questions — for lupus and autoimmune disease.Nat. Rev. Drug Discov. 2023; https://doi.org/10.1038/d41573-023-00166-xCrossref Google Scholar The "holy grail" of targeted therapies in autoimmunity, however, is the specific targeting of antigen-specific, pathogenic cells without the depletion of protective immunity. For this purpose, chimeric autoantibody receptors (CAARs) are being developed, whereby CAAR cells express the autoantigen on their surfaces and deploy cytotoxic effector functions against antigen-specific cells that bind to the autoantigen.10Ellebrecht C.T. Bhoj V.G. Nace A. Choi E.J. Mao X. Cho M.J. Di Zenzo G. Lanzavecchia A. Seykora J.T. Cotsarelis G. et al.Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease.Science. 2016; 353: 179-184https://doi.org/10.1126/science.aaf6756Crossref PubMed Scopus (390) Google Scholar Cellular therapeutics for autoimmune diseases are only now dawning and are likely to significantly reduce morbidity and mortality among patients with chronic disease, at least those who can afford them. New innovations are therefore urgently needed to make cellular therapies for autoimmune diseases affordable and accessible (e.g., in off-the-shelf approaches or in vivo CAR T cell generation). D.L.W. and L.O. received funding from the European Union under grant agreement 101057438 (geneTIGA; genetiga-horizon.eu). However, the views and opinions expressed are those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them. D.L.W. and L.O. researched the content, discussed and wrote the manuscript. D.L.W. is named as an inventor on multiple patent applications on cell and gene therapies and is a scientific co-founder of TCBalance Biopharmaceuticals GmbH, focused on regulatory T cell therapy.