From immunoablation to immunomodulatory therapy, novel systemic lupus erythematosus cell therapies are moving towards the clinic with the latest review

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with potential multiorgan damage and complex etiology
.
Neither biologics nor targeted therapies developed can cure SLE, and patient needs remain unmet
.
In order to provide more specific and sustainable disease treatment, the academic community has proposed new treatment methods, such as hematopoietic stem cell transplantation (HSCT), chimeric antigen receptor (CAR)-T cell therapy, etc
.
Foreign scholars reviewed the current evidence and future direction of cell therapy for SLE treatment, which was recently published in the journal J Allergy Clin Immunol.
(impact factor 14.
290).

The investigators briefly describe the advantages and disadvantages of the new treatment for SLE, as shown in the following figure:

Fig.
1 Advantages and disadvantages of the new SLE treatment

Treatment strategies

The short-term treatment goals of SLE are to control disease activity, improve clinical symptoms, and achieve clinical remission or the lowest possible degree of disease activity; The long-term goals are to prevent and reduce recurrence, reduce adverse drug reactions, prevent and control organ damage caused by diseases, achieve long-term sustained remission of the disease, reduce the mortality rate, and improve the quality of
life of patients.
At present, the treatment concept of SLE focuses on long-term suppression of autoimmune response, mainly through immunosuppressants and biologics and other antirheumatic drugs (DMARDs), which often need to be continued or repeated, which may increase the risk of infection in patients
.
In order to provide long-term drug-free remission, the academic community has proposed a new treatment concept, mainly by continuously inducing immune tolerance to consume autoimmune cells, thereby resetting the immune system, which is a potential SLE treatment
.

Antirheumatic drugs that improve the condition

The updated SLE treatment recommendations of the European Union Against Rheumatism (EULAR) recommend hydroxychloroquine at a dose not exceeding 5 mg/kg (actual body weight) for all patients; Depending on the patient, the addition of immunosuppressants such as azathioprine, methotrexate, mycophenolate mofetil (MMF), or cyclophosphamide (CYC)
may be selected.
Chinese SLE guidelines also point out that long-term use of hydroxychloroquine as the basic treatment is recommended for patients with SLE who have no contraindications; For patients who do not respond well to glucocorticoids plus hydroxychloroquine, immunosuppressants
are recommended.
For patients with severe organ involvement, EULAR guidelines recommend rituximab, while Chinese guidelines recommend the addition of immunosuppressants
to initial treatment for patients with organ involvement.
In maintenance therapy, EULAR guidelines indicate that glucocorticoids should be reduced to less than 7.
5 mg/day and discontinued
if the condition allows.
Chinese guidelines also suggest that for patients with long-term stable disease, a gradual reduction of glucocorticoids
may be considered.

Novel cell therapies

Hematopoietic stem cell transplantation

Autologous HSCT, originally used for the salvage treatment of life-threatening SLE, has now become one of the
clinical options for patients who do not respond well to current standard therapy.
After HSCT therapy, the responding patient resolves clinically and may return to serum antinuclear antibody negative, which is less common
with conventional therapy.
Early use of HSCT also has the potential to prevent the incidence of
organ failure and adverse events associated with HSCT toxicity.
In addition, allogeneic HSCT (allo-HSCT) is also an option for patients with SLE, but is not widely used
due to the risk of graft-versus-host disease (GvHD) and other complications.

Chimeric antigen receptor T cells

CAR-T cell therapy is one of the
potential treatments for SLE.
Several CD19-targeting CAR-T cell drugs have been approved for the treatment
of B-cell malignancies and multiple myeloma.

Preliminary results from a recent trial using an anti-CD19 CAR-T cell therapy strategy in patients with refractory SLE showed rapid remission with no significant adverse effects
.
However, given that anti-CD19 CAR-T cell therapy may lead to more intense B cell depletion, a possible increased risk of infection, and side effects such as cytokine release syndrome and neurotoxicity, further evaluation
is needed.

Treg cells

Treg cells eliminate inflammation against self-antigens by restoring immune tolerance
.
Several strategies have been developed to enhance the Treg cell response
in SLE patients.
One approach is to induce direct/indirect Treg cell expansion through immunosuppressants, for example, sirolimus alone or in combination with other drugs, which has been shown to be effective in improving disease activity in multiple clinical trials, and studies have shown significant reductions in prednisone doses in SLE patients treated with sirolimus
.
Another approach is treatment
with interleukin (IL)-2.
Patients with SLE show impairment of IL-2 production, and several studies have shown that low-dose IL-2 alone or in combination with standard of care treatment of SLE improves disease activity and clinical manifestations, and reduces autoantibody and complement consumption
.
Several IL-2 variants (muteins) currently under development are being used in clinical trials that selectively bind to high-affinity IL-2 receptors preferentially expressed by Treg cells, thereby enhancing immunomodulatory effects
.

Adoptive transplantation of polyclonal Treg cells

Treg cells control the activation of the immune system and are ideal for
adoptive transplantation.
The only clinical report on adoptive Treg cell therapy for SLE showed significant improvement in skin symptoms in patients with active cutaneous SLE, biopsy showing an increase in Treg cells and IL-17-producing CD41 and CD81 cells, and a decrease
in IFN-γ-secreting T cells.
Although experience in the treatment of SLE is limited, overall data suggest that adoptive transplantation of Treg cells is safe and effective in autoimmunity (moderate efficacy).

The emergence of gene editing technology, which allows the massive expansion of antigen-specific Treg cells, has greatly contributed to the development of
this field.

Genetically engineered T cells

Gene editing techniques can be used to increase the number of
disease-associated antigen-specific regulatory cells.
Two different treatments have been developed, including T cell receptor (TCR)-T cell therapy and CAR T cell therapy, which have been proven in
preclinical studies.
The choice of treatment depends on the antigen of interest, TCR can recognize both extracellular and intracellular antigens, but is limited by the major histocompatibility complex (MHC); CAR recognizes only extracellular antigens but is not affected
by MHC.
Given the complex pathogenesis of SLE and autoimmune responses to a variety of autoantigens, identifying potential targets for genetically engineered T cell therapy remains challenging
.

conclusion

In order to control autoimmune cells, there are currently two therapeutic ideas: one is to eliminate autoreactive immune cells (immunoablation therapy), and the other is to restore immune tolerance (immunomodulatory therapy).

Autologous/allogeneic HSCT enables immunoablation and has been used for SLE therapy, but its high transplant-related mortality and long-term complications require further evaluation
.
In terms of immunomodulatory therapy, Treg cells play a central role in maintaining self-tolerance and are ideal targets for this therapy
.
Overall, the treatment of SLE is rapidly evolving, novel cell therapies can fundamentally change cell interactions and clinical outcomes, and the exact role of SLE treatment in the future needs to be further evaluated
.

References:

1.
Doglio M, Alexander T, Del Papa N, et al.
New insights in systemic lupus erythematosus: From regulatory T cells to CAR-T-cell strategies[J].
J Allergy Clin Immunol.
2022 Sep 19:S0091-6749(22)01056-9.
doi: 10.
1016/j.
jaci.
2022.
08.
003.
Epub ahead of print.
PMID: 36137815.

2.
2020 guidelines for the diagnosis and treatment of systemic lupus erythematosus in China[J].
Chinese Journal of Internal Medicine, 2020(03) : 172-173-174-175-176-177-178-179-180-181-182-183-184-185.