Novel Tool Helps Identify Key Targets to Strengthen CAR NK Cell Therapies

Natural killer (NK) cells became markedly better at killing cancer cells after scientists removed key gene targets identified through a new genome-wide CRISPR screening tool, according to new research from The University of Texas MD Anderson Cancer Center.

The study, published today in Cancer Cell, opens new avenues for discovering approaches to enhance the antitumor activity of chimeric antigen receptor (CAR) NK cell therapies against multiple cancer types via PreCiSE, a comprehensive CRISPR discovery platform optimized for primary human NK cells.

“Targeted gene editing is a powerful tool to enhance the anticancer activity of NK cells,” said corresponding author Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation and Cellular Therapy and vice president and head of the Institute for Cell Therapy Discovery & Innovation.“PreCiSE is more than a screening tool. It is 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 research was led by Rezvani together with co first-authors Alexander Biederstaedt, M.D., formerly a postdoc in the Rezvani laboratory and now with the Technical University of Munich and Rafet Basar, M.D., Ph.D., assistant professor of Stem Cell Transplantation & Cellular Therapy.

Using PreCiSE, which was developed by the research team, investigators uncovered multiple checkpoints and pathways that control NK cell activity when facing pressures found in the environment surrounding a tumor. This tumor microenvironment tends to have numerous factors suppressing immune activity.

Editing these targets strengthened both innate and CAR-mediated NK cell function, improved metabolic fitness, increased pro-inflammatory cytokine production and expanded cytotoxic NK subsets in models of cancer that no longer responded to treatment.

While the study highlights three validated targets – MED12, ARIH2 and CCNC – the significance extends far beyond any single gene. PreCiSE delivers an unbiased map of NK cell regulators that can be prioritized, edited and combined to design more effective CAR NK cell therapies.

In the study, researchers validated top targets in vivo using multiple tumor models and under defined immune-suppressive stressors. Some regulators, such as MED12 and CCNC, intersect with pathways known in T cell biology, while others, including ARIH2, appear NK specific, underscoring the value of a platform built for NK cells themselves.

“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 said.

The Rezvani Laboratory has led advances in engineered NK cell therapy and has taken CAR NK approaches into clinical trials for patients with advanced hematologic and solid malignancies. Through the Institute for Cell Therapy Discovery & Innovation, Rezvani and her team will continue to develop and advance impactful cell therapies for patients in need. The current findings will be key in further enhancing the efficacy and activity of CAR NK cells for more cancer types.

A full list of collaborating authors and their disclosures can be found with the full paper.

This work was supported in part by the generous philanthropic contributions to the Institute for Cell Therapy Discovery & Innovation, including lead commitments from Meg and Kirk Gentle, Lindonlight Collective, The Marcus Foundation, Inc., The Margery L. Block Charitable Foundation, Melville Foundation and Tanoto Foundation. Additional support was provided by the James B. and Lois R. Archer Charitable Foundation, Ann and Clarence Cazalot, Jr., The Cockrell Foundation, The Cyvia & Melvyn Wolff Family Foundation, Vijay and Marie Goradia, Melvyn N. Klein, Marek Family Foundation, Gayle Stoffel, The McCombs Foundation, Tom Walters and Hollis Kazmann, MD Anderson’s Accelerator Fund, and the National Institutes of Health (1 R01 CA211044-01, 5 P01CA148600-03, 1 R01CA280827-01, 1 R01CA288617-01, 5P50CA281701-02, P50CA127001).