Background/Purpose: Treatment of autoimmune disease with T cell engagers (TCEs) leads to profound peripheral B cell depletion, followed by their reconstitution. However, the dynamics of B cell depletion as well as concomitant T cell activation, are poorly understood.

Methods: 14 patients with RA were treated with the CD19xCD3 TCE blinatumomab, 10 patients with SSc, IIM, IgG4-RD and GD were treated with the BCMAxCD3 TCE teclistamab. All patients had active, multi-drug-resistant AID. Longitudinal high dimensional flow cytometry was performed on peripheral blood mononuclear cells (PBMCs). 1-year follow-up was available for 8/14 patients treated with blinatumomab. 6-months follow-up was available for 8/10 patients treated with teclistamab.

Results: TCE therapy led to a rapid B cell depletion (Fig. 1A-B). 11/14 RA patients had circulating B cells at baseline (median 114/nl), and 3/14 patients had no B cells because of recent rituximab therapy. Complete B cell depletion was reached in 8/11 RA patients (in 2 patients after the first cycle, in 4 patients after the second cycle and in 2 patients after a third cycle). Teclistamab led to complete B cell depletion in all patients (in 4/10 patients after the first dose and in 6/10 patients after the third dose). A significant decrease of serum immunoglobulins and free light chains indicated effective depletion of the plasma cell compartment via teclistamab, in contrast to blinatumomab.B cells reconstituted after a median of 61 days after blinatumomab and a median of 157 days after teclistamab (Fig. 1C). Reconstituted B cells were mostly of a naive phenotype. Correspondingly, CD19+ CD27+ memory B cells decreased substantially (blinatumomab: average 16% to 7%; teclistamab: average 8% to 2%). One year after blinatumomab treatment initiation (6/14 patients), both CD27+IgD+ non-switched and CD27+ IgD- switched memory B cells re-emerged, while CD20+CD27- naive B cells slightly decreased (Fig. 1D-G). Plasmablasts were depleted after both therapies and stayed depleted at long-term follow up. Circulating T cells transiently decreased during TCE therapy (Fig. 2A-B). A relative shift towards CD8+ cells during teclistamab indicated a stronger activation and expansion of cytotoxic T cells (Fig. 2C-D). TCE therapy led to a noticeable increase in exhaustion related T cell phenotypes. PD1+ CD8+ T cells accumulated after the first cycle (blinatumomab: from 11.2 to 20.7%; teclistamab: from 6.9 to 24.3%). CD8+ CD62L- CD45RA- CD8+ effector memory (EM) and CD62L- CD8+ effector memory re-expressing CD45RA (EMRA) T cells expressed more PD-1 compared to the other CD8+ subpopulations, suggesting increased exhaustion (Fig. 2E-F). Teclistamab led to an increase in CD8+ TEM and TEMRA, which also expressed more PD-1 compared to the other CD8+ subpopulations. CD4+ T cells were less influenced in both therapies, a slight increase of CD4+ CD62L+ CD45RA- central memory (CM) T cells was observed during both treatments.

Conclusion: Together, these data demonstrate the dynamic impact of TCEs on B cell depletion and reconstitution in AIDs. Furthermore, strong effects on the T cell compartment are observed, raising the intriguing possibility that their mechanism of action is not limited to the B cell depletion alone.

Fig. 1: A-B. Quantification of B cells during therapy with A. blinatumomab and B. teclistamab. C. B cell aplasia after treatment with TCEs, D-G. Frequencies of D. Naive, E. Memory, F. switched memory, and G. non switched memory B cells at short term follow-up (FU) and at 1-year follow-up (long term FU) after Blinatumomab.

Fig. 2: A-B. Quantification of CD3+ T cells during therapy with A. blinatumomab and B. teclistamab. C-D. T CD4+/CD8+ cell ratio during treatment with TCEs, E. expression of PD-1 in T cell subpopulations during treatment with teclistamab at baseline (t0), after the 3rd injection (t1), at 14-days (t2) and 1-month follow up (t3) and at 3-months follow up (FU3M), F. expression of PD-1 in T cell subpopulations during treatment with blinatumomab at baseline (t0), during the first infusion (t1), between the first and second infusion (t2), during the second infusion (t3), after the second infusion (t4), at 3-months follow-up and at 6-9-months follow-up.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dynamic-effects-of-t-cell-engager-therapy-on-b-and-t-cells-in-autoimmune-disease/