Combination immunotherapy shrank a variety of metastatic gastrointestinal cancers

A new, more targeted form of tumor-infiltrating lymphocyte (TIL) therapy — a personalized approach to cancer immunotherapy — has significantly enhanced treatment effectiveness for patients with metastatic gastrointestinal (GI) cancers. The results, from a clinical trial led by researchers at the National Institutes of Health (NIH), were published on April 1, 2025, in Nature Medicine. This advancement raises the possibility of extending cellular immunotherapy to a broader range of solid tumors, a goal that has long challenged researchers.

TIL therapy involves isolating immune cells (TILs) from within a patient’s tumor that specifically recognize and attack cancer cells. These TILs are then expanded in large numbers in the laboratory and infused back into the patient to help combat the disease.

In the trial, patients with various types of metastatic GI tumors also received the immune checkpoint inhibitor pembrolizumab (Keytruda), designed to further enhance the immune response. The combination treatment proved notably more effective: nearly 24% of patients receiving selected TILs plus pembrolizumab experienced significant tumor shrinkage, compared to only 7.7% in the group that received selected TILs alone. Patients who received non-selected TILs showed no tumor response.

“We are witnessing the first successful expansion of TIL-based cellular therapy into common solid cancers,” said Dr. Steven A. Rosenberg, lead investigator from the NIH’s National Cancer Institute (NCI).

“It’s like we've found the first crack in the wall of solid tumors — and now we’re working to open that even further using immune-based approaches.”

Clinical Trial Overview

The study involved 91 patients with metastatic GI cancers — including esophageal, stomach, pancreatic, colon, and rectal cancers — all of whom had disease progression despite undergoing a median of four prior lines of treatment.

• Phase 1: 18 patients were treated with non-selected TILs. There were no objective responses (defined as ≥30% tumor shrinkage).
• Phase 2: 39 patients received selected TILs, resulting in 3 patients (7.7%) showing objective responses.
• Phase 3: 34 patients received selected TILs plus pembrolizumab, and 8 patients (23.5%) had an objective response.

All patients also received standard chemotherapy and high-dose interleukin-2 (IL-2) prior to TIL infusion.

Durability and Safety

Tumor responses were observed across several GI cancer types — including colorectal, pancreatic, and bile duct cancers — in both the second and third phases of the trial.

• Response duration ranged from 8 months to over 5.8 years in those receiving TILs alone, and from 4 months to 3.5 years in the TIL + pembrolizumab group.
• Approximately 30% of patients treated with selected TILs experienced serious side effects.

Future Directions

Researchers are now focusing on identifying TILs that can target multiple specific tumor proteins, known as neoantigens, to boost response rates to selected TIL therapy in combination with pembrolizumab.

TIL therapy itself has a long history — it was first developed in the late 1980s by Dr. Rosenberg and colleagues at NIH. In 2024, the FDA approved the first TIL therapy for solid tumors: lifileucel (Amtagvi), for the treatment of advanced melanoma.

This new study, co-led by Dr. Rosenberg, Dr. Frank J. Lowery, and Dr. Stephanie L. Goff from the NCI, marks a promising leap forward in extending cell-based immunotherapy to more common and difficult-to-treat cancers.

Source

Combination immunotherapy shrank a variety of metastatic gastrointestinal cancers | National Institutes of Health (NIH)