CRISPR-engineered T cells in patients with refractory cancer

Area of Science:

• Immunology
• Genetics
• Oncology

Background:

• CRISPR-Cas9 gene editing offers a promising strategy to enhance T cell-mediated cancer immunotherapy.
• Engineering T cells aims to improve their ability to target and eliminate cancer cells.

Purpose of the Study:

• To evaluate the safety and feasibility of multiplex CRISPR-Cas9 gene editing in human T cells for cancer treatment.
• To assess the efficacy of engineered T cells expressing a synthetic T cell receptor (TCR) and lacking PD-1 in patients with refractory cancer.

Main Methods:

• A first-in-human phase 1 clinical trial involving three patients with refractory cancer.
• Multiplex CRISPR-Cas9 editing was used to delete endogenous TCR genes (TRAC, TRBC) and PDCD1, and introduce a cancer-specific TCR transgene (NY-ESO-1).
• Adoptive transfer of engineered T cells and monitoring of engraftment, persistence, and safety.

Main Results:

• Durable engraftment of engineered T cells with successful edits at all three targeted genomic loci was observed.
• While chromosomal translocations were detected, their frequency diminished over time.
• Engineered T cells persisted for up to 9 months, indicating minimal immunogenicity.

Conclusions:

• Multiplex CRISPR-Cas9 gene editing is a feasible approach for engineering T cells for cancer immunotherapy.
• The persistence of modified T cells suggests potential for durable antitumor responses.
• This study provides a foundation for further clinical development of CRISPR-based cancer therapies.