Brexucabtagene autoleucel

Mantle cell lymphoma (MCL) is a heterogeneous sub-category of B cell non-Hodgkin's lymphoma typified by overexpression of cyclin D1 and SOX-11 as well as mutations in numerous genes including TP53; overall, these changes lead to increased cell growth, apoptosis inhibition, and cell-adhesion-mediated drug resistance. Based on the 2016 World Health Organization guidelines, MCL can be generally subdivided into aggressive nodal and indolent leukemic non-nodal subtypes. Bruton's tyrosine kinase (BTK) inhibitors can be used following a relapse of front-line therapy, but patients who relapse after BTK inhibitor therapy have a poor prognosis.

Chimeric antigen receptors (CARs) are synthetic immunoreceptors that can be introduced into T cells ex vivo using viral transduction and that allow for major histocompatibility complex (MHC)-independent direction of T cells to any cell possessing the complementary antigen. Brexucabtagene autoleucel employs a murine anti-CD19 single-chain variable fragment (scFv) linked to internal CD28- and CD3ζ-derived co-stimulatory domains. Brexucabtagene autoleucel is prepared from the patient's own peripheral blood mononuclear cells using a leukapheresis methodology that excludes CD19-expressing tumour cells to avoid potential activation and exhaustion of CAR T cells during manufacturing. Collected cells are activated with anti-CD3 and anti-CD28 antibodies along with IL-2, transduced with a replication-incompetent retroviral vector, and subsequently expanded prior to infusion.

Once infused into the patient, the CAR T cells bind to CD19 antigens on the surface of both normal and cancerous B cells, leading to CAR T cell activation and expansion. Activated CAR T cells secrete cytokines and chemokines including, but not limited to, IL-6, IL-8, IL-10, IL-15, TNF-α, IFN-γ, and soluble IL-2 (sIL2Rα), leading to tumour cell lysis and anti-tumour activity.