A groundbreaking clinical trial has demonstrated promising results for a novel CRISPR-based immunotherapy in treating advanced gastrointestinal cancers, offering new hope for patients with previously incurable disease.
Researchers at the University of Minnesota have successfully completed the first-in-human trial using CRISPR/Cas9 gene-editing technology to enhance the immune system's ability to combat late-stage gastrointestinal (GI) cancers. The results, recently published in The Lancet Oncology, indicate the therapy is both safe and potentially effective against metastatic disease.
Enhancing Immune Response Through Genetic Engineering
The innovative approach targets tumor-infiltrating lymphocytes (TILs), a type of immune cell, using CRISPR/Cas9 technology to deactivate a specific gene called CISH. This gene normally functions as a regulatory checkpoint that inhibits T cell activity against cancer.
"We believe that CISH is a key factor preventing T cells from recognizing and eliminating tumors," explained Dr. Branden Moriarity, Associate Professor at the University of Minnesota and co-director of the Center for Genome Engineering. "Since CISH acts inside cells, it couldn't be blocked using traditional methods. So we used CRISPR-based genetic engineering to block it."
By disabling the CISH gene, researchers were able to significantly enhance the TILs' ability to recognize and attack cancer cells, creating a potentially powerful new weapon against GI cancers that have historically been resistant to treatment.
Promising Clinical Outcomes
The trial enrolled 12 patients with highly metastatic, end-stage GI cancers, primarily colorectal cancer. The results demonstrated that the therapy was generally safe, with no serious adverse effects observed from the gene-editing process.
Several patients experienced disease stabilization, but the most remarkable outcome was observed in one patient who achieved a complete response. In this individual, metastatic tumors disappeared within several months and have not returned for over two years.
"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. Emil Lou, gastrointestinal oncologist with the University of Minnesota Medical School, Masonic Cancer Center, and M Health Fairview, who served as the clinical principal investigator for the trial. "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."
One-Time Treatment with Lasting Effects
A significant advantage of this approach compared to conventional cancer therapies is that it requires only a single treatment. While many cancer treatments demand ongoing doses to maintain effectiveness, this gene-editing technique provides permanent modification to the patient's T cells.
"With our gene-editing approach, the checkpoint inhibition is accomplished in one step and is permanently hardwired into the T cells," noted Dr. Beau Webber, an associate professor at the University of Minnesota Medical School.
The research team successfully delivered more than 10 billion engineered TILs without adverse side effects, demonstrating the feasibility of producing large quantities of genetically modified T cells in a clinically compliant environment – a crucial achievement for advancing the therapy toward broader clinical application.
Manufacturing Challenges and Future Directions
While the early results are encouraging, the researchers acknowledge that the process remains complex and costly. The team is now focused on improving production methods and understanding why the therapy worked so effectively in the patient who experienced a complete response.
"We need to better understand the factors that contributed to the exceptional response in one patient so we can potentially replicate those outcomes in more individuals," Dr. Lou explained. "This will help us refine the approach for future trials and potentially expand its application to other cancer types."
The research was supported by Intima Bioscience, and the team is planning expanded trials to further evaluate the therapy's effectiveness across a broader patient population.
Implications for Cancer Treatment
This trial represents a significant step forward in applying CRISPR gene-editing technology to cancer immunotherapy. By demonstrating both safety and potential efficacy in humans, the research opens new possibilities for treating advanced GI cancers that have traditionally had poor prognoses.
If further developed successfully, this approach could potentially transform treatment paradigms for metastatic colorectal cancer and other GI malignancies, offering new hope to patients with limited therapeutic options.
