Neoantigen-specific tumor-infiltrating lymphocytes (TILs) in combination with the PD-1 inhibitor pembrolizumab led to responses among patients with metastatic gastrointestinal cancers, according to the results of a study from researchers at the National Institutes of Health published in Nature Medicine. Although meaningful clinical responses to TILs have been achieved previously in metastatic melanoma, no responses have been seen in gastrointestinal cancers before this study.
“We're seeing the first extension of cellular therapy with TILs into the common solid cancers,” said study investigator Steven A. Rosenberg, MD, PhD, Chief of the Surgery Branch and Head of the Tumor Immunology Section at the National Cancer Institute Center for Cancer Research. “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.”
Study Methods and Results
A total of 91 patients with treatment-refractory mismatch repair–proficient metastatic gastrointestinal cancers were enrolled in the single-arm phase II study. In the first phase of the study, 18 patients received bulk, unselected TILs with lymphodepleting chemotherapy and high-dose interleukin-2, but no responses were observed. Then, the TILs were screened and selected for neoantigen recognition, which were provided to 39 patients. Three of these patients experienced an objective response (7.7%; 95% confidence interval [CI] = 2.7%–20.3%).
A high level of PD-1 was noted in the infused TILs, so the investigators then gave patients pembrolizumab in addition to the neoantigen-selected TILs. Among 34 patients, objective responses were seen in eight patients (23.5%; 95% CI = 12.4%–40%). Responses in this group lasted between 4 months and 3.5 years.
Safety was a secondary endpoint of the trial. Transient severe hematologic toxicities were observed in all patients due to chemotherapy. Ten percent of patients required critical care support. Among patients treated with neoantigen-selected TILs and pembrolizumab, 30% experienced serious adverse events.
Exploratory analyses showed that responses were associated with recognition of an increased amount of targeted neoantigens and CD4-positive neoantigen-reactive TILs.
The study authors concluded that "These results could potentially provide a cell-based treatment in a population not traditionally expected to respond to immunotherapy."
An expansion phase of the study is accruing specifically for patients with colorectal cancer.
Disclosure: For full disclosures of the study authors, visit nature.com.
