The effectiveness of a new CAR-Treg-based therapy demonstrated in a SLE (Systemic Lupus Erythematosus) model

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that primarily affects the young female population and is characterized by the production by B-lymphocytes of antibodies mistakenly directed toward various organs and tissues of the body. Lupus can occur in any organ and apparatus, which is why it is a prime example among all so-called “systemic” autoimmune diseases.

Several preclinical studies have attested to the efficacy of CAR-T-based therapies to selectively reduce B-lymphocytes, responsible in the pathogenesis of SLE, in mouse models genetically predisposed to Lupus. However, this type of approach exposes individuals to the risk of infection because of the overall drastic decrease in B-lymphocytes, including those deputed to produce protective antibodies to infectious agents.

Within the research just published in Nature Communications a new CAR-Treg cell-based therapy capable of exerting an immunosuppressive effect directly in the lymphoid organs, i.e. the site where antigen presentation and the generation of antibodies responsible for inflammation in the autoimmune disease occurs, was tested for the first time on humanized mouse models of SLE disease.

The study was coordinated by Professor Chiara Bonini, head of the Unit of Experimental Hematology and Full Professor of Hematology at the Vita-Salute San Raffaele University, and Dr. Matteo Doglio, a medical researcher at the Unit of Experimental Hematology, both from Ospedale San Raffaele. 

Autoimmune diseases are conditions in which the body's immune system mistakenly attacks its own healthy tissues, viewing them as foreign agents. Under normal conditions, the immune system plays the role of defense, protecting the body from bacteria, viruses and other harmful substances. However, in autoimmune diseases, this system becomes overactive and mistakenly attacks healthy cells and tissues, causing inflammation and damage. 

"The ideal therapy for autoimmune diseases should aim to correct the erroneous immune response without unduly compromising the body's defensive capability, and this is where the idea to use CAR-Tregs came from. Conventional CAR-Ts, in fact, cannot distinguish the B-lymphocytes responsible for inflammation from all other lymphocytes, while CAR-Tregs are able to perform targeted selection by simply shutting down overactive cells without causing their death," says Professor Bonini.

What are CARs

CARs are synthetic receptors, not existing in nature, generated in the laboratory to redirect T-lymphocytes against specific targets. This technology is commonly used in T-lymphocytes to fight cancers, especially hematological cancers, and is already in use in clinical practice. 

The same technology can also be used on regulatory T-lymphocytes or Treg, a group of T-lymphocytes charged with normal control of the immune system to prevent exaggerated inflammatory reactions or deputed to prevent the onset of autoimmunity. In this context, CARs can redirect Tregs against relevant targets in the context of autoimmune diseases, enhancing their activity.

Researchers created a humanized mouse model. Dr. Doglio states: "The immune system of the mouse quickly became very similar to the human immune system, at which point it was possible to induce SLE disease and practice injection of CAR-modified regulatory T-lymphocytes. This is the first time CAR-Treg has been studied in mouse models with a fully humanized immune system."

The researchers were thus able to observe that in humanized mouse models of Lupus a single injection of CAR-Treg was sufficient to: 

• reduce inflammation;
• restore the natural balance of the immune system. 

The organs affected by the disease, particularly the lymphoid organs, regained normal function following the infusion, eradicating the disease altogether.

The researcher continues: "Following the infusion of CAR-Tregs, it was possible to observe the response of each organ that was first compromised due to the disease. For example, the lungs of lupoid mouse models had an inflammatory reaction characterized by granulomatous-type lesions; after treatment, not only the inflammation was reduced by 60%, but the lung structure was preserved."

"All the reagents that were used in the study are already compatible with the clinic. We hope that our research will soon embark on the process necessary to develop a specific drug for other autoimmune diseases as well, not just Lupus.

In addition, we have assumed, but for now it remains only a hypothesis, to use CAR-Tregs in: 

• organ transplantation to prevent rejection;
• bone marrow transplantation to control GVHD (graft-versus-host disease).

Due to their immunoregulatory ability, they may be able to drastically reduce the likelihood that the transplanted organ will be rejected," Professor Bonini concludes.

The CAR-Treg technology developed in this research has been patented and is ready to embark on the path to turn it into an innovative therapy for SLE patients.

The study was funded by the Ministry of Research and University (PRIN 2017WC8499; PRIN 2022SLL3YZ), the Ministry of Health and the Alliance Against Cancer (CAR T Current Research Project: RCR-2019-23669115), the EU IMI initiative (T2EVOLVE consortium) to CB and was partially supported by the Ministry of Health (Finalized Research Grant No. GR-2016-02364847).