The autologous approach, which bypasses complex exogenous manufacturing, has been successful in a SLE patient, the NEJM reports.
A single infusion of in vivo CD19 CAR T-cell therapy has shown the ability to wipe out disease-driving B cells and dramatically reduce symptoms in patients with refractory systemic lupus erythematosus, offering a potential paradigm shift in treatment.
Traditional autologous CAR T-cell therapies targeting CD19 have shown promise in autoimmune diseases but are limited by high costs and the need for conditioning chemotherapy.
This novel approach employs cell-targeted lipid nanoparticles (LNPs) or lentiviral vectors to generate CAR T-cells directly in the patient, potentially circumventing these barriers.
CAR T-cell therapy was initially developed to treat certain kinds of tumour and blood diseases, such as lymphoma and leukaemia.
The findings were published as correspondence in The New England Journal of Medicine.
The investigational therapy, HN2301, is an engineered CD8 T-cell–targeted LNP encapsulating CD19 CAR messenger RNA that delivers CD19 CAR messenger RNA to CD8+ T cells. Preclinical studies in nonhuman primates showed effective in vivo transfection, rapid B-cell depletion, and minimal toxicity.
“In vitro, HN2301 successfully reprogrammed CAR T-cells and killed autologous B cells from healthy donors and patients with systemic lupus erythematosus (SLE),” the authors wrote.
In the first-in-human trial, five patients with SLE resistant to multiple therapies received HN2301 after stopping immunosuppressive drugs one week prior.
CD8+ CD19 CAR T cells appeared in peripheral blood within six hours, peaked quickly, and returned to baseline within two to three days, with off-target CAR expression below 10%.
B-cell depletion was rapid and dose-dependent, reaching complete depletion in higher-dose recipients and persisting for up to ten days. CAR T-cell activation was confirmed by CD69 up-regulation on CD8+ T cells, the researchers wrote.
They noted that the therapy was well tolerated. No grade 3 or 4 cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome occurred.
Three patients received a single tocilizumab dose to manage mild cytokine release syndrome. Liver enzymes and blood counts remained stable aside from transient lymphocyte reductions.
Immunological markers improved, with reductions in anti-dsDNA and antinucleosome antibodies and normalisation of complement in some patients.
“At the last visit [three months after HN2301 treatment], scores on the Systemic Lupus Erythematosus Disease Activity Index 2000 had decreased [indicating less disease activity] in all five patients,” the researchers wrote.
“These data support the potential role of in vivo CAR T-cell therapy in autoimmune disease. Cell-targeted LNP technology can successfully generate functionally active CD19 CAR T cells in patients with SLE in vivo that have the capacity to deplete B cells and affect disease-associated autoantibodies and disease activity, with only low-grade cytokine release syndrome and no other major toxic effects.
“More data are necessary to determine the durability of effect and the appropriate dose and treatment schedule to achieve the immune reset necessary for long-term drug-free remission.”
Associate Professor Alberta Hoi, Monash Health Consultant Rheumatologist, Clinical Trial Lead and researcher in the School of Clinical Sciences at Monash University, told Rheumatology Republic it was a novel study.
“mRNA technology is not that new, and most of us are familiar with its application in vaccinations, such as covid vaccines,” she said.
“But what is new in this setting is the specific delivery system, the LNP delivery system that has a target to CD8+ T cells, which then helps to offload the messenger package, to the right cellular type to convert them in vivo into CD19 targeting cells.
“I presume the main advantage is the manufacturing cost is significantly less than, say, a monoclonal antibody.”
Professor Hoi is well-versed in the use of CAR T-cell therapy to treat autoimmune diseases like lupus.
Related
Earlier this year Monash Health and Monash University released details of a trial of CAR T-cell therapy in one patient with lupus, led by Professor Hoi. It was touted as the first time a patient had been successfully treated for lupus with CAR T-cell therapy.
The treatment in a female patient, 32-year-old Lani Watson had been effective in re-engineering patient’s immune cells to target and eliminate harmful immune responses.
“Lani’s response to the treatment has been fantastic – she’s now off her immunosuppressant that she was previously dependent on,” Professor Hoi told media in May this year.
“This new treatment offers significant hope for people suffering with lupus, it’s a game changer.”
Professor Jake Shortt, Clinical Director of Monash Health Haematology and Head of Haematology Research, School of Clinical Sciences at Monash University said at the time the trial showed the capability of treating autoimmune disease at Monash Health.
“Monash Health, in partnership with Monash University, is focused on developing treatments of the future for autoimmune disease as well as cancers,” he said.
“CAR T-cell therapy is in the new frontier of treatments, and Monash Health has demonstrated it has the infrastructure and expertise to deliver this treatment and show how well it can work – delivering life-changing results for people like Lani.
“By trialling new treatments like this, people in Melbourne South-East and across Victoria now have world-leading and cutting-edge treatments closer to home.”
Professor Hoi told RR that testing the treatments in lupus was helpful given it was such a prototype of immune disease, but there were a “whole range of others [autoimmune diseases] that have huge unmet need”. These included myositis and even ulcerative colitis she said.
She said it was important to recognise that it was still very early days in understanding the long-term efficacy of CAR T-cell therapy in autoimmune diseases.
“I very much would like to see the next study to be a larger cohort and with more experience,” she said.
“At the moment there’s still a lot of unknown from the published case series.”
