Immune Dimming or Immune Reset in RA: How Far Should We Go? Save

CD19-directed CAR T-cell therapy has rapidly moved from experimental oncology into autoimmune disease, driven in large part by striking reports in SLE, where sustained drug-free remission has raised the possibility of a true immune reset. More broadly, these developments have also revived interest in whether profound immune depletion is required at all, or whether less intensive strategies that “dampen” pathogenic immune circuits may achieve similar clinical benefit. In RA, where multiple effective therapeutic classes already exist, the relevance of such deep immune interventions—and where they sit between immune reset and immune modulation—remains uncertain.

In abstract OP0203, Bucci and colleagues proposed an open-label study of low-dose CD3×CD19 T-cell engager therapy (blinatumomab) in multidrug-resistant RA. The treatment induced rapid clinical improvement accompanied by peripheral and synovial B-cell depletion and a marked reduction in synovial inflammatory activity on imaging. However, these effects were not sustained, with relapse occurring in the vast majority of patients after treatment cessation. Interestingly, the authors suggest that re-treatment with bioDMARDs after blinatumomab often restored drug responsiveness, even in patients previously classified as refractory. This however needs to be taken with caution when follow-up was short and patients received steroids in combination with blinatumomab.

In abstract OP008, Albach and colleagues presented prospective data from the COMPARE trial of CD19 CAR-T cells in treatment-refractory, ACPA-positive RA. Six patients with severe treatment-refractory RA (median 6.5 previous bio/tsDMARDS) received a single infusion of autologous CD19 CAR T cells following lymphodepletion, with complete withdrawal of background immunosuppression. Authors report that CAR T-cell was overall feasible and clinically manageable. Cytokine release syndrome occurred in all patients but remained mild to moderate (grade 1–2), with no neurotoxicity observed. Transient cytopenias were expected and reversible, and no unexpected safety signals emerged over follow-up of up to 36 weeks. Efficacy data show sustained and profound B-cell depletion accompanied by marked reductions in pathogenic autoantibodies, with sustained normalisation of ACPA and RF titres. Clinically, all patients improved, with a median DAS28-CRP reduction of over 40%, and half achieving remission despite complete discontinuation of conventional immunosuppression during follow-up period.

These findings support efficacy of deep immune depletion in refractory RA, in line with previous observations in other systemic auto-immune conditions. While early remission rates are impressive; a general observation across the board is that durable remission is not guaranteed, and non-response and loss of response are emerging concerns of CAR T-cell therapy in autoimmunity, alongside tolerance. In that context, we need to see this data as proof that immune dimming/reset is possible, but not yet proof that it is the optimal or necessary route to sustained disease control in RA.