Next-Generation Neoantigen-Targeted TIL Therapy Shows Activity in Gastrointestinal Cancers for the First Time

Gastrointestinal (GI) cancers are among the leading causes of cancer-related death worldwide. New treatments are needed, particularly for patients with metastatic disease resistant to standard therapies. Recent advances in immunotherapy are therefore important, especially innovative approaches combining neoantigen-specific tumor-infiltrating lymphocytes (TILs) with pembrolizumab.

On April 1, 2025, Nature Medicine published a phase 2 clinical trial showing that neoantigen-specific TILs combined with pembrolizumab produced meaningful clinical responses in GI cancers. The preliminary findings are considered promising, particularly for patients who have not responded to previous treatments.

How Does It Differ from Previous TIL Treatments?

The only TIL therapy currently approved by the FDA, lifileucel, is used only in advanced melanoma and is known not to be effective in GI cancers. The main reason is that TILs used in GI cancers generally consist of nonreactive or exhausted T cells.

Lead investigator Dr. Frank J. Lowery and colleagues developed a new method to overcome this problem by selecting and expanding TILs reactive to patient-specific neoantigens. In an earlier case study, this method produced a durable response lasting approximately 3 years in a patient with pancreatic cancer.

Study Design and Details

This single-center, nonrandomized phase 2 study involved 91 patients . All participants had microsatellite-stable GI cancers resistant to standard treatments. The study examined several GI cancer types, including colorectal, pancreatic, biliary tract (cholangiocarcinoma), gastric, esophageal, and ampullary cancers.

Participants were divided into three treatment groups:

• Bulk, unselected TIL therapy (18 patients)

• Selected neoantigen-reactive TIL therapy (39 patients)

• Selected neoantigen-reactive TIL therapy combined with pembrolizumab (34 patients)

All patients received lymphodepleting chemotherapy and high-dose IL-2. The study's primary objective was to assess objective tumor response.

Notable Study Results

The objective response rates were particularly noteworthy:

• Response rate in the unselected TIL group: 0%

• Response rate in the neoantigen-selected TIL group: 7.7%

• Response rate in the neoantigen-selected TIL group with pembrolizumab: 23.5%

The addition of pembrolizumab was highlighted as critical to preventing T-cell exhaustion and substantially improving response rates. The longest response lasted up to 70 months.

Adverse Reactions and Safety

Every patient experienced at least one Grade 3 or higher adverse reaction. Most were attributable to chemotherapy and high-dose IL-2. Intensive care support was required by 10% of patients, and one patient died from adenoviral hepatitis. Pembrolizumab-related adverse reactions included pneumonitis controlled with steroids and treatment-resistant colitis.

This shows that safety and tolerability must be assessed as carefully as treatment effectiveness.

When Could FDA Approval Occur?

Principal investigator Dr. Steven A. Rosenberg describes these results as pioneering and says that FDA approval of this treatment will take several more years. At present, its most likely application is in microsatellite-stable GI cancers resistant to standard treatments.

The team continues working to optimize treatment, target more neoantigens, and accelerate TIL manufacturing. The investigators state that response rates exceeded 40% when three or more neoantigens were targeted.

Interpretation

This study signals a fundamental paradigm shift in the future of immunotherapy for gastrointestinal cancers. If confirmed in further studies, the findings could provide a meaningful treatment option for the first time for patients with resistant GI cancers inadequately served by current options.

The applicability of TIL therapy across cancer types is attracting increasing attention. It may be effective particularly in gastrointestinal cancers unresponsive to standard treatments. However, its high cost, complex manufacturing process, and unsuitability for some patients are important limitations to integration into clinical practice.

Advantages and Disadvantages Compared with Current Treatments

Advantages of this innovative treatment include personalized, targeted immunotherapy and durable clinical responses. Disadvantages include the complexity and high cost of treatment, time-consuming cell production, and difficulties selecting patients.

The study is considered an important step toward promising outcomes in GI cancers, although the need for larger, multicenter studies is emphasized.