New CRISPR Tool Enhances NK Cell Cancer Therapies

Researchers at The University of Texas MD Anderson Cancer Center have developed a novel tool that significantly enhances the effectiveness of natural killer (NK) cell therapies against cancer. Using a new genome-wide CRISPR screening method called PreCiSE, scientists identified key gene targets that, when removed, allowed NK cells to more effectively kill cancer cells. The findings, published in the journal Cancer Cell, suggest new strategies for improving chimeric antigen receptor (CAR) NK cell therapies across various cancer types.

Katy Rezvani, MD, PhD, who is the corresponding author of the study, emphasized the tool’s transformative potential. “Targeted gene editing is a powerful tool to enhance the anticancer activity of NK cells,” said Rezvani, who is also a professor of Stem Cell Transplantation and Cellular Therapy and vice president of the Institute for Cell Therapy Discovery & Innovation. She described PreCiSE as not merely a screening tool, but as a detailed roadmap that reveals how tumors suppress NK cells and how CAR NK cells can be engineered to resist these suppressive pressures.

The research team, led by Rezvani along with co-first authors Alexander Biederstaedt, MD, and Rafet Basar, MD, PhD, utilized the PreCiSE platform to pinpoint several checkpoints and pathways that regulate NK cell activity in the tumor microenvironment, which is often rife with factors that inhibit immune responses. By editing these identified targets, researchers enhanced both innate and CAR-mediated NK cell functions. This led to improved metabolic fitness, increased production of pro-inflammatory cytokines, and a broader range of cytotoxic NK cell subsets in models where cancer had become resistant to standard treatments.

The study unveiled three validated targets: MED12, ARIH2, and CCNC. Their significance goes beyond individual genes. PreCiSE provides an unbiased map of NK cell regulators that researchers can prioritize, edit, and combine to develop more effective CAR NK cell therapies. Some of these regulators, like MED12 and CCNC, intersect with pathways previously studied in T cell biology, while ARIH2 appears to be unique to NK cells, highlighting the advantages of a platform specifically tailored for NK cell research.

“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,” Rezvani noted. The Rezvani Laboratory has made substantial contributions to engineered NK cell therapies and is currently conducting clinical trials for patients with advanced hematologic and solid malignancies.

The implications of these findings are substantial. The work will be instrumental in further enhancing the efficacy of CAR NK cells for a broader range of cancer types.

Funding for this research was supported by various philanthropic contributions to the Institute for Cell Therapy Discovery & Innovation, including lead commitments from several foundations. Additional support came from the National Institutes of Health through multiple grant numbers, underscoring the collaborative effort behind this groundbreaking study.

For more details, a full list of collaborating authors and their disclosures can be found in the published paper.