MICA: "Off-the-Shelf" CAR-based immunotherapy of SLE by targeting B cells and plasma cells

Lupus is a life-long illness where the immune system produces autoantibodies to attack its own healthy tissue causing inflammation and damage to organs such as the kidney and heart. Worldwide 1 in 2000 women are affected by lupus. Yet no cure has been identified and current treatments are not well tolerated and are only partially effective. One way to effectively treat lupus patients would be to eliminate their autoreactive B cells which are known to be the source of autoantibodies. Studies in mice and humans have shown that chimaeric antigen receptor (CAR)-T cells targeting B cells successfully eliminate most of the disease manifestations achieving clinical remission. This fellowship aims to develop a new CAR-based treatment by using specialised T cells called iNKT cells. These cells are unique because they recognise lipids on the surface of B cells. Since lipids are common to all individuals, CAR-iNKT cells can be made from one healthy person and used to treat any lupus patient without the risk of harm to the patient. The main purposes of this project are i) to compare the efficacy of CAR approaches targeting B cells (using CD19 as marker) versus those targeting plasma cells (identified by BCMA); ii) to develop CAR-iNKT cells and test their of ability to treat lupus in an in vivo experimental model; iii) to explore in vitro how lupus patient B cells respond to CAR-modified cells. The proposed research will provide the pre-clinical rationale for clinical development of the most effective CAR-based immunotherapy as a potentially transformative treatment for patients with SLE.

Systemic lupus erythematosus (SLE) is an autoantibody-mediated inflammatory disease that often leads to severe organ damage. In many patients, the response to current treatment options is either incomplete or highly toxic. A simple, yet radical conceptual therapeutic strategy would be to target and deplete B cells and/or plasma cells, i.e., the cellular sources of pathogenic autoantibodies. While antibody-mediated B cell depletion with an anti-CD20 antibody (rituximab) has been shown to have limited clinical impact, a more profound depletion of B cells by autologous chimaeric antigen receptor (CAR)-T cell technology has achieved complete remissions in lupus pre-clinical and early clinical studies. Therefore, the aim of this fellowship is to compare B cell- and plasma cell-directed CAR-T and CAR-iNKT cell immunotherapy for the treatment of experimental lupus. iNKT cells are a subset of CD1d-restricted, glycolipid-specific T cells that, unlike conventional T cells, do not cause acute graft-versus-host disease and thus can be used for off-the-shelf immunotherapy. The specific aims of the proposal are to: a) compare the ability of autologous CD19, BCMA and bispecific CD19-BCMA CAR-T cells to induce lasting disease remission in a spontaneous murine lupus model; b) establish allogeneic iNKT cells as an alternative platform for CAR-based immunotherapy for lupus and c) explore the feasibility of future CAR-based therapy using in vitro assays with cells from lupus patients. The proposed research will provide the rationale for optimal clinical development of cellular immunotherapy for SLE i.e., B cell vs plasma cell targeting, autologous CAR-T vs allogeneic CAR-iNKT immunotherapy.