Clinical Trial Update - Meganuclease-Edited CAR T-Cell Therapies

The latest trial is sponsored by Precision BioSciences (US) and it will evaluate the safety and efficacy of PBCAR19B, a gene-edited allogeneic (donor-derived) anti-CD19 CAR T cell therapy for relapsed or refractory NHL.

PBCAR19B is a so-called 'stealth cell' anti-CD19 CAR T product that is designed to prevent immune rejection by recipients. The new therapy is engineered using Precision BioSciences’ next-generation meganuclease platform called “ARCUS”. The ARCUS platform produces meganucleases (See Fact Box) with customised activity and specificity, which are capable of distinguishing target sites that differ by only 1 base pair.

PBCAR19B – For Improved Persistence of Allogeneic CAR T Cells

PBCAR19B is designed to improve allogeneic CAR T cell persistence by preventing rejection by recipient T cells and natural killer (NK) cells. PBCAR19B cells are developed through three meganuclease-mediated modifications.

Firstly, an anti-CD19 CAR construct is inserted into the native T cell receptor (TCR) locus. Disruption of the donor's native TCR mitigates the risk of graft-vs-host disease that may occur if histo-incompatibility between donor and recipient causes the infused cells to reject their new host.

The PBCAR19B vector also harbours a short hairpin RNA that suppresses beta-2 microglobulin (B2M) expression. B2M is a component of the Class 1 major histocompatibility complex (MHC) that is present on the surfaces of all T cells. B2M disruption eliminates the expression of all MHC I molecules on CAR T cells, thus reducing the risk of self-presenting to recipient T cells, allowing persistence in their new host. This approach is being investigated in a number of CAR-T cell programs and is reviewed elsewhere.

Lastly, PBCAR19B cells are engineered to express the conserved HLA-E transgene. While B2M disruption eliminates all MHC I molecules to boost persistence, it also leaves the CAR T cells vulnerable to NK cells. HLA-E surface expression in the absence of all other MHC molecules prevents NK-mediated lysis without stimulating allogeneic T cells. This strategy is being explored for the creation of universal donor cells for CAR T cancer therapy.

PBCAR19B Trial for Non-Hodgkin Lymphoma

In pre-clinical studies, PBCAR19B was found to delay both T cell and natural killer cell-mediated allogeneic rejection. Precision BioSciences reported in January 2021 that it had been granted IND clearance for PBCAR19B from the U.S. Food and Drug Administration (FDA).