Neoantigen-Specific TIL/Pembrolizumab Elicit Responses in GI Cancers

Treatment with tumor-infiltrating lymphocytes selected for neoantigen recognition plus pembrolizumab elicited a partial response rate of 15.1% in patients with GI cancers.

The adoptive transfer of unselected autologous tumor-infiltrating lymphocytes (TILs) selected for neoantigen recognition plus pembrolizumab (Keytruda) treatment strategy surpassed trial design parameters for those with colorectal cancer and demonstrated it could become a cell-based treatment option in a patient population not generally expected to respond to immunotherapy, according to results from a phase 2 study (NCT01174121) published in Nature Medicine.

The confirmed partial response rate per RECIST was 15.1% (n = 11/73; 95% CI, 8.6%-25.0%) in all patients; 7.7% (n = 3/39; 95% CI, 2.7%-20.3%) of the responses came from patients who were treated with TILs selected for neoantigen recognition and 23.5% (n = 8/34; 95% CI, 12.4%-40.0%) of the responses came from the same treatment when pembrolizumab was added. The duration of responses in the group without pembrolizumab were 8, 24, and more than 70 months, and in the group with pembrolizumab, they were 4, 7, 7, 8, 10, 11, more than 17, and 42 months.

The study authors noted a patient with pancreatic ductal adenocarcinoma with metastasis in the liver, lymph nodes, and peritoneum who achieved a partial response consisting of complete resolution of 1 liver metastasis and 44.1% overall tumor shrinkage before progression of non-target disease at 7 months, which stemmed from treatment with TILs.

Additionally, 8 patients, who were not included in the 11 who achieved objective responses, experienced a target tumor reduction of greater than 30% at follow-up assessment; 3 were in the group without pembrolizumab and 5 were in the group with pembrolizumab.

The study highlighted a patient with pancreatic cancer who showed the complete regression of dozens of liver metastases at 6 weeks of follow-up and who had 3 tumors recurrent at 3 months, one of which was found not to harbor the TP53 mutation.

“Adoptive transfer of unselected autologous [TILs] has mediated meaningful clinical responses in patients with metastatic melanoma but not in cancers of gastrointestinal epithelial origin,” lead study author Steven A. Rosenberg, MD, PhD, the chief of the Surgery Branch at the National Cancer Institute (NCI) in Bethesda, Maryland, and a professor of surgery at the Uniformed Services University of Health Sciences at the George Washington University School of Medicine and Health Sciences, and coauthors wrote in the paper. “The interim results of this single-institution trial demonstrate that TILs selected for neoantigen reactivity can mediate tumor regression even in treatment-refractory metastatic [gastrointestinal] cancers that are not thought to be sensitive to immunotherapy.”

The trial enrolled a total of 73 patients between 18 and 72 years with metastatic gastrointestinal cancer who experienced disease progression after standard chemotherapy. Enrollment occurred in 2 stages; in the first patients underwent resection of 1 or more metastatic tumor deposit for the generation of TILs with an institutional review board (IRB)-approved protocol (NCT00068003) and in the second phase, after successful growth of TILs, patients were re-evaluated for eligibility and enrollment onto the IRB-approved treatment (NCT01174121).

Eligible patients were measurable metastatic disease, confirmation of diagnosis by the NCI Laboratory of Pathology, disease refractory to approved systemic therapy, an ECOG performance status of 0 or 1, adequate bone marrow reserve, and adequate hepatic reserve, among others. Those with concurrent systemic steroid therapy, active infections, or active or uncompensated major medical illness were not excluded from participating in the trial.

The trial’s primary end point was response to TIL therapy per RECIST v1.0. Secondary end points were safety and toxicity.

Regarding safety, all patients experienced severe, temporary lymphopenia prior to the transfer of TILs because of treatment design, hence all patients experienced grade 3 or higher adverse effects (AEs). Serious AEs were observed in 30% of patients and 1 treatment-related death occurred due to adenoviral hepatitis 49 days after TIL infusion. Also, escalation of care and critical support were required by 7 patients; 3 required mechanical ventilation, 1 required continuous renal replacement therapy, and 3 required both.

Of patients who received pembrolizumab before the cells, 24% experienced a grade 3 or higher AE, 2 of which were serious AEs due to pembrolizumab (treatment-refractory inflammatory colitis and steroid-responsive pneumonitis).

Reference

Lowery FJ, Goff SL, Gasmi B, et al. Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial. Nat Med. Published online April 1, 2025. doi:10.1038/s41591-025-03627-5