Chimäre Antigenrezeptor-T-Zellen – Die Evolution zellulärer Immuntherapie von malignen zu nicht-malignen Erkrankungen

Zusammenfassung

Immunonkologische Therapien wie Immuncheckpoint-Inhibitoren (ICIs) und bispezifische Antikörper haben die Behandlung von soliden und hämatologischen Tumorentitäten mit einem neuen Arsenal an Möglichkeiten ausgestattet. Dabei spielen T-Zellen eine zentrale Rolle bei der Bekämpfung entarteter Zellen. Moderne Gen-Transfer- und -Engineering-Methoden haben im letzten Jahrzehnt die Kombination von synthetischer Biologie und adoptiver, zellulärer Immuntherapie ermöglicht und somit die Ausstattung von Patienten-T-Zellen mit chimären Antigenrezeptoren (CAR). Diese vereinen die Antigen-bindenden Eigenschaften von Antikörpern mit den Signal-gebenden Domänen des T-Zell-Rezeptors und erlauben den so entstehenden CAR-T-Zellen die Zerstörung von Tumorzellen in Antigen-spezifischer Art und Weise. Diese „living drugs“ haben insbesondere die Behandlung B-Zell-vermittelter, hämatologischer Erkrankungen revolutioniert und zeigen neben hohen Ansprech- ebenso langjährige Remissionsraten. Die Möglichkeit CAR gegen neue Zielantigene zu generieren und auch die Eigenschaften von T-Zellen über Genom-Editierung zu steuern führt das Feld nicht nur immer weiter in den Bereich der soliden Tumore, sondern gleichsam in das Feld nicht-maligner Erkrankungen. Insbesondere die tiefe B-Zell-Depletion über CD19-CAR-T-Zellen hat bei ersten Patienten mit Systemischem Lupus erythematosus (SLE) und anderen Kollagenosen zu beachtlichen Erfolgen geführt. Dabei beschränkt sich die bisher publizierte Erfahrung auf kleine Fallserien und Fallberichte. Auf Basis dieser Daten ist ebenso der Einsatz von CAR-T-Zellen in anderen B-Zell-vermittelten Autoimmunitäten denkbar und wird die Rheumatologie in Zukunft gewiss beschäftigen. Mehrere Phase 1- und 2-Studien zu CAR-T-Zell-Therapien bei Autoimmunerkrankung werden aktuell entwickelt oder schon initiiert. Der vorliegende Artikel soll die Grundzüge der CAR-T-Zell-Technologie erläutern sowie ihre Perspektiven für die Verwendung im Bereich nicht-maligner Erkrankungen beleuchten.

Abstract

Immunotherapies such as immune checkpoint inhibitors (ICIs) and bispecific antibodies have brought a new arsenal of possibilities to the treatment of solid and haematological tumour entities. T cells play a central role in the fight against malignant cells. In the past decade, modern gene transfer and engineering methods have made it possible to combine synthetic biology and adoptive cellular immunotherapy and thus to equip patient T cells with chimeric antigen receptors (CARs). Combining the antigen-binding properties of antibodies with the signalling domains of the T cell receptor, CARs allow the generated CAR T cells to destroy tumour cells in an antigen-specific manner. In particular, these “living drugs” have revolutionised the treatment of B cell-mediated haematological diseases, and they show high response and long-term remission rates. The ability to generate CARs against new target antigens and to control the properties of T cells via genome editing is moving the field further into the area of solid tumours as well as into applications for non-malignant diseases. In particular, deep B cell depletion via CD19 CAR T cells has led to considerable success in the first patients with systemic lupus erythematosus (SLE) and other collagenoses. The experience published to date is limited to small case series and case reports. Based on these data, the use of CAR T cells in other B cell-mediated autoimmunities is also conceivable and will certainly be a focus in the field of rheumatology in the future. Several phase 1 and 2 studies on CAR T cell therapies for autoimmune diseases are currently being developed or have already been initiated. This article intends to explain the main features of CAR T cell technology and highlight its prospects for use in the field of non-malignant diseases.

Schlüsselwörter

CAR-T-Zellen - Zelltherapie - Nicht-maligne Erkrankungen

Keywords

CAR T cells - cellular therapy - non-malignant diseases

Publication History

Article published online:
07 August 2024

• Literatur

• 1 Gong MC, Latouche JB, Krause A. et al. Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen. Neoplasia 1999; 1: 123-127 DOI: 10.1038/sj.neo.7900018.
• 2 Krause A, Guo HF, Latouche JB. et al. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. Journal of Experimental Medicine 1998; 188: 619-626 DOI: 10.1084/jem.188.4.619.
• 3 Guedan S, Luu M, Ammar D. et al. Time 2EVOLVE: predicting efficacy of engineered T-cells - how far is the bench from the bedside?. Journal for ImmunoTherapy of Cancer 2022; 10 DOI: 10.1136/jitc-2021-003487.
• 4 Melenhorst JJ, Chen GM, Wang M. et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature 2022; 602: 503-509 DOI: 10.1038/s41586-021-04390-6.
• 5 Bergmann C, Müller F, Distler JHW. et al. Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells. Ann Rheum Dis 2023; 82: 1117-1120 DOI: 10.1136/ard-2023-223952.
• 6 Mackensen A, Müller F, Mougiakakos D. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 2022; 28: 2124-2132 DOI: 10.1038/s41591-022-02017-5.
• 7 Mougiakakos D, Krönke G, Völkl S. et al. CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. New England Journal of Medicine 2021; 385: 567-569 DOI: 10.1056/NEJMc2107725.
• 8 Pecher A-C, Hensen L, Klein R. et al. CD19-Targeting CAR T Cells for Myositis and Interstitial Lung Disease Associated With Antisynthetase Syndrome. JAMA 2023; 329: 2154-2162 DOI: 10.1001/jama.2023.8753.
• 9 Routy B, Le Chatelier E, Derosa L. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359: 91-97 DOI: 10.1126/science.aan3706.
• 10 Jetani H, Navarro-Bailón A, Maucher M. et al. Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia. Blood 2021; 138: 1830-1842 DOI: 10.1182/blood.2020009192.
• 11 Luu M, Riester Z, Baldrich A. et al. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat Commun 2021; 12: 4077 DOI: 10.1038/s41467-021-24331-1.
• 12 Rosenberg SA, Yang JC, Sherry RM. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clinical Cancer Research 2011; 17: 4550-4557 DOI: 10.1158/1078-0432.CCR-11-0116.
• 13 Di Pilato M, Kfuri-Rubens R, Pruessmann JN. et al. CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment. Cell 2021; 184: 4512-4530.e22 DOI: 10.1016/j.cell.2021.07.015.
• 14 Lesch S, Blumenberg V, Stoiber S. et al. T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours. Nat Biomed Eng 2021; 5: 1246-1260 DOI: 10.1038/s41551-021-00737-6.
• 15 Bell M, Lange S, Sejdiu BI. et al. Modular chimeric cytokine receptors with leucine zippers enhance the antitumour activity of CAR T cells via JAK/STAT signalling. Nat Biomed Eng 2024; 8: 380–396 DOI: 10.1038/s41551-023-01143-w.
• 16 Donnadieu E, Luu M, Alb M. et al. Time to evolve: predicting engineered T cell-associated toxicity with next-generation models. Journal for ImmunoTherapy of Cancer 2022; 10 DOI: 10.1136/jitc-2021-003486.
• 17 Querques I, Mades A, Zuliani C. et al. A highly soluble Sleeping Beauty transposase improves control of gene insertion. Nature Biotechnology 2019; 37: 1502-1512 DOI: 10.1038/s41587-019-0291-z.
• 18 Prommersberger S, Reiser M, Beckmann J. et al. CARAMBA: a first-in-human clinical trial with SLAMF7 CAR-T cells prepared by virus-free Sleeping Beauty gene transfer to treat multiple myeloma. Gene Therapy 2021; 28: 560-571 DOI: 10.1038/s41434-021-00254-w.
• 19 Martínez Bedoya D, Dutoit V, Migliorini D. Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma. Front Immunol 2021; 12: 640082 DOI: 10.3389/fimmu.2021.640082.
• 20 Luu M, Schütz B, Lauth M. et al. The Impact of Gut Microbiota-Derived Metabolites on the Tumor Immune Microenvironment. Cancers 2023; 15 DOI: 10.3390/cancers15051588.
• 21 Rodriguez-Garcia A, Lynn RC, Poussin M. et al. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy. Nat Commun 2021; 12: 877 DOI: 10.1038/s41467-021-20893-2.
• 22 Tran E, Chinnasamy D, Yu Z. et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med 2013; 210: 1125-1135 DOI: 10.1084/jem.20130110.
• 23 Chamberlain CA, Bennett EP, Kverneland AH. et al. Highly efficient PD-1-targeted CRISPR-Cas9 for tumor-infiltrating lymphocyte-based adoptive T cell therapy. Molecular Therapy - Oncolytics 2022; 24: 417-428 DOI: 10.1016/j.omto.2022.01.004.
• 24 Ataide MA, Komander K, Knöpper K. et al. BATF3 programs CD8+ T cell memory. Nature Immunology 2020; 21: 1397-1407 DOI: 10.1038/s41590-020-0786-2.
• 25 Petri K, Zhang W, Ma J. et al. CRISPR prime editing with ribonucleoprotein complexes in zebrafish and primary human cells. Nat Biotechnol 2022; 40: 189-193 DOI: 10.1038/s41587-021-00901-y.
• 26 Ghosh A, Smith M, James SE. et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nature Medicine 2017; 23: 242-249 DOI: 10.1038/nm.4258.
• 27 Maude SL, Laetsch TW, Buechner J. et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. New England Journal of Medicine 2018; 378: 439-448 DOI: 10.1056/NEJMoa1709866.
• 28 Munshi NC, Anderson LD, Shah N. et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. New England Journal of Medicine 2021; 384: 705-716 DOI: 10.1056/NEJMoa2024850.
• 29 Seif M, Kakoschke TK, Ebel F. et al. CAR T cells targeting Aspergillus fumigatus are effective at treating invasive pulmonary aspergillosis in preclinical models. Science Translational Medicine 2022; 14: eabh1209 DOI: 10.1126/scitranslmed.abh1209.
• 30 Aghajanian H, Kimura T, Rurik JG. et al. Targeting cardiac fibrosis with engineered T cells. Nature 2019; 573: 430-433 DOI: 10.1038/s41586-019-1546-z.
• 31 Haghikia A, Hegelmaier T, Wolleschak D. et al. Anti-CD19 CAR T cells for refractory myasthenia gravis. Lancet Neurol 2023; 22: 1104-1105 DOI: 10.1016/S1474-4422(23)00375-7.