Anti-CD19 CAR T cells for refractory myasthenia gravis

Building upon a study published in The Lancet Neurology showing the feasibility of transiently expressed B-cell maturation antigen (BCMA)-targeted RNA chimeric antigen receptor (CAR) T-cell therapy in patients with myasthenia gravis,1Granit V Benatar M Kurtoglu M et al.Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study.Lancet Neurol. 2023; 22: 578-590Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar we report a case that indicates that a different CAR T-cell approach that targets CD19 with a stably expressed CAR, delivered following a conventional lymphodepleting regimen, might be safe and effective in the treatment of severe and refractory myasthenia gravis. Myasthenia gravis is caused by a B-cell-driven dysfunction of neuromuscular transmission, often mediated by anti-acetylcholine receptor (anti-AchR) antibodies. The disorder clinically manifests as muscle weakness and fatigue, and poses substantial challenges in terms of effective therapy.2Dalakas MC Immunotherapy in myasthenia gravis in the era of biologics.Nat Rev Neurol. 2019; 15: 113-124Crossref PubMed Scopus (102) Google Scholar We report the first case of successful treatment of a patient with severe, treatment-refractory, anti-AchR-positive generalised myasthenia gravis using fully human autologous anti-CD19 CAR T cells. Our patient, a 33-year-old woman, was diagnosed with anti-AchR-positive generalised myasthenia gravis in 2012 at another academic centre. Between November, 2021, and May, 2023, she experienced difficulties in swallowing and breathing, became unable to walk without assistive devices, and had several myasthenic crises resulting in five admissions to the intensive care unit at our institution that required invasive ventilation. Previous treatment attempts, including thymectomy (in April, 2022, performed at another academic centre), acetylcholinesterase inhibitors (initiated in 2012 at our institution), and B-cell-depleting antibodies (rituximab, administered in April and October, 2021, at our institution) did not stabilise the disease course, which was class V according to the Myasthenia Gravis Foundation of America criteria (defined as intubation, with or without mechanical ventilation, except when used during routine postoperative management).3Jaretzki 3rd, A Barohn RJ Ernstoff RM et al.Myasthenia gravis: recommendations for clinical research standards.Neurology. 2000; 55: 16-23Crossref PubMed Scopus (1132) Google Scholar Moreover, a proteasome inhibitor (bortezomib, administered in May and November, 2022), immunosuppressive drugs (mycophenolate mofetil, administered for 21 months preceding the CAR T-cell infusion), and immunoglobulin therapy (initiated in October, 2021) had proven futile in providing long-term relief (appendix p 4). Most recently, between March and May, 2023, the patient showed clinical progression despite being on glucocorticoids, mycophenolate mofetil, and bortezomib. Given the refractory nature of the disorder, and following successful use of anti-CD19 CAR T cells in autoimmune rheumatic diseases,4Mougiakakos D Krönke G Völkl S et al.CD19-targeted CAR T cells in refractory systemic lupus erythematosus.N Engl J Med. 2021; 385: 567-569Crossref PubMed Scopus (125) Google Scholar, 5Müller F Boeltz S Knitza J et al.CD19-targeted CAR T cells in refractory antisynthetase syndrome.Lancet. 2023; 401: 815-818Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar we decided to treat her with a rationally designed CAR T approach. We used a CAR construct that is associated with lower cytokine production and toxicity than constructs that contain a murine anti-CD19 (FMC63) single-chain variable fragment and a CD28 hinge and transmembrane domain, such as the commercially available axibactagene ciloleucel product.6Brudno JN Lam N Vanasse D et al.Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma.Nat Med. 2020; 26: 270-280Crossref PubMed Scopus (153) Google Scholar Ongoing immunosuppression was tapered to low-dose glucocorticoids before leukapheresis and CAR T-cell infusion. Mycophenolate mofetil was resumed after successful collection, up to 2 days before the start of lymphodepletion. Autologous T cells were transduced with a second generation anti-CD19 CAR T construct (KYV-101, Kyverna Therapeutics, Emeryville, CA, USA) comprising a fully human CD19 binding domain, a CD8α hinge and transmembrane domain, a CD28 costimulatory domain, and a CD3ξ activation domain.6Brudno JN Lam N Vanasse D et al.Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma.Nat Med. 2020; 26: 270-280Crossref PubMed Scopus (153) Google Scholar Following successful in vitro expansion and lymphodepletion with fludarabine (30 mg/m2 on day –6, –5, and –4) and cyclophosphamide (300 mg/m2 on day –6, –5, and –4), our patient received a single infusion of 1 × 108 anti-CD19 CAR T cells (day 0). Consistent with previous experience using this CAR construct in patients with lymphoma,6Brudno JN Lam N Vanasse D et al.Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma.Nat Med. 2020; 26: 270-280Crossref PubMed Scopus (153) Google Scholar CAR T cells reached their peak expansion on day 16 (131 cells per μL; 16% of total CD3 T cells). Notably, CD4 cells mainly drove CAR T-cell expansion. By day 62, CAR T cells were still detectable (0·5 cells per μL; 0·19% of total CD3 T cells; appendix p 5). The patient had no adverse events related to CAR T-cell therapy, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, insufficient haematopoietic reconstitution (except pre-existing sideropenic anaemia), or hypogammaglobulinemia of less than 5 g/dL. However, she did have self-limiting and resolving grade 1 transaminitis (according to Common Terminology Criteria for Adverse Events, version 5) that did not require treatment (appendix p 6). Circulating CD19 B cells, already reduced due to previous treatments, were eliminated by day 8 and have not reconstituted as of day 62 (appendix p 7). We measured a 70% reduction in pathogenic anti-AchR antibodies from 2434 nmol/mL at day 0 to 718 nmol/mL at day 62, whereas protective vaccination IgG titres were maintained (appendix p 7). These observations, consistent with findings in other autoimmune diseases,4Mougiakakos D Krönke G Völkl S et al.CD19-targeted CAR T cells in refractory systemic lupus erythematosus.N Engl J Med. 2021; 385: 567-569Crossref PubMed Scopus (125) Google Scholar, 5Müller F Boeltz S Knitza J et al.CD19-targeted CAR T cells in refractory antisynthetase syndrome.Lancet. 2023; 401: 815-818Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar indicate that a substantial proportion of pathogenic anti-AchR autoantibodies are produced by plasmablasts and short-lived plasma cells, which do express CD19 and therefore are susceptible to being depleted by KYV-101, whereas protective autoantibodies, produced by bone marrow long-lived plasma cells that do not express CD19,7Halliley JL Tipton CM Liesveld J et al.Long-lived plasma cells are contained within the CD19(-)CD38(hi)CD138(+) subset in human bone marrow.Immunity. 2015; 43: 132-145Summary Full Text Full Text PDF PubMed Scopus (317) Google Scholar are shielded from the effects of CD19 CAR T cells. The serological findings were paralleled by the patient's improved muscle strength and fatigue over the first 2 months after CD19 CAR T infusion, evidenced by the steady increase in the time that the patient could hold out her arm horizontally, her enhanced walking ability without any supportive devices, and the reduction of the clinical multiparameter Besinger disease activity and the Quantitative Myasthenia Gravis scores3Jaretzki 3rd, A Barohn RJ Ernstoff RM et al.Myasthenia gravis: recommendations for clinical research standards.Neurology. 2000; 55: 16-23Crossref PubMed Scopus (1132) Google Scholar, 8Besinger UA Toyka KV Hömberg M Heininger K Hohlfeld R Fateh-Moghadam A Myasthenia gravis: long-term correlation of binding and bungarotoxin blocking antibodies against acetylcholine receptors with changes in disease severity.Neurology. 1983; 33: 1316-1321Crossref PubMed Google Scholar (figure). These results were observed despite very limited exposure to prednisolone (10 mg/day) and pyridostigmine (360 mg/day of short-acting form and 180 mg/day of long-acting form), which we intend to withdraw in the coming months. Together with previous observations in patients with autoimmune rheumatic diseases,4Mougiakakos D Krönke G Völkl S et al.CD19-targeted CAR T cells in refractory systemic lupus erythematosus.N Engl J Med. 2021; 385: 567-569Crossref PubMed Scopus (125) Google Scholar, 5Müller F Boeltz S Knitza J et al.CD19-targeted CAR T cells in refractory antisynthetase syndrome.Lancet. 2023; 401: 815-818Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar this evidence suggests that use of anti-CD19 CAR T cells might be effective for a broad range of diseases that are based on autoreactive B cells and autoantibodies. New treatment approaches are particularly needed for patients with neurological diseases, because of their severity and the few treatment options currently available. DB is an employee and shareholder of Kyverna Therapeutics. GS has received consulting fees from Kyverna Therapeutics and Cabaletta. All other authors declare no competing interests. AH and TH contributed equally. DM provided the pivotal conceptual framework of the study. AH and DM have verified the data presented; all authors had full access to all the data analysed in the case report and accept responsibility for submitting this Correspondence for publication. The study was supported by the Deutsche Forschungsgemeinschaft (FOR2886, RTG2408, TRR221, CRC1181). Download .pdf (.78 MB) Help with pdf files Supplementary appendix