Therapeutic potential of CAR T-Cell Therapy in Autoimmune Diseases

The article discusses the promising new era of immune therapies based on immune effector cells (IEC), particularly Chimeric Antigen Receptor (CAR) T-cell therapy. Originally successful in treating hematological malignancies, recent favorable outcomes in systemic autoimmune diseases have garnered interest in using CAR T-cell therapy for immune-mediated inflammatory disorders (IMIDs).

T-cells, which mediate cell immunity against cancer and pathogen-infected cells, can become exhausted due to chronic infections or prolonged immune system activation. This exhaustion is marked by increased expression of immune checkpoint proteins that suppress T-cell function. Approaches to block these inhibitory receptors target rejuvenation of T-cell function to modulate pathogenic cells.

CAR T-cell therapy included harvesting T lymphocytes and genetically modifying them to express chimeric receptors. These receptors are fusions of antibody-derived variable regions and TCR-derived signaling/co-stimulatory domains. The modified T-cells are then transferred back to the patient to target and eliminate pathogenic cells, such as cancer or chronic infections.

CAR T-cell therapy has proven effective in managing B-cell and plasma cell malignancies, with six products approved by the FDA and the European Medicines Agency (EMA) for various lymphomas and leukemias, including large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), mantle cell lymphoma, and multiple myeloma. Although initially developed for adults, these therapies have also been adapted for pediatric use, particularly in treating B-cell ALL. Additionally, numerous other candidates are under development or in clinical trials.

Muller et al. demonstrated the therapeutic potential of a single infusion of CD19 CAR T-cells in 15 patients with various rheumatic disorders, including systemic lupus erythematosus, idiopathic inflammatory myositis, and systemic sclerosis. All patients demonstrated a clinically meaningful response during a median follow-up of 15 months, and concomitant immunosuppression was discontinued.

The FDA recently approved the first clinical trial for CAR T-cell therapy (REACT-01) in children with refractory systemic lupus erythematosus.In India, a patient at Tata Memorial Hospital received the first infusion of Actalycabtagene autoleucel, developed into NexCAR19, for refractory B-cell ALL patients. Despite its high cost, NexCAR19, recently approved by the Center Drugs Standard Control Organization (CDSCO) and launched in India, may also be applied to refractory autoimmune diseases.

Therefore, adaption of CAR technology to treat autoimmune diseases has shown initial promise. Autologous T cells, genetically redesigned ex vivo, can target antigens to control disease when natural T-cells fail. For this approach to be effective, the extracellular binding domains and intracellular signaling domains must be optimized, along with well-defined manufacturing protocols, optimal cell dosage, timing, and administration routes. Further clinical studies are crucial to assess the efficacy, safety, and long-term cure potential of CAR T-cell therapy in autoimmune diseases.

Source: Thakral D, Ramanan T, Bagri NK. CAR T-Cell Therapy: A Promising Modality for Autoimmune Diseases. Indian Pediatr. 2024 Aug 26:S097475591600688. Epub ahead of print. PMID: 39193924.