CAR T-cell therapy has provided a much-needed personalized treatment approach for patients with certain kinds of blood cancer and has the potential to help those with autoimmune diseases. The use of CAR T-cell therapy to treat patients with systemic lupus erythematosus (SLE) and other autoimmune diseases was discussed in a talk at the recent 2024 Congress of Clinical Rheumatology (CCR) West.

Following this presentation, featured expert George C. Tsokos, MD, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Tsokos are presented here.

At the recent CCR West meeting, Georg Schett, MD, gave a presentation discussing the use of CAR T-cell therapy in patients with autoimmune disease, including SLE. During the presentation, he reported data from patients with lupus who received CD19-directed CAR T cells and longer-term follow-up from a case series published earlier this year. Patients experienced spectacular improvements, and their anti–double-stranded DNA antibodies disappeared, which is very exciting. The side effects were still limited and not serious, but the issue is that patients are still receiving myeloablation, with their whole immune system wiped out. So, people are concerned about whether the benefits that are seen with the CAR T-cell therapy are coming from the CAR T cells or the myeloablation. I would submit that both contribute but hope that most of the benefits are due to the CAR T-cell treatment.

Something that I think may empower a patient’s T cells to better eliminate pathogenic B cells is to manipulate them to be dual targeted. That way, their CAR T cells have 2 separate guns, so to speak, instead of 1. There was a 2024 open-label phase 1 trial evaluating CAR T cells directed against both CD19 and BCMA. This enables the CAR T cells to eliminate B cells that may become autoantibody producing, as well as B cells that have matured and are already producing autoantibodies. A logical question is: Can CAR T-cell therapy be performed without myeloablation? Since the immune system does not have unlimited “space” or resources to support immune cells, myeloablation might be necessary to ensure that the infused CAR T cells expand and survive.

I think that there are 2 major concerns about using CAR T-cell therapy for patients with SLE. The first is the risk of infections, because you are ablating all the existing immune protection that the patient has developed over the years. Their risk of infections will need to be properly evaluated. It is good that no serious infections have been observed thus far with CAR T cells, but it is too early to celebrate. The other risk that I would be watching long-term is the potential development of malignancies. Since the immune system is being ablated in patients who receive CAR T-cell therapy, immune surveillance for malignant cells and the ability to eliminate them may be reduced in these patients.

Even with CAR T-cell therapy, patients may still be at risk for flares down the road because, in essence, CAR T-cell therapy has not eliminated the cause of a person’s SLE. The factors that contribute to the development of lupus are, in broad strokes, genetic, epigenetic, and hormonal; these factors are all still present in a patient receiving treatment with CAR T-cell therapy. In some ways, CAR T-cell therapy may just be resetting the immune clock back to zero, although I hope that I am wrong about that. Regardless, it is a consideration, and the excitement surrounding CAR T-cell therapy will not obviate the need for careful watching and a consideration of problems in patients who receive it.

Where I think CAR T-cell therapy could be going, in addition to CAR T cells with multiple targets, is the development of allogeneic CAR T cells that could be used to treat any patient with SLE. The cells could be manipulated to silence all the histocompatibility antigens, such as human leukocyte antigen molecules, to ensure that there is no graft-vs-host disease. Another approach that I like a lot is the development of CAR T cells from induced pluripotent stem cells. This involves taking fibroblasts and engineering them into CAR T cells. Eventually, it would be a dream to have virus constructs such as adenoviruses that can induce the expression of CARs in the T cells.

There is a lot of excitement about CAR T cells—and I am excited too—but this excitement should not stop us from being thoughtful. We want to ensure that CAR T cells will be easy to use and have limited, if any, side effects.