MINNEAPOLIS/ST. PAUL — In a groundbreaking advance that combines cutting-edge gene-editing technology with immunotherapy, researchers at the University of Minnesota have successfully completed a first-in-human clinical trial aimed at treating advanced gastrointestinal cancers. This study represents a pivotal moment in oncologic therapy, employing CRISPR/Cas9 technology to genetically modify tumor-infiltrating lymphocytes (TILs) in patients battling metastatic colorectal cancer. Published recently in The Lancet Oncology, the results demonstrate not only the safety of this innovative approach but also preliminary signs of its potential efficacy, heralding a new frontier in the fight against one of the most lethal forms of cancer.
Colorectal cancer in its late stages poses a formidable challenge to clinicians and scientists alike. Despite significant progress in understanding the molecular underpinnings of this disease, stage IV colorectal cancer remains a largely incurable condition with limited treatment options. Dr. Emil Lou, a gastrointestinal oncologist and the study’s principal investigator, emphasizes the urgency of novel interventions, stating that this trial initiates a bold paradigm shift by bringing a laboratory innovation directly into the clinical setting. The approach is designed to leverage the body’s own immune system to recognize and eradicate metastatic tumor cells through precise genetic manipulation.
Central to this trial is the innovative use of the CRISPR/Cas9 system, a revolutionary gene-editing tool that allows scientists to make targeted alterations within the genome. The researchers focused on editing a critical intracellular immune checkpoint gene known as CISH, which naturally acts to suppress T cell activity within tumors. By knocking out CISH selectively within TILs isolated from patients’ tumors, the team effectively reprogrammed these immune cells to overcome the cancer’s defense mechanisms. This intracellular checkpoint had previously eluded therapeutic targeting by traditional antibody or small molecule inhibitors, making CRISPR-mediated editing a breakthrough strategy to unleash the full cytotoxic potential of T cells.
In this phase 1 clinical trial, twelve patients with highly metastatic, end-stage colorectal cancer were treated with autologous TILs engineered to lack functional CISH. The production process involved isolating tumor-infiltrating lymphocytes, applying CRISPR/Cas9 editing ex vivo to disable the CISH gene, and expanding the modified cells to over 10 billion before reinfusion. Remarkably, the infusion of these gene-edited immune cells was well tolerated, with no serious adverse events linked to the gene-editing procedure, highlighting the feasibility and safety of scaling this approach for clinical use.
Among the trial participants, several individuals experienced stabilization of their disease, indicating a halt in tumor progression. Notably, one patient achieved a complete response—the first time metastatic tumors disappeared completely and have not recurred in more than two years. This dramatic outcome provides compelling evidence that targeting intracellular checkpoints via gene editing can provoke powerful and durable anti-tumor immune responses. Such a complete remission in end-stage colorectal cancer is unprecedented, suggesting new therapeutic possibilities for patients with limited options.
Co-director of the Center for Genome Engineering, Dr. Branden Moriarity, explains the scientific rationale behind targeting CISH, underscoring that it functions intracellularly to impede T cell receptor signaling and cytokine responsiveness. Due to its intracellular localization, CISH was previously inaccessible to conventional checkpoint inhibitor therapies, typically designed to target extracellular proteins. Thus, the utilization of CRISPR/Cas9 allows for a permanent genetic "hardwiring" of checkpoint resistance into T cells, fundamentally transforming their capability to recognize and eliminate cancer cells.
Unlike traditional immune checkpoint inhibitors requiring repeated dosing, this gene-editing strategy imparts a sustained, one-time modification. According to Dr. Beau Webber, associate professor and a key member of the research team, this approach ensures that checkpoint blockade is embedded within the genome of the infused T cells themselves, potentially providing long-lasting therapeutic effects without the need for continuous administration. This permanent modification circumvents issues related to drug pharmacokinetics and patient compliance, offering a streamlined immunotherapeutic modality.
Integral to the success of this trial was the development of a robust, clinically compliant manufacturing process capable of producing large quantities of genetically engineered TILs without compromising cell viability or function. This milestone demonstrates the scalability of CRISPR-engineered cell therapies for solid tumors and sets the stage for more extensive clinical studies. The ability to generate billions of modified T cells provides the clinical muscle necessary to mount effective immune responses in the hostile tumor microenvironment.
Despite the optimism surrounding these findings, several challenges remain before this therapy can become widely accessible. Currently, the process is complex and resource-intensive, requiring sophisticated laboratory infrastructure and specialized expertise. The research team is actively pursuing strategies to streamline production protocols, reduce costs, and increase the rapidity of manufacturing. Additionally, efforts are focused on understanding the molecular and cellular mechanisms that contributed to the extraordinary complete response in the single patient to optimize patient selection and treatment regimens.
This trial exemplifies the extraordinary potential of synthetic biology and genome engineering to revolutionize cancer treatment. By directly manipulating intracellular immune checkpoints, scientists can now engineer immune cells with heightened precision and durability. The implications extend well beyond colorectal cancer, foreshadowing a new era of personalized, gene-edited immunotherapies targeting a broad spectrum of malignancies. The intersection of gene editing and immuno-oncology promises accelerated innovation, offering renewed hope to patients confronting devastating diseases.
The research was generously supported by funding from Intima Bioscience, a biotechnology company dedicated to advancing cellular therapies. The collaborative effort between academic investigators and industry partners underscores the importance of interdisciplinary cooperation to translate laboratory discoveries into transformative clinical solutions. As the field progresses, partnerships of this nature will be integral to overcoming scientific and logistical hurdles inherent to pioneering therapies.
Looking forward, the University of Minnesota Medical School and the Masonic Cancer Center remain dedicated to advancing this promising therapeutic frontier. Their commitment to high-impact translational research continues to position them as leaders in the battle against cancer, fostering an environment where innovative science rapidly crosses the barrier into clinical application. The outcomes of this trial represent a significant beacon of hope for patients with metastatic colorectal cancer and pave the way for future large-scale, multi-center studies to validate and expand upon these initial successes.
Subject of Research: People
Article Title: Targeting the intracellular immune checkpoint CISH with CRISPR-Cas9-edited T cells in patients with metastatic colorectal cancer: a first-in-human, single-centre, phase 1 trial
News Publication Date: 02-May-2025
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Keywords: Gene editing; Gene therapy; Cancer treatments; Cancer immunotherapy; Checkpoint therapy
