Permanent gene editing of T cell DNA shown to be safe in first clinical trial

New gene-editing therapy shows early success in fighting advanced GI cancers. Illustration provided by University of Minnesota

Cancer Digest – May 4, 2025 – Researchers have successfully shown that a permanent "edit" of the DNA in immune cells that attack colorectal cancer is safe, and results of that first in-human clinical trial show signs of effectiveness for the new treatment.

Dr. Emil Lou, MD, PhD of the University of Minnesota’s Medical School led the first of its kind clinical trial that involves genetically de-activating a certain gene in a type of T cell called tumor infiltrating lymphocytes, or TILs. The de-actived gene, called CISH allows the T cells to better recognize the cancer cells and eliminate them. The trial results, first presented at the American Association of Cancer Research in April, were published in the May 2025 journal Lancet Oncology.

“Despite many advances in understanding the genomic drivers and other factors causing cancer, with few exceptions, stage IV colorectal cancer remains a largely incurable disease,” said Dr. Lou in a press release. “This trial brings a new approach from our research labs into the clinic and shows potential for improving outcomes in patients with late-stage disease.”

In the early stage clinical trial designed to determine safety of a new treatment, 12 patients with end-stage colorectal cancer were given infusions containing 10 billion genetically modified T cells. The primary aim was to determine safety and optimal dose. A second aim was to see if the modified T cells attack the cancer. 

After a median followup of a little more than four months, six of the 12 (50%) had stable disease, meaning the cancer had not grown worse, in the first month following treatment. Four of those patients remained stable after 56 days. One patient had a complete and ongoing response, meaning the cancer disappeared, almost two years following treatment.

Side effects of the treatment included fever, fatigue, anemia, bleeding, and loss of appetite that occurred in some but not all patients.

The difference between this T cell treatment and current treatments involving modified T cells is that the researchers permanently modified the T cells by deleting the CISH gene that prevented TILs from recognizing the cancer cells. In other words, the modified T cells infused into the patient will continue to replicate and persist in the patient’s immune system for the rest of their lives. In current T cells therapies the modified T cells eventually are depleted over time, requiring ongoing doses.

“With our gene-editing approach, the checkpoint inhibition is accomplished in one step and is permanently hardwired into the T cells,” co-author Beau Webber, PhD, associate professor at the University of Minnesota Medical School and Masonic Cancer Center researcher said in a press release.

The trial was funded by Intima Bioscience, which developed the method for deleting the CISH gene from TILs. 

“In metastatic colorectal cancer, where treatment options are limited and survival outcomes are uniformly fatal, CISH represents a promising new target that may overcome the limitations of current immunotherapies," Dr. Lou said in a press release. "We believe these data, including an exceptional complete response attributed to CISH knockout, resoundingly support the potential role of CISH checkpoint inhibition in addressing this significant unmet need and underline the possibility of small molecule drugging of CISH to democratize access to patients beyond this proof-of-concept cell therapy clinical trial.”

(Note: The National Cancer Institute of the NIH formally defines an exceptional response as a complete response in which less than 10% of patients respond overall.)

The process is expensive and complex. Next steps will attempt to streamline the process and make the treatment a viable option for advanced cancers.

Sources: University of Minnesota press release,  The Lancet Oncology, and Intima Bioscience press release.