Chimeric Antigen Receptor Based Therapy as a Potential Approach in Autoimmune Diseases: How Close Are We to the Treatment?

Abstract

Despite significant breakthroughs in understanding of immunological and physiological features of autoimmune diseases, there is currently no specific therapeutic option with prolonged remission. Cell-based therapy using engineered-T cells has attracted tremendous attention as a practical treatment for autoimmune diseases. Genetically modified-T cells armed with chimeric antigen receptors (CARs) attack autoreactive immune cells such as B cells or antibody-secreting plasma cells. CARs can further guide the effector and regulatory T cells (Tregs) to the autoimmune milieu to traffic, proliferate, and exert suppressive functions. The genetically modified-T cells with artificial receptors are a promising option to suppress autoimmune manifestation and autoinflammatory events. Interestingly, CAR-T cells are modified to a new chimeric auto-antibody receptor T (CAAR-T) cell. This cell, with its specific-antigen, recognizes and binds to the target autoantibodies expressing autoreactive cells and, subsequently, destroy them. Preclinical studies of CAR-T cells demonstrated satisfactory outcomes against autoimmune diseases. However, the lack of target autoantigens remains one of the pivotal problems in the field of CAR-T cells. CAR-based therapy has to pass several hurdles, including stability, durability, trafficking, safety, effectiveness, manufacturing, and persistence, to enter clinical use. The primary goal of this review was to shed light on CAR-T immunotherapy, CAAR-T cell therapy, and CAR-Treg cell therapy in patients with immune system diseases.

Keywords: CAAR-Tregs; CAR-T cells; Tregs; adoptive cell therapy; autoimmune diseases; cytotoxic T cells; immunotherapy.

Figure 1

A common CAR construction. (A): CAR is comprised of antigen-recognition domain (scFv), a hinge domain or spacer (CD28, CD8α, CD7, IgG4, and IgG1), a transmembrane domain (CD28, CD8α, CD7, CD4, CD3z, and OX40), a co-stimulatory domain (CD244, CD28, CD27, OX40, ICOS, and CD137), and a signaling domain (CD3z, DAP10, and DAP12). (B): The process of CAR-T manufacturing from peripheral blood mononuclear cells to genetically modified-T cells and administration. CAR-T therapy starts with accumulating the patient’s white blood cells by leukapheresis. The apheresis products are enriched or deleted for a specific cell subset and then activated by one of following methods, including interleukins (IL-2, IL-7, and IL-15), anti-CD3/CD28 antibody-coated magnetic beads, soluble CD3 antibody, artificial antigen-presenting cells, plate-bound antibodies, and adhesion molecules. The activated T cells are introduced with the CAR transgene through lentiviral or retroviral and non-viral methods (electroporation of naked DNA and plasmid-based transposon/transposase). Afterwards, the engineered-T cells undergo an expansion process in static culture bags or dynamic culture vessels or rotating bioreactors. Eventually, cell numbers are calculated based on the patient’s disease burden, weight, and another formulation. The CAR modified-T cells transfer to either a container for infusion purposes or cryopreserved for storage.

Figure 2

The mechanism of action of CAAR-T cells and CAR-Treg cells against autoimmune disease. (A): MOG CAR-Treg cells effectively bind and is localized to the MOG⁺ oligodendrocytes in CNS and exert their immunosuppressive manner to protect myelin against immune attack. (B): (a); T cell expressing CAAR specific for B cell receptors targets aberrant B cells. (b); further, it inhibits B cell development from secreting autoreactive antibodies and prevents B cells from presenting autoantigens to autoreactive T cells, which leads to suppression of T cell-mediated autoimmune diseases.