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Re-Educating the Immune Response To Treat Type 1 Diabetes

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“The immune system can be seen as an army that protects us from foreign invaders and pathogens, but sometimes this army can go rogue and attack our own tissues and that’s what’s called autoimmune disease.” – Dr. Leonardo Ferreira.

What is CAR T-cell therapy?

Chimeric antigen receptor (CAR) T-cell therapy involves the use of T cells engineered to display a CAR on the surface. The CAR has an extracellular domain that recognizes a certain antigen expressed on the surface of the target cells, enabling it to bind with high specificity. 

This allows the immune function of the T cells to be leveraged in a tailored manner, in order to control both the cells targeted by the T cells, and the response produced following the binding of the antigen of interest.

The CAR is designed based on a variable fragment from a monoclonal antibody against the antigen of interest and is attached to an intracellular domain that activates the T cell. The diversity of the engineered CAR enables CAR T-cell therapies to be used against many different diseases.

What has CAR T-cell therapy been used for?

CAR T cells have largely been trialed to combat cancers, with regulatory approval being granted by the US Food and Drug Administration (FDA) to treat various blood cancers including multiple myeloma, B cell lymphoma and acute lymphoblastic leukemia. In these instances, the CAR binds to an antigen on the surface of the cancer cell and the activated T cell then destroys it. Research is currently ongoing as to whether CAR T cells can be used to target and destroy solid tumors, but progress is being challenged by tumor antigen heterogeneity and the immunosuppressive tumor microenvironment, as well as other factors.

Outside of oncology, CAR T cells are being explored as a therapeutic strategy for numerous other indications, such as systemic lupus erythematosus, HIV and COVID-19 as well as other autoimmune conditions.

How can we use CAR T-cell therapy for Type 1 diabetes?

Dr. Leonardo Ferreira, assistant professor of microbiology and immunology at the Medical University of South Carolina and the Hollings Cancer Center, is exploring whether CAR T-cell therapies could be used to treat patients with Type 1 diabetes (T1D).

T1D is an autoimmune condition where the islet cells of the pancreas, responsible for producing insulin, are targeted and destroyed by the bodies’ immune system. According to Ferreira, preventing the immune system from attacking the islet cells “has not yet been possible, perhaps because the immune system is so complex". The only treatment currently available is a pancreatic islet cell transplant, which carries the risk of transplant rejection.

“If small molecules as traditional drugs can’t treat it [T1D], maybe we need to tap into the immune system itself to stop the immune disease” – Ferreira.

Ferreira's research group is hoping to “tap into the immune system” and “re-educate” the immune response to treat T1D. To mitigate against the risk of transplant rejection and prevent the transplanted islet cells from being destroyed due to the autoimmune disease, the team is using regulatory T cells (Tregs), the “generals” of the immune system, for CAR T-cell therapy.

“If we can coax these cells into becoming living drugs, we can re-educate the immune system” – Ferreira.

Tregs are a subset of T lymphocytes that are involved in immune suppression, which enables self-tolerance and maintains immune homeostasis in the body. By making use of the immunosuppressive nature of these Tregs, Ferreira’s team hopes to protect donor islet cells from immune attack.

“The regulatory T cell has all these different mechanisms by which it suppresses immune responses specifically,” Dr. Ferreira explains. “It’s almost like a polypharmaceutical.”

The chimeric antigen receptor, in this instance, binds specifically to a protein called HLA-A2, which is present on the donor islet cells. “HLA-A2 is a major histocompatibility complex present in 30% of the population,” Ferreira clarifies. “So you can imagine having a donor of the islet cells that is HLA-A2 positive and has HLA-A2 on the surface of the donated cells whereas the recipient does not [have the protein present]”. This enables selective targeting of the CAR T cells to the transplanted islet cells.

Ferreira and colleagues were able to show that the HLA-A2 targeting CAR T regulatory cells could specifically associate with the donor islet cells and suppress the activation of T effector cells, protecting the donor cells from “autoimmune attack and from alloimmune attack as well”.

To watch Leo’s full talk, click here!