PBCAR19B, an Immune Evading Allogeneic CAR T Stealth Cell, Demonstrates Potent Anti-Tumor Responses and Prolonged B Cell Depletion Supporting Sustained Immune Evasion in Patients with Relapsed/Refractory (R/R) B-Cell Lymphoma (NHL)

作者：Usama Gergis, Aaron J. Martin, A. Vogel, Jeff Smith, Andreas K. Klein, Ran Reshef, Rajneesh Nath, Adam J. Olszewski, Alan F. List, Alex F. Herrera, Michael D. Jain · 发表于：Blood · 年份：2024 · DOI：10.1182/blood-2024-210499 · 被引用次数：2 · 研究领域：CAR-T cell therapy research、Viral Infectious Diseases and Gene Expression in Insects

Background: The efficacy of CAR T cell products has been limited by host immune rejection. PBCAR19B or “Stealth Cell” is a of cluster of differentiation (CD)19-directed allogeneic CAR T-cell therapy designed to evade immune rejection in order to extend target engagement and improve clinical efficacy. PBCAR19B is derived from healthy donor T cells in which a stealth construct is inserted into the T cell receptor alpha constant (TRAC) gene locus via a TRAC-specific ARCUS nuclease. In addition to the anti-CD19 CAR gene, the stealth construct carries a microRNA that suppresses expression of beta-2 microglobulin (B2M), a component of Class 1 major histocompatibility complex (MHC) molecules found on the cell surface. Reducing or knocking down Class 1 expression on allogeneic CAR T cells has been shown to reduce CAR T cell killing by cytotoxic T cells. The stealth construct also carries a HLA-E gene intended to prevent rejection of CAR T cells by NK cells that can be stimulated as a result of reduced MHC expression on the cell surface. Together, these key features position PBCAR19B as a potential off-the-shelf-treatment with improved persistence in CD19-related indications. Methods: PBCAR19B was administered as a single infusion to adult subjects with measurable CD19+ R/R NHL. Prior hematopoietic cell transplant or treatment with a CD19-directed autologous CAR T therapy was permitted. Two lymphodepletion (LD) regimens were tested, including standard (sLD), fludarabine 30 mg/m2/day ×...