MD Anderson Team Enhances CAR NK Cell Therapies Using Genome-Wide CRISPR Screening

A team from The University of Texas MD Anderson Cancer Center developed a genome-wide CRISPR screening tool optimized for use in primary human natural killer (NK) cells. The tool, called PreCiSE, enabled researchers to identify multiple gene targets whose removal significantly increased the ability of NK cells to kill cancer cells.

In their study published in Cancer Cell, the researchers used PreCiSE to systematically screen for checkpoints and molecular pathways that regulate NK cell activity. The tumor microenvironment typically dampens immune responses, but by editing key genes identified through the screen, the team was able to enhance both innate and chimeric antigen receptor (CAR)-mediated NK cell function. This led to improvements in metabolic fitness, increased production of pro-inflammatory cytokines, and expansion of cytotoxic NK cell subsets in experimental models of cancers that had stopped responding to standard treatments.

The PreCiSE platform provided what corresponding author Katy Rezvani described as “a roadmap that reveals how tumors suppress our cells and how to reengineer CAR NK cells to resist those pressures across many cancer types.” The ability to prioritize, edit, and combine gene targets discovered through the platform opens possibilities for designing more effective CAR NK cell therapies. Among the important targets highlighted were MED12, ARIH2, and CCNC. While MED12 and CCNC are linked to pathways familiar from T cell biology, ARIH2 appeared to be NK cell-specific, demonstrating the unique insight gained from a platform tailored for NK cells.

According to the research, validation of these targets in multiple tumor models was performed under defined immune-suppressive stressors. Editing these genes not only made NK cells more effective in killing cancer cells but also improved their resistance to factors in the tumor microenvironment that typically weaken immune responses.

The Rezvani Laboratory has already moved CAR NK approaches into clinical trials for patients with advanced blood and solid cancers. The current findings with the PreCiSE platform are expected to significantly aid further development of more effective and resilient CAR NK cell therapies for a wider range of cancers. Rezvani noted, “This has given us significant insight into the next generation of cell therapies that have the potential to be more powerful, precise and resistant to cancer.”