Immune Reset In Rheumatology: Moving Beyond Disease Suppression Toward Durable Remission

By Meabh Doherty, Business Analyst, and Farah Suleman, Junior Business Analyst, Lifescience Dynamics

Despite major advances in targeted therapies, autoimmune rheumatic diseases are still largely managed through long-term immunosuppression. For patients living with conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s disease (SjD), and systemic sclerosis (SSc), treatment can reduce inflammation and slow organ damage, but durable remission without ongoing medication remains a significant challenge.

However, EULAR 2026 highlighted growing momentum behind “immune reset,” an approach adapted from oncology that is quickly gaining traction in autoimmune rheumatic diseases. Across CAR-T therapies and T-cell engagers (TCEs), the focus is shifting from suppressing inflammation toward eliminating autoreactive B-cell populations that sustain autoimmune disease, potentially enabling the immune system to repopulate with healthy naïve B-cells. Unlike conventional monoclonal antibodies, which primarily deplete circulating B cells, these approaches aim to achieve deeper depletion of pathogenic immune reservoirs in blood and tissues. While evidence remains early, immune reset approaches could raise the efficacy ceiling in autoimmune rheumatic disease and reduce reliance on chronic immunosuppression.

CAR-T Establishes The Foundation For Immune Reset

Autologous CAR-T therapies remain the most clinically advanced immune reset approach, involving the collection and genetic reprogramming of a patient’s own T cells to recognize and eliminate disease-driving B cells. While early clinical experience centered on SLE, EULAR 2026 demonstrated how rapidly the field is expanding into other B-cell-driven autoimmune diseases, including RA and SSc.

Among the most notable developments were updated results from the Phase 1 COMPARE trial, building on findings first reported at ACR 2025 and marking the first prospective evaluation of CD19-directed CAR-T therapy in RA (OP008). Kyverna Therapeutics' mivocabtagene autoleucel (miv-cel) continued to demonstrate the hallmarks of immune reset, with deep B-cell depletion followed by reconstitution with a predominantly naïve B-cell phenotype in six heavily pretreated (~six prior b/tsDMARDs), anti-citrullinated protein antibodies (ACPA)-positive RA patients. The therapy also maintained a favorable safety profile, with predominantly low-grade cytokine release syndrome (CRS) and no reported neurotoxicity. Importantly, the study moves the field beyond anecdotal case reports and provides prospective evidence that immune reset may be achievable in RA, with the ongoing randomized Phase 2 comparison against rituximab expected to define whether this approach can deliver meaningful advantages over current standards of care.

While autologous CAR-T therapies have established proof of concept for immune reset, their widespread adoption remains constrained by complex manufacturing, intensive lymphodepleting chemotherapy, and reliance on specialist treatment centers. As a result, EULAR 2026 highlighted growing momentum behind next-generation immune reset approaches designed to retain the depth of immune depletion associated with CAR-T while improving accessibility and scalability. Among the most notable was Artiva Biotherapeutics' late-breaking abstract (LB0003), which reported encouraging early clinical responses with its allogeneic NK-cell therapy AB-101 in combination with rituximab across RA, SSc, and SjD. As an off-the-shelf therapy administered predominantly in outpatient settings, AB-101 reflects a broader shift toward developing immune reset approaches that can be delivered without the logistical complexity of autologous CAR-T.

Beyond CAR-T: Expanding Access To Immune Reset

TCEs also emerged as a major focus at the conference, including through the dedicated “BiTE me: Bi-specific T-cell Engagers in RMDs” session. These off-the-shelf therapies simultaneously bind CD3 on a patient’s existing T cells and an antigen on disease-driving immune cells, bringing them into proximity and redirecting the T cells to eliminate their targets. Unlike autologous CAR-T, TCEs do not require individualized cell manufacturing or lymphodepleting chemotherapy. Their immediate availability, potentially lower costs, and greater flexibility in dosing and retreatment could support broader use.

However, findings presented at EULAR suggested that TCEs may deliver varying depths and durations of immune modulation. In patients with multidrug-resistant RA (MDR-RA), low-dose blinatumomab (CD3×CD19 TCE) achieved deep B-cell depletion in peripheral blood and synovial tissue, but not within lymph nodes (OP0203). Although patients initially responded, 14 of 15 subsequently relapsed, with several regaining responsiveness to previously failed therapies. This introduced the concept of “immune dimming,” whereby transient attenuation of pathogenic immune activity may restore treatment sensitivity without achieving a durable immune reset. In contrast, data for Cullinan Therapeutics’ CLN-978 (CD19×CD3 TCE) demonstrated deep B-cell depletion across blood and lymphoid tissues, including disruption of B-cell follicular architecture within lymph nodes, suggesting that the depth and location of depletion may influence durability (POS1179).

Alternative targets and emerging TCE approaches may further improve the depth and durability of response. Teclistamab (BCMA×CD3 TCE) generated clinical responses in 15 of 16 patients with severe refractory autoimmune diseases, including nine who achieved drug-free remission, although all developed hypogammaglobulinemia requiring immunoglobulin replacement (OP078). Other approaches are seeking to enhance T-cell activity or simplify treatment delivery. In the Phase 1 CC312-I-001 trial, CC312 (CD19×CD3×CD28 tri-specific TCE) demonstrated deep B-cell depletion and sustained early responses in patients with severe refractory SLE (LB0004). Meanwhile, first-in-human findings for mRNA-based ABO2203 showed that in vivo expression of a CD19×CD3 TCE could achieve rapid B-cell depletion without reported CRS, immune effector cell-associated neurotoxicity syndrome, or hepatotoxicity (POS0378).

TCEs may therefore occupy a spectrum between transient “immune dimming” and more durable immune reset, depending on the target, depth of tissue depletion, and construct design. Their off-the-shelf availability, flexible dosing, and potential for retreatment could position them between conventional biologics and cellular therapies. However, longer-term studies will be needed to determine whether these practical advantages can be maintained alongside durable disease control.

Durability Will Define The Next Phase Of Immune Reset

Although early findings are encouraging, whether immune reset can consistently deliver durable treatment-free disease control remains uncertain. The EULAR 2026 session “I failed CAR-T – what’s next?” highlighted growing attention toward relapse and its management. A case series evaluating relapse following CD19-directed CAR-T found that six of 50 patients relapsed, with recurrence most frequent among those with idiopathic inflammatory myopathies (OP076). Findings from the first reported case of SLE relapse following CD19-directed CAR-T provided further insight into the potential drivers of recurrence, with memory and atypical B-cell populations reemerging before renewed disease activity despite conventional biomarkers remaining normal (OP0333). This suggests that the composition of the reconstituted immune system may be more informative than B-cell counts alone.

Improved biomarkers may therefore be needed to identify patients at risk of relapse and guide post-treatment monitoring, retreatment, and treatment sequencing. Alternative targets such as BCMA, which is expressed on antibody-producing plasma cells, may provide an option following relapse after CD19-directed therapy. However, the hypogammaglobulinemia observed with deeper plasma cell depletion highlights the need to balance durability against the preservation of protective immunity. Patient selection will also be critical in determining whether immune reset approaches remain reserved for severe refractory disease or move earlier in the treatment pathway.

Multiple immune reset approaches are likely to emerge with distinct roles across patient populations and treatment settings. Autologous CAR-T may remain suited to patients for whom the potential for deep immune reprogramming justifies greater treatment complexity, while more flexible off-the-shelf approaches could support broader use if early findings translate into sustained disease control. The focus is therefore shifting beyond whether immune reset is possible toward the durability of treatment-free disease control, long-term safety, patient selection, and practical implementation at scale.

About The Authors

Meabh Doherty is a business analyst at Lifescience Dynamics with experience supporting projects across immunology, oncology, cardiology, and rare diseases. She holds a Ph.D. from Queen’s University Belfast, where she developed nanomedicine formulations designed to modulate cancer cell metabolism and reduce radio resistance, as well as a BSc in pharmaceutical sciences.

Farah Suleman is a junior business analyst at Lifescience Dynamics with experience supporting clients across a range of projects including immunology, oncology, and rare diseases. She holds an MSci in biochemistry from UCL, where she investigated novel therapeutic strategies to target the malarial parasite Plasmodium falciparum.