Mechanistic Studies of CART Cell-Induced B Cell Depletion in SLE

Mechanistic studies of CART cell-induced B cell depletion in SLE 

While treatments such as anti-CD20 antibodies (i.e., rituximab) can deplete B cells and induce remission in some patients, they are not always effective. CD19-targeted CAR-T cells, are highly effective at eliminating B cells at a deeper level, including tissue B cells, and have shown great promise in achieving long-term remission without the need for ongoing immunosuppression. However, there is still much to learn about how these therapies work and why they are effective in some patients but not others. Dr. Sanz will investigate how CD19 CAR T cell therapy can induce long-lasting remission (decrease or absence of symptoms) in individuals with lupus. 

Dr. Sanz will conduct detailed studies on patients treated with different types of CAR T cells at Emory University. He will compare these patients to those treated with anti-CD20 antibodies and to patients with other conditions such as lymphoma and multiple myeloma who receive similar treatments. The study aims to understand the extent and quality of B cell depletion, the mechanisms behind the “resetting” of the immune system, and the factors that influence the success of CAR T cell therapy. By analyzing blood and lymph node samples, Dr. Sanz hopes to identify markers that predict treatment response and to develop strategies for selecting patients who are most likely to benefit from this therapy. 

What this means for people with lupus 

Dr. Sanz’s research could lead to a better understanding of how CAR T cell therapy works in lupus and help identify which patients are most likely to respond to treatment. This could improve the effectiveness of CAR T cell therapy and provide new insights into managing and potentially curing lupus. 

While the use of anti-CD20 antibodies had shown that profound B cell depletion can induce prolonged disease remission in SLE, this outcome is only achieved in a portion of patients. Although still limited to open case series, the use of CD19 CART cells have demonstrated unprecedented potential to induce long-lasting remission of refractory SLE in the absence of background immunosuppression. Similar results in other autoimmune diseases have brought B cell depleting CAR T cells to the forefront of SLE therapies. The available reports have proposed that CD19 CART cells induce profound and sustained clinical responses through the resetting of the B cell compartment. However, this conclusion derives from the repopulation of pre-treatment B cells with a new repertoire as assessed by VDJ sequencing. Of significant interest, SLE patients treated with CART cells experience substantially faster disappearance of these cells and much shorter duration of B cell aplasia relative to lymphoma patients and even Rituximab-treated patients with profound B cell depletion. Thus, as larger clinical trials get underway, much remains to be understood about the factors that may influence the behavior and efficacy of CART cells in SLE; the immunological consequences of these treatments; and the degree and mechanisms of immune resetting. Our objective is to conduct detailed mechanistic analysis of CART cells-induced BCD depletion in SLE through ancillary studies of patients treated at Emory with different types of CART cells. Given the low numbers of patients currently available at any given center, we will also study lymphoma and multiple myeloma patients treated with the same modalities as well as SLE patients treated with anti-CD20-induced B cell depletion. Our specific aims are:

Aim 1. Magnitude and quality of B cell depletion through blood and lymph node studies Aim 2. Immune resetting studies

Sub-aim 2.1: VDJ repertoire

Sub-aim 2.2: Elimination of the SLE molecular signature in repopulating B cells

Sub-Aim 2.3: Re-establishment of B cell Tolerance in SLE:

2.3.1: Changes in the antibody autoreactome

2.3.2: Repopulation of autoreactive B cells and tolerogenic checkpoints

Aim 3. Understanding the impact anti-CAR cells antibodies in SLE

Combined, our studies will provide an in-depth analysis of the immunological consequences of CART cell treatments and provide a roadmap for understanding determinants and mechanisms of success and avenues to select the patients more likely to respond and strategies for future studies.