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without authorization.
of organ failure and even death.
B cells and related pathways or cytokines are important therapeutic targets for SLE, and drugs targeting B cells have been used in clinical practice, such as
, blocking B cells for SLE is a promising therapeutic strategy
.
Chimeric antigen receptor T (CAR-T) cell immunotherapy can target B cells by recognizing the highly specific and ubiquitous surface antigen CD19 of B cells, and has a significant
effect in the treatment of
In addition, two preclinical studies conducted in lupus-susceptible mice support the effectiveness
of CD19 CAR-T cell therapy in SLE.
In this context, German scholars conducted a small clinical trial to evaluate the tolerability and efficacy
of CD19 CAR-T cell therapy in 5 patients with severe or drug-resistant SLE.
The study was recently published in the top medical journal NatMed.
(impact factor 87.
241).
Overview of the findings
Patients were enrolled consecutively between 14 February 2021 and 2 February 2022 (4 females and 1 male), aged 18 to 24 years, had active SLE, and had a high SLE activity index of -2000 (SLEDAI-2K) (patients 1 and 2 were both 16; Patient 3 is 10; Patient 4 is 8; Patients 5 are 9), all have histologically confirmed glomerulonephritis involving multiple organs (heart, lungs, and joints) but not the central nervous system
.
Although patients are young, all patients have previously received a variety of immunosuppressive therapies such as pulse glucocorticoid therapy (5/5), hydroxychloroquine (5/5), mycophenolate mofetil (MMF; 5/5), belimumab (5/5),
1.
Clinical efficacy of CAR-T cell therapy
Disease activity
in patients following CD19 CAR-T cell therapy was assessed using SLEDAI-2K.
After 3 months of CAR-T cell therapy, SLE signs and symptoms continued to improve in 5 patients, 4 of whom had an SLEDAI-2K score of 0 and only 2 had an SLEDAI-2K score of 2 with residual low-level proteinuria, which may be attributed to the cumulative impairment
of previous glomerular filtration function.
After 3 months, residual proteinuria gradually improved
with the addition of angiotensin-converting enzyme (ACE) inhibitors.
After 3 months of CAR-T cell therapy, 5 patients were able to have nephritis, complement levels returned to normal,
.
In summary, all patients met the DORIS criteria for remission and lupus low disease activity status, and it is important to note that all immunomodulators and immunosuppressants, including glucocorticoids and hydroxychloroquine, can be discontinued, resulting in drug-free remission
.
2.
Safety and tolerability
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are frequently observed toxic side effects
of CD19 CAR-T cell therapy in the treatment of lymphoma and leukemia.
In this study, 5 patients with SLE had no or only mild CRS, and 3 developed
with
Throughout the process, no ICANS was seen in SLE patients, suggesting that the toxicity of CAR-T cell therapy may be less pronounced
in SLE patients.
Discussion and conclusions
This is an unprecedented clinical trial with data showing that CD19 CAR-T cell therapy not only effectively depletes B cells in SLE patients, but also achieves drug-free remission
.
This sheds light on the role of CAR-T cell therapy in non-malignant diseases and may provide new options
for the treatment of autoimmune diseases.
The investigators elaborated three findings
based on this trial.
First, CAR-T cells are feasible and safe for treating autoimmune diseases; Second, after CAR-T cell therapy, the B-cell-mediated autoimmune response in SLE is rapid and continues to disintegrate
.
Third, even though B-cell reconstitution occurred about 100 days after CAR-T cell therapy, SLE did not recur and no patient required any type of immunosuppressive therapy
.
Although the data from this study provide a potential new treatment option for patients with severe SLE, the investigators are also cautious that the good efficacy and small toxicity of CAR-T cell therapy at this stage are based on a small number of patients and need to be treated
with caution.
References: Mackensen A, Müller F, Mougiakakos D, et al.
Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus[J].
Nat Med.
2022 Sep 15.
doi: 10.
1038/s41591-022-02017-5.
Epub ahead of print.
PMID: 36109639.
