?? Gene-Edited Universal CAR-T: Preventing GVHD and Immune Rejection

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized cancer treatment, but its widespread use is limited by the need for autologous T cells, which need to be engineered specifically for the patient. To overcome this challenge, researchers are developing gene-edited universal CAR-T cells, enabling off-the-shelf allogeneic cell therapy. However, a major obstacle to allogeneic CAR-T therapy is graft-versus-host disease (GVHD) and immune rejection, which occurs when donor-derived CAR-T cells attack recipient tissue or are eliminated by the host immune system.

To prevent GVHD, scientists are using CRISPR and other gene-editing technologies to knock out T-cell receptor (TCR) genes, such as TRAC (T-cell receptor alpha constant). Removing TCR expression eliminates the risk of T cells recognizing host tissue as foreign, thereby reducing the risk of GVHD. In addition, knocking out HLA molecules on CAR-T cells helps prevent host immune rejection, allowing the infused cells to survive longer and effectively target cancer cells.

Another approach is to engineer CAR-T cells to express immune checkpoint molecules or stealth modifications to protect them from natural killer (NK) cell- and macrophage-mediated clearance. By incorporating HLA-E or CD47 expression, universal CAR-T cells can evade attack by the innate immune system, thereby improving their survival and therapeutic efficacy.

These advances in gene-edited allogeneic CAR-T therapy make cancer immunotherapy more accessible, scalable, and cost-effective. As research progresses, universal CAR-T cells are expected to become a widely available, off-the-shelf solution, eliminating manufacturing delays and expanding treatment access for hematologic malignancies and solid tumors.

Reference

[1] Ziyu Wu et al., Trans Oncol 2024 (doi: 10.1016/j.tranon.2024.102147)