A new form of tumor infiltrating lymphocyte (TIL) therapy combined with pembrolizumab has demonstrated significant efficacy against metastatic gastrointestinal cancers, according to findings from a National Institutes of Health (NIH) clinical trial published April 1, 2025, in Nature Medicine.
The study showed that nearly 24% of patients treated with selected TILs plus pembrolizumab experienced substantial tumor shrinkage, compared with only 7.7% of patients who received selected TILs without pembrolizumab. Patients treated with non-selected TILs showed no tumor response.
"We're seeing the first extension of cellular therapy with TILs into the common solid cancers," said Steven A. Rosenberg, M.D., Ph.D., the study's lead investigator at NIH's National Cancer Institute. "We see a little crack in the solid wall of cancer by using cell-based immunotherapy for the common solid cancers, and we think we have ways to open that crack even further."
Trial Design and Patient Population
The clinical trial enrolled 91 patients with metastatic gastrointestinal cancers, including esophageal, stomach, pancreatic, colon, and rectal cancers. All participants had disease progression despite receiving a median of four prior treatment regimens, representing a heavily pretreated population with limited therapeutic options.
The study was conducted in three phases:
- In the pilot phase, 18 patients received TILs that had not been selected for anti-tumor activity, resulting in no objective responses.
- In the second phase, 39 patients were treated with selected TIL therapy, with three patients (7.7%) achieving objective responses.
- In the third phase, 34 patients received pembrolizumab immediately before selected TIL therapy, with eight patients (23.5%) experiencing objective responses.
All participants had previously received standard chemotherapy and high-dose interleukin-2 before TIL therapy administration.
Mechanism of Action and Treatment Process
The personalized immunotherapy approach involves a multi-step process. First, researchers identify and select immune cells (TILs) from the patient's tumor that specifically recognize and attack the cancer cells. These selected TILs are then expanded in the laboratory to produce large quantities before being reinfused into the patient.
In the most successful arm of the trial, patients received the immune checkpoint inhibitor pembrolizumab (Keytruda) immediately before TIL therapy. This combination was designed to prevent the newly introduced immune cells from becoming inactivated by the patient's own immune system, thereby enhancing the anti-tumor response.
Efficacy Across Multiple Cancer Types
A notable finding was the therapy's effectiveness across various gastrointestinal cancers. Objective responses were observed in patients with colon, rectal, pancreatic, and bile duct cancers—malignancies that have historically been resistant to immunotherapy approaches.
Response durations were also impressive, ranging from 8 months to more than 5.8 years in the group receiving selected TIL therapy alone, and between 4 months and 3.5 years in the combination therapy group.
Safety Profile
The treatment was not without side effects, with serious adverse events occurring in 30% of patients treated with selected TILs. However, these were generally manageable within the context of the advanced disease setting and the limited options available to these patients.
Future Directions
Building on these promising results, the research team is now developing methods to identify TILs that recognize multiple specific proteins within tumors, known as neoantigens. This approach aims to increase the proportion of patients who respond to the combination of selected TIL therapy with pembrolizumab.
"This represents a significant step forward in extending cellular therapies beyond hematologic malignancies and melanoma to the more common solid tumors," said Frank J. Lowery, Ph.D., one of the study's co-leaders. "The ability to achieve durable responses in heavily pretreated gastrointestinal cancers suggests we're on the right track."
Historical Context
TIL therapy was initially developed in the late 1980s by Dr. Rosenberg and his colleagues at NIH. The approach uses a patient's own TILs to fight their tumor cells. In a significant milestone for the field, the Food and Drug Administration approved the first TIL therapy for a solid cancer, lifileucel (Amtagvi), last year for treating advanced melanoma.
The current study extends this therapeutic approach to gastrointestinal cancers, which represent some of the most common and lethal malignancies worldwide. The ability to achieve meaningful responses in these tumor types offers new hope for patients with limited treatment options.
The study was co-led by Dr. Rosenberg and NCI investigators Frank J. Lowery, Ph.D., and Stephanie L. Goff, M.D., highlighting the collaborative nature of this groundbreaking research.
