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BCMA-targeted CAR-T cells (TGF-beta resistant, inducible IL-18 production)

Development stage: Preclinical
Lead developer: Medical College of Wisconsin
Modality: CRISPR-Cas9 → CRISPR Systems → Programmable Nucleases → Gene Editing → Gene Therapies, CAR-T Cells → Engineered T Cells → Adoptive Cell Transfer → Cell Therapies
Administration: Intravenous

Overview

BCMA-targeted CAR-T cells (TGF-beta resistant, inducible IL-18 production) is an experimental next-generation chimeric antigen receptor (CAR) T-cell therapy designed for the treatment of relapsed and/or refractory multiple myeloma (RRMM). This cell therapy is engineered to overcome the immunosuppressive bone marrow environment (BME) by incorporating three specific genetic modifications: the expression of a dominant-negative TGF-beta receptor 2 (dnTGFBR2) to provide resistance to TGF-beta-mediated suppression, the CRISPR/Cas9-mediated disruption of the PDCD1 (PD-1) gene to prevent T-cell exhaustion, and the site-specific monoallelic knock-in of an IL-18 gene into the PDCD1 locus. This configuration allows for the inducible secretion of IL-18 driven by the endogenous PDCD1 promoter upon T-cell activation, which enhances Th1-driven immune responses and improves the durability of the anti-tumor effect while simultaneously silencing PD-1 expression.

Other names: TGF-beta resistant BCMA CARTs with inducible IL-18BCMA-targeted CAR-T cells with dnTGFBR2 and PD-1-driven IL-18

Targets

TGFBR2 (TGF-β receptor type 2)BCMA (B-cell maturation antigen)IL-18R (Interleukin-18 receptor complex)

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