Twelve people whose stomach or colon cancers had defeated every available treatment were infused with their own immune cells, reprogrammed using CRISPR gene editing to attack tumors more aggressively. In results published in The Lancet Oncology earlier this year, the University of Minnesota team behind the first-in-human trial reported that the approach shrank tumors in several patients and caused no serious side effects linked to the gene editing itself. For cancers that almost never respond to immunotherapy, even partial responses in a phase 1 safety trial are unusual enough to draw attention.
What the trial actually did
The study, registered as NCT04426669, enrolled 12 adults with metastatic gastrointestinal cancers, primarily colorectal and gastric, that had progressed through standard chemotherapy and, in some cases, targeted drugs. Surgeons first extracted tumor-infiltrating lymphocytes (TILs), the immune cells that had already migrated into each patient’s tumor but were failing to control it. In the lab, researchers used CRISPR-Cas9 to knock out a single gene called CISH in those cells, expanded them to massive numbers, and infused them back into the patient.
The scale was striking. According to a University of Minnesota institutional news release, which carries the usual limitations of promotional communications and should not be treated as peer-reviewed data, the team safely delivered more than 10 billion gene-edited cells per patient, a threshold that had not been attempted before with CISH-knockout TILs in humans. Patients also received lymphodepleting chemotherapy and high-dose interleukin-2 before and after infusion, both standard parts of TIL therapy meant to clear space for the new cells and stimulate their growth.
Investigators Emil Lou, Branden Moriarity, and Beau Webber led the trial. Its primary goal was safety and feasibility, not measuring cure rates, but the clinical signals went beyond what a safety study needs to show.
Why target CISH instead of PD-1
Most immunotherapy drugs approved for cancer, such as pembrolizumab (Keytruda) and nivolumab (Opdivo), work by blocking checkpoint proteins on the surface of T cells, most commonly PD-1. That strategy has transformed treatment for melanoma, lung cancer, and a handful of other tumor types. But it has largely failed in the most common form of colorectal cancer, called microsatellite-stable (MSS), which accounts for roughly 85% of cases. These tumors create a hostile local environment that suppresses immune cells through multiple pathways, and blocking one surface receptor is often not enough.
CISH operates differently. The protein sits inside the T cell, downstream of the T-cell receptor itself, and acts as an internal brake on killing power. A 2015 study in the Journal of Experimental Medicine showed that deleting Cish in mouse T cells supercharged their ability to expand and kill tumor cells, producing durable regression of established cancers. Later preclinical experiments in human T cells performed under laboratory conditions confirmed the effect and revealed a bonus: in those lab-based studies, CISH disruption also reduced PD-1 expression on the cell surface, essentially weakening two brakes at once. Whether this PD-1 reduction occurs in patients’ cells in vivo has not been confirmed by the current trial.
That dual mechanism, demonstrated so far in preclinical work, is what makes the approach compelling for solid tumors that resist conventional immunotherapy. Rather than trying to override the tumor’s suppressive signals from the outside, the edited cells are rewired internally to push through them.
What the results showed
The Lancet Oncology paper reports measurable tumor shrinkage in several patients, including partial responses and cases of prolonged disease stabilization. In a population where cancers had already beaten multiple lines of therapy, any regression is noteworthy. The safety data were equally important: across all 12 patients, the CRISPR editing process produced no dose-limiting toxicities or serious adverse events attributable to the gene modification. Side effects that did occur, such as low blood counts and fevers, were consistent with the chemotherapy and interleukin-2 that accompany any TIL infusion, not with the editing itself.
Quality-control assays did not detect problematic off-target edits at predicted genomic sites, an important reassurance given longstanding concerns about CRISPR precision. Still, the investigators acknowledge that rare off-target effects or late toxicities would be nearly impossible to detect in a 12-patient study with limited follow-up.
Where this fits in the TIL therapy landscape
TIL therapy is not entirely new. In February 2024, the FDA approved lifileucel (sold as Amtagvi) for advanced melanoma, making it the first commercially available TIL product. That approval validated the basic concept of harvesting a patient’s own tumor-fighting cells, growing them in the lab, and reinfusing them. But lifileucel uses unedited TILs and is approved only for melanoma, a cancer already known to respond to immunotherapy.
The Minnesota trial pushes the concept in two directions at once: into gene editing, which aims to make the cells fundamentally more potent, and into gastrointestinal cancers, where unedited TILs and checkpoint inhibitors have shown limited benefit. If CISH-knockout TILs prove effective in later trials, they could open a treatment path for patients who currently have almost no immunotherapy options.
What remains uncertain
Plenty. The trial was designed to test safety, not efficacy, and 12 patients cannot establish reliable response rates or survival benefits. Full per-patient outcome data, including how long tumor shrinkage lasted and whether any patients achieved complete responses, have not yet appeared in a publicly accessible dataset. Without those details, outside researchers cannot independently assess which patients benefited most or model who might be the best candidates.
Durability is a central question. Lab studies show CISH-knockout T cells maintain stronger function over time in controlled conditions, but whether those cells survive, reach tumor sites, and keep working for months or years inside a patient is something a phase 1 trial with short- to medium-term follow-up cannot definitively answer. If the edited cells fade, patients might need repeat infusions, raising both logistical and cost concerns.
The absence of a control arm, standard for phase 1 studies, means the observed tumor responses cannot be cleanly separated from the effects of the chemotherapy and interleukin-2 that every patient also received. Those agents alone can occasionally produce transient shrinkage. Proving that the CRISPR edit adds meaningful benefit over unedited TILs will require randomized phase 2 or phase 3 trials. As of June 2026, the investigators have not publicly detailed a specific next-phase protocol, though the clean safety data would typically support one.
Manufacturing is another bottleneck. Each patient’s therapy is built from scratch: surgical extraction, gene editing, weeks of cell expansion, and rigorous quality testing. The Minnesota team proved this can work at a single academic center for 12 patients, but scaling to dozens of treatment sites or commercial production is a different challenge entirely. Lifileucel’s rollout has already highlighted how difficult and expensive personalized cell therapies are to deliver at scale, and adding a gene-editing step only increases complexity.
Benchmarks that will shape the future of CISH-knockout TIL therapy
Several milestones will determine whether CISH-knockout TIL therapy moves from promising experiment to viable treatment. The most important is reproducibility: can other centers, using the same protocol, generate similar safety and response signals? Close behind is durability data. If edited cells persist and continue functioning over six months, a year, or longer, the case for the approach strengthens considerably. Stratification by tumor subtype will also matter. If the therapy shows particular activity in microsatellite-stable colorectal cancers, the clinical impact could be outsized, given how few options those patients currently have.
Randomized comparisons against unedited TILs and against approved checkpoint inhibitors will ultimately be needed to establish where CISH-knockout therapy fits in the treatment sequence. And manufacturing innovations that reduce turnaround time and cost will determine whether the therapy can ever reach patients outside major academic medical centers.
For now, this is an experimental approach best pursued within clinical trials. But the Minnesota results offer something concrete: proof that billions of gene-edited immune cells can be built, safely delivered, and directed against solid tumors that have resisted nearly everything else. In a field where most immunotherapy advances have bypassed gastrointestinal cancers, that is a meaningful step forward.
More from Morning Overview
*This article was researched with the help of AI, with human editors creating the final content.
