Patients with heavily pretreated metastatic GI cancers were treated with neoantigen-reactive TILs alone (SEL-TIL) or with pembrolizumab (SEL-TIL+P). 15.1% of SEL-TIL and 23.5% of SEL-TIL+P patients had a PR, and 8 additional patients experienced target lesion reduction of >30%. Serious AEs occurred in 30% of patients, with 7 requiring critical care and one infection-related death. Responders’ TIL products were reactive to a significantly greater number of neoantigens and contained a greater number of reactive CD4+, but not CD8+ T cells, while their tumors were enriched for pathways related to inflammation and wound healing.
Contributed by Morgan Janes
ABSTRACT: Adoptive transfer of unselected autologous tumor-infiltrating lymphocytes (TILs) has mediated meaningful clinical responses in patients with metastatic melanoma but not in cancers of gastrointestinal epithelial origin. In an evolving single-arm phase 2 trial design, TILs were derived from and administered to 91 patients with treatment-refractory mismatch repair proficient metastatic gastrointestinal cancers in a schema with lymphodepleting chemotherapy and high-dose interleukin-2 (three cohorts of an ongoing trial). The primary endpoint of this study was the objective response rate as measured using Response Evaluation Criteria in Solid Tumors 1.0; safety was a descriptive secondary endpoint. In the pilot phase, no clinical responses were observed in 18 patients to bulk, unselected TILs; however, when TILs were screened and selected for neoantigen recognition (SEL-TIL), three responses were seen in 39 patients (7.7% (95% confidence interval (CI): 2.7-20.3)). Based on the high levels of programmed cell death protein 1 in the infused TILs, pembrolizumab was added to the regimen (SEL-TIL + P), and eight objective responses were seen in 34 patients (23.5% (95% CI: 12.4-40.0)). All patients experienced transient severe hematologic toxicities from chemotherapy. Seven (10%) patients required critical care support. Exploratory analyses for laboratory and clinical correlates of response were performed for the SEL-TIL and SEL-TIL + P treatment arms. Response was associated with recognition of an increased number of targeted neoantigens and an increased number of administered CD4(+) neoantigen-reactive TILs. The current strategy (SEL-TIL + P) exceeded the parameters of the trial design for patients with colorectal cancer, and an expansion phase is accruing. These results could potentially provide a cell-based treatment in a population not traditionally expected to respond to immunotherapy. ClinicalTrials.gov identifier: NCT01174121 .
Author Info: (1) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (2) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, M
Author Info: (1) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (2) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. stephanie.goff@nih.gov. (3) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (4) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (5) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (6) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (7) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (8) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (9) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (10) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (11) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (12) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (13) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (14) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (15) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (16) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (17) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (18) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (19) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (20) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (21) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (22) National Cancer Institute, Center for Cancer Research, Thoracic Surgery Branch, Bethesda, MD, USA. (23) National Cancer Institute, Center for Cancer Research, Surgical Oncology Program, Bethesda, MD, USA. (24) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (25) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (26) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (27) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (28) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (29) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (30) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (31) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (32) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (33) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. sar@nih.gov.
