Investigating the role of BAFF in CAR-T cell associated adverse events

PROJECT SUMMARY Despite the impressive therapeutic success of chimeric antigen receptor (CAR)-T cell therapy in treating previously incurable hematological malignancies, its use is associated with significant safety concerns. The most common and potentially life-threatening adverse events (AEs) after CAR-T cell infusion are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The incidence of high- grade events makes up a quarter to a half of cases of patients who experience these toxicities. In addition to risk to patient safety, management of these AEs increases health care resource utilization and financial burden. Both events are associated with a heightened immune effector state following CAR-T cell infusion, yet their underlying pathophysiology remains elusive. After infusion, the activated CAR-T cell repertoire stimulates recruited macrophages to propagate a dysregulated pro-inflammatory state which can cause vascular leakage and CRS. Progression into the central nervous system causes ICANS. IL-6 is a central mediator in this mechanism and its neutralization with tocilizumab is standard of care for treating CRS. However, CRS may recur in some tocilizumab-treated patients and, significantly, tocilizumab does not prevent progression to ICANS, which is managed with glucocorticoids. Novel discoveries into the mechanisms of CRS and ICANS may uncover treatment strategies that could more effectively manage both AEs. To this end, we are interested in studying a novel role for B-cell activating factor (BAFF) in CRS/ICANS pathophysiology. BAFF is a TNF family cytokine that drives B-cell maturation and survival and classically studied for its pro-tumorigenic effects in B-cell malignancies. We recently found that serum BAFF levels are significantly elevated with increased IL-6 relative to pre-treatment levels in patients who experienced CRS following CAR-T cell infusion. When exploring a potential role of BAFF in CRS/ICANS pathophysiology, we found that interferon gamma (IFNγ) stimulates monocytes to secrete BAFF and upregulates two receptors of BAFF. BAFF stimulation of peripheral blood mononuclear cells and, more specifically, monocytes, results in increased expression of multiple pro-inflammatory cytokines involved in CRS/ICANS pathophysiology. Conversely, neutralization of soluble BAFF with belimumab resulted in decreased expression and production of these cytokines. Based on this preliminary data, we hypothesize that IFNγ released from activated CAR-T cells stimulates recruited monocytes to increase BAFF production and expression of BAFF receptors. BAFF ligation may be an early event that stimulates production of pro-inflammatory cytokines to propagate the CRS and ICANS sequelae. Clinically, targeting BAFF may represent a promising therapeutic approach to blunt the dysregulated proinflammatory cascade at an early stage and limit the development of both AEs. Based on the pro-tumorigenic role of BAFF, this could concurrently help to limit disease burden. In summary, discoveries made in this proposal will add mechanistic insight to the most common toxicities that accompany CAR-T cell therapy and potentially lead to novel therapeutic approaches to make this life-saving therapy safer.