Checkpoint Gene Found to be Promising Immunotherapy Target

Research led by the University of Minnesota has found that CISH, an intracellular checkpoint gene, plays a key role in suppressing the ability of human T-cells to recognize and attack cancer cells. When CISH is disabled, T-cells more effectively recognize mutated proteins produced by tumors. CISH inhibition also preserved T-cell fitness and made T-cells more responsive to existing checkpoint therapies, suggesting a new avenue to make breakthroughs in cancer immunotherapy.

“It is a true bench-to-bedside story that is currently being deployed in patients with metastatic gastrointestinal cancer who have exhausted virtually all other treatment options,” says Beau Webber, PhD, an assistant professor at the University of Minnesota Medical School and member of the Masonic Cancer Center. “This work is the culmination of a tremendous, multidisciplinary effort encompassing basic mechanistic immune biology, cutting-edge techniques in genome editing, and the latest advancements in adoptive cellular immunotherapy.” 

Gene editing allows researchers to hard-wire checkpoint inhibition into the specific immune cells that are fighting the tumor, thereby accelerating clinical translation of new approaches. Intracellular checkpoint genes, like CISH, are of particular interest because they offer a new avenue to enhance immune cell function against cancer. 

Since CISH resides within the cell, it cannot be inhibited using antibody blockades in the same way that other checkpoint molecules have been targeted. To overcome this challenge, the research team led by university faculty Branden Moriarity, PhD, and Webber used CRISPR gene editing to safely and effectively knockout the CISH gene in human T-cells. This process robustly enhanced T-cells’ ability to recognize and kill tumor cells and served as the preclinical basis for the first-in-human clinical trial using CRISPR engineered T cells at the University of Minnesota, and only the second CRISPR clinical trial authorized by the Food and Drug Administration at the time. The results are outlined in a recent issue of the journal Med.

The clinical trial in metastatic gastrointestinal cancer patients is ongoing. The team is also conducting correlative studies to evaluate the efficacy and safety of CISH-edited tumor-infiltrating lymphocytes and investigating additional strategies to further improve the function of engineered immune cells against solid cancers.