Brexucabtagene Autoleucel

Uses

Brexucabtagene Autoleucel is a modified autologous chimeric antigen receptor (CAR) T cell therapy employing a modified murine anti-CD19 single-chain variable fragment linked to CD28 and CD3ζ co-stimulatory domains for the treatment of patients with relapsed and refractory mantle cell lymphoma.

Brexucabtagene Autoleucel is a modified autologous chimeric antigen receptor (CAR) T cell immunotherapy indicated for the treatment of relapsed or refractory mantle cell lymphoma (MCL) in adult patients.

Brexucabtagene Autoleucel has been granted accelerated approval based on results from a single-arm, open-label, multicentre clinical trial; continued approval may be contingent on confirmatory trials.

Brexucabtagene Autoleucel is also used to associated treatment for these conditions: Refractory Mantle Cell Lymphoma, Relapsed Mantle Cell Lymphoma

How Brexucabtagene Autoleucel works

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.

Toxicity

Toxicity information regarding brexucabtagene autoleucel is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as severe infections, severe and prolonged cytopenia, hypogammaglobulinemia, cytokine release syndrome, and neurological toxicities. Symptomatic and supportive measures are recommended.

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Elimination Route

Patients in the ZUMA-2 clinical trial received a target dose of 2 x 10⁶ CAR T cells/kg, which expanded to a variable degree among responders and non-responders; peak levels were reached within the first seven to 15 days following infusion. Median peak CAR T cell levels were 102.4 cells/μL (range 0.2 to 2589.5) in responders and 12.0 cells/μL (range 0.2 to 1354.0) in non-responders. The corresponding median AUC_0-28 for responders and non-responders was 1487.0 cells/μL*day (range 3.8 to 2.77E+04) and 169.5 cells/μL*day (range 1.8 to 1.17E+04), respectively.

These values were also assessed based on the co-administration of immunosuppressive therapy. Patients receiving neither corticosteroids nor tocilizumab had a peak of 24.7 cells/μL with an AUC_0-28 of 360.4 cells/μL*day, patients receiving only corticosteroids had a peak of 24.2 cells/μL and an AUC_0-28 of 367.8 cells/μL*day, and patients receiving only tocilizumab had a peak of 86.5 cells/μL and an AUC_0-28 of 1188.9 cells/μL*day. The highest counts were in patients receiving both corticosteroids and tocilizumab, with a peak of 167.2 cells/μL and an AUC_0-28 of 1996.0 cells/μL*day.

Finally, separating patients into those < 65 years of age of ≥ 65 years of age, patients in the lower age group had a median peak of 112.5 cells/μL and a median AUC_0-28 of 1640.2 cells/μL*day. Older patients had a median peak count of 74.1 cells/μL and a median AUC_0-28 of 876.5 cells/μL*day.

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