Restoration of Immune Cell Homeostasis in Tissue via CD19 CAR-T Cell Mediated B Cell Clearance in SLE

CD19 chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable clinical results, allowing more than15 individuals with severe, refractory lupus to reach lasting, drug-free remission (decrease or absence of symptoms with no other treatments needed). This therapy involves reengineering a patient’s T cells to target and eliminate B cells, a key driver of lupus. After treatment, the B cells are rapidly cleared from the blood. About 90-150 days later, B cells return, but in a naive state— like pressing the reset button, the returning B cells have not yet learned to attack anything. While both monoclonal antibodies (lab-made molecules that bind to specific targets), like Rituximab, and CAR T cell therapy eliminate B cells from the blood, Rituximab does not effectively deplete B cells in tissues, which may explain its overall lower efficacy. Dr. Grieshaber-Bouyer will study tissues from people with lupus treated with CD19 CAR T cells to determine the mechanisms supporting this immune reset.

Dr. Grieshaber-Bouyer hypothesizes that CD19 CAR T cell therapy leads to an immune reset through multiple mechanisms, including the clearance of B cells from tissues such as the lymph nodes and the reshaping and normalization of other immune cells, including T cells. As part of the ongoing CAR-T cells in SysTemic B celL mediated autoimmunE Disease (CASTLE) trial, he will use state-of-the-art technology to compare immune cells from people with systemic lupus erythematosus (SLE) receiving CD19 CAR T cell therapy to those receiving Rituximab therapy.

What this means for people with lupus

Understanding how CD19 CAR T cell therapy leads to lasting remission could provide new endpoints for clinical trials and define new markers of remission in lupus. Additionally, findings from Dr. Grieshaber-Bouyer’s study could improve immune monitoring of patients over time, leading to better long-term management of the disease

CD19 CAR-T cell therapy has demonstrated remarkable clinical efficacy in patients suffering from severe, refractory SLE. Therefore, cell therapies represent a promising direction for rheumatology and clinical development is advancing swiftly. In contrast, many immunological mechanisms of CAR-T cell therapy in SLE are much less clear. To further advance the field, it is required to better understand precisely which aspects of the complex SLE pathophysiology are altered by CAR-T cell therapy, and how these changes compare to other therapies such as Rituximab. While both monoclonal antibodies and CAR-T cells deplete B cells in circulation, CAR-T cells might be superior to depleting B cells deeper in the tissue, but this has so far not been comprehensively tested. Therefore, tissue level analyses as ancillary studies to CART cell trials are essential.

Furthermore, it is surprising and not entirely understood how the depletion of B cells alone is capable of inducing drug-free remission of SLE for many years since the disease is also driven by other types of immune cells, such as autoreactive T cells and by proinflammatory changes in myeloid cells. Thus, a better characterization of the autoimmune T cells and myeloid cells involved in SLE patients undergoing CAR-T cell therapy in comparison to monoclonal antibodies, is necessary. Finally, approaches to quantify and monitor the degree of immune reset are currently lacking, impeding the use of molecular/surrogate endpoints in clinical trials and facilitating comparison between treatment approaches.

The overarching objective of this proposal is to understand the mechanisms by which an immune reset is induced in SLE patients receiving CD19 CAR-T cell therapy by performing deep immune profiling of tissue niches and blood leukocytes. These studies will be performed concomitantly to our ongoing academic phase I/IIA trial (CASTLE). We pursue the overall hypothesis that CD19 CAR-T cell therapy interrupts SLE pathophysiology on multiple levels, leading to an immune reset. We hypothesize that this entails (i) clearance of B cells from lymph nodes with subsequent remodeling of the immune cell network, (ii) reshapes the T cell receptor repertoire and (iii) normalizes overall T cell and myeloid cell activation. These hypotheses will be tested via high dimensional immune cell profiling of longitudinal patient samples obtained from SLE patients receiving CD19 CAR-T cells as part of our CASTLE trial, and compared to patients receiving Rituximab therapy. This will allow us to uncover the molecular mechanisms associated with deep B cell depletion induced by CD19 CAR-T cell therapy. Furthermore, it will allow us to define molecular remission in SLE, which is important for benchmarking therapies, as molecular endpoint in clinical trials and to define meaningful features for longitudinal immune surveillance.