Bispecific T cell engager therapy for refractory rheumatoid arthritis, 2024, Schett et al

Bispecific T cell engager therapy for refractory rheumatoid arthritis

Abstract
Bispecific T cell engagers (BiTEs) kill B cells by engaging T cells. BiTEs are highly effective in acute lymphoblastic leukemia. Here we treated six patients with multidrug-resistant rheumatoid arthritis (RA) with the CD19xCD3 BiTE blinatumomab under compassionate use. Low doses of blinatumomab led to B cell depletion and concomitant decrease of T cells, documenting their engager function.

Treatment was safe, with brief increase in body temperature and acute phase proteins during first infusion but no signs of clinically relevant cytokine-release syndrome. Blinatumomab led to a rapid decline in RA clinical disease activity in all patients, improved synovitis in ultrasound and FAPI-PET-CT and reduced autoantibodies. High-dimensional flow cytometry analysis of B cells documented an immune reset with depletion of activated memory B cells, which were replaced by nonclass-switched IgD-positive naïve B cells.

Together, these data suggest the feasibility and potential for BiTEs to treat RA. This approach warrants further exploration on other B-cell-mediated autoimmune diseases.

https://www.nature.com/articles/s41591-024-02964-1

 

I'm sure @Jonathan Edwards can comment on the science.

Thought it was worth mentioning that this is the same team running the CAR-T cell trials in Erlangen.

 

Thanks.

I need to look in detail.

It seems an intelligent approach. The question is whether it can induce complete reversal of the process and Long term remission. It might be a way to unwind the autoimmune loop by attrition rather than by 're-booting' as for traditional B cell depletion.

 

This is definitely exciting and critical study to initiate the efforts to treat RA with deep depletion of B cells. However, one must be cautious interpreting the efficacy. The DAS28-CRP and RF/CCP level started to rise at 24 weeks. This is amid abatacept maintenance starting month 4. I wonder how deep the depletion is achieved compared to rituximab. Essentially rituximab and blinatumomab are both antibodies (although at significantly different dose); their function needs a second player (NK cells/macrophages vs T cells). Then the tissue penetration and depletion efficiency could be similar.

To me the interesting thing is: 1) if abatacept can be reused in previously abatacept-failed patients, have they checked whether anti-drug antibodies (ADA) are also depleted (assuming ADAs are from plasmablast of course)? 2) Rituximab cannot be given with another biologics (6 months) but looks like you can be on abatacept starting month 4 after blinatumomab. Is there a safety concern with this? If not, this will truly be life changing for those run-out-of-biologics-options RA patients.

 

@Sean_Liu When we first started using rituximab for RA we switched from one biologic to another if needed and overlapped if needed - mostly with etanercept. I am not sure in what sense rituximab cannot be given with another biologic.

Your points are interesting. If DAS28 is rising that early (despite abatacept) then it doesn't look too good.

 

Sorry I did not know that. Well, you are right- this does not look as miraculous. It might be similar to Tafasitamab. The only hope is to see if it depletes anti-drug antibodies. If so, it can still help many patients to restart their wonder biologics (TNFi).