So, what’s an immune reset, anyway?

You might have heard of an “immune reset” for Chimeric Antigen Receptor (CAR) therapies in autoimmune diseases. But what does it mean, exactly?

Here’s the 2024 definition from Georg Schett et al’s paper “”Advancements and challenges in CAR T cell therapy in autoimmune diseases”:

“…deep depletion of B cells, including autoreactive B cell clones, could restore normal immune function, referred to as an immune reset.”

Autoimmune diseases, such as systemic lupus erythematosus (SLE), represent some of the hardest conditions to treat. These diseases need lifelong medication with limited success in achieving full remission. But CAR-T is changing that.

In 2022, Schett et al posted this incredible result: “Remission of SLE according to [disease remission] criteria was achieved in all five patients after 3 months and the median (range) Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0…Drug-free remission was maintained during longer follow-up (median (range) of 8 (12) months after CAR T cell administration).”

From lifelong drugs, to a “one and done” cure.

The concept of an immune reset: “one and done” cure

To make a CAR T-cell therapy, you engineer T cells to target and destroy B cells expressing a target. In the 2022 paper, that was the CD19 antigen. The CD19 antigen turns out to be a key player in many autoimmune diseases. By deeply depleting “autoreactive” B cells, this therapy not only halts disease progression but resets the immune system. (An autoreactive B cell is a type of immune cell that mistakenly recognizes the body’s own tissues as foreign and initiates an immune response against them.)

This approach could yield a one-time cure.

How is an immune reset measured?

It’s an emerging area, so we’re seeing two ways:

1. Using Cytometry: “Bad” B cells go away, “good” B cells appear
   1. Bad B cell eliminated: Within two days of CAR T-cell infusion, the bad B cells, i.e. CD19+B cells disappeared. Here’s Figure 2c from the 2022 paper:
   2. Good B cells appeared: B cells reappeared after an average of 110 ± 32 days but with a big change. These new B cells were predominantly naive (CD21+CD27−) with no memory or autoreactive profiles. (Remember, autoreactive is bad since those kinds of cells attack your own body.) This is Figure 4C from the 2022 paper. BL means Baseline, RC means reconstitution.
      1. 

2. Using ELISA: Autoantibody Clearance
   1. Reduction in Anti-dsDNA Levels: Autoantibodies, such as anti-double-stranded DNA (dsDNA), became undetectable in all patients by the three-month mark in the study.
   2. Comprehensive Autoantibody Decline: Beyond dsDNA, other pathogenic autoantibodies, including those targeting nucleosomes and single-stranded DNA, showed similar declines, reflecting a broad reset of immune activity​.

Wrapping up

CAR-T has the possibility of being a lifetime “one-and-done” cure to autoimmune disease. It seems that achieving an “immune reset” is a critical step. The science is still evolving, so watch this space!