Are we putting the CAR-T before the horse? Save

CAR T-cells have been a revolutionary development in rheumatology. We have seen a population of patients with severe refractory autoimmune conditions almost overnight presented with the prospect of not just improvement, but of a cure.

Georg Schett’s group in Berlin has pioneered this research and presented almost unbelievable results of CAR T-cell therapy to date. To date, CAR T-cells in rheumatology have mostly focused on SLE, and subsequently systemic sclerosis and autoimmune myositis. These are severe diseases with few or no highly effective treatment options. The results have been impressive. Patients have entered apparently sustained drug free remission. There appears to be an immunological reset following CAR T-cell treatment, raising the prospect of a return to a pre-disease state. The trade off has always been the need for myeloablative pre-conditioning, the potential for immune reconstitution type reactions to the CAR T-cells, and the direct and indirect costs attendant on both.

Two studies at ACR 2025 present opposite sides of the coin in this regard. Firstly a potential route forward with less costs and risk but potentially sustained benefit, and in contrast secondly an insight that broadening the disease base targeted with CAR T-cells may not yield results as positive as those seen with the initial conditions studied.

In abstract #0663,  Fazeli and colleagues present results of an “off-the-shelf” CAR-T cell treatment. This was a phase 1 study in 10 SLE patients. It utilises a clonal stem cell bank for CAR-T cells. This technology reduces the intensity of or avoids entirely the need for conditioning chemotherapy and apheresis, and the risks of side effects inherent in this. Shorter hospital stays were also seen, around 3 days. A similar study was recently published in the New England Journal of Medicine by a Chinese group. The data presented to date is positive but it is still preliminary. The key question is will this prove to be CAR T-lite or CAR T-2.0? Will the less intensive regime provide the same immunologic reset as seen with the initial CAR T-cell studies?

A note of caution however, was sounded by abstract #0471. Albach and colleagues from the Berlin group presented data on refractory rheumatoid arthritis patients treated with CAR T-cells. The procedural and safety aspects appeared consistent with those of earlier studies. The efficacy however appeared less dramatic. There were major effects on B-cell depletion and both RF and CCP antibody levels. However, this did not necessarily appear to translate into as significant a clinical impact. Only 4 of the 6 patients achieved ACR20, and only 2 of the 6 an ACR50. These response rates are not nothing, considering that this is a refractory population, but it does suggest that CAR T-cells may not be the panacea for all of our diseases which initial evaluations suggested they could be. It also suggests that we need to be contemplative when we consider extending these approaches to diseases like rheumatoid arthritis, where there exist many extant highly effective treatment options.

The question remains as to the exact role and niche for CAR T-cells. It appears evident however that this technology has revolutionised rheumatology, stimulated research efforts, and provided patients with no other option a potential route to a cure.