Overcoming Barriers in CAR-T Therapy Through Precision Gene Editing

Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a revolutionary approach to treating B-cell malignancies, such as CD19+ cancers. However, its application has been limited by challenges, including high costs, safety concerns with viral vectors, and limited efficacy in solid tumors. A recent review published in Frontiers in Oncology highlighted recent advancements in gene-editing technologies that introduce new opportunities for more precise, cost-effective, and scalable CAR-T therapies.

Current key challenges for CAR-T therapies include difficulty in trafficking CAR-T cells to tumor sites, the suppressive tumor microenvironment hindering CAR-T cell activity, and the high costs and complexity of personalized production. Gene editing has emerged as a potential solution by enabling precise modifications at the genomic level. Tools such as CRISPR/Cas9 offer a cost-effective method for targeted editing and facilitating virus-free gene insertion into safe genomic regions, reducing the risks associated with traditional vectors. Base editors also enhance precision by altering single nucleotides without inducing double-strand breaks (DSBs). Prime editors allow all possible base-to-base conversions and enable small gene insertions or deletions without requiring donor DNA samples.

The development of “off-the-shelf” CAR-T cells using allogeneic sources also represents a major breakthrough in cost management. By disrupting genes such as TRAC and B2M, gene editing eliminates the risk of graft-versus-host disease and immune rejection, creating universal CAR-T products that are more accessible and cost-effective. Additionally, gene editing enhances CAR-T cell persistence and efficacy by targeting inhibitory regulators such as PD-1 and CTLA-4, which helps prevent exhaustion and improve antitumor responses.

Emerging therapies, such as pluripotent stem cell (iPSC)-derived CAR-T cells, offer scalable and standardized solutions to address donor variability. They are showing promise in clinical trials, providing uniformity in production and enhancing therapeutic consistency.

The integration of advanced gene-editing technologies with CAR-T cell therapy has the potential to overcome current limitations, broaden therapeutic applications, and enhance accessibility. Continued innovation in editing tools, delivery methods, and manufacturing processes will be essential to realize the full potential of genome-edited CAR-T therapies.

“The clinical use of gene editing tools is increasingly expanding and the number of clinical trials with genome-edited CAR-T cells indicates a bright future for these products,” the researchers concluded. “Nevertheless, there are few available clinical data about the efficacy and safety of genome-edited CAR-T cells. Moreover, the genotoxicity of programmable nuclease and the long-term consequences of disrupted genes remain a concern. This highlights the need for more clinical trials with genome-edited CAR-T cells and the necessity for long-term follow-up of treated patients.”

Reference

Moradi V, Khodabandehloo E, Alidadi M, Omidkhoda A, Ahmadbeigi N. Progress and pitfalls of gene editing technology in CAR-T cell therapy: a state-of-the-art review. Front Oncol. 2024;14:1388475. doi:10.3389/fonc.2024.1388475