Abstract
Background: Preclinical studies suggest that irreversible electroporation (IRE) of a tumor lesion increases the effect of immune checkpoint inhibition in pancreatic cancer (PC).
Patients and Methods: In this phase II study, patients with PC received pembrolizumab 400 mg intravenously and, on day 10, percutaneous IRE of a liver metastasis. Blood samples were analyzed by multicolor flowcytometry for immune cell subsets. mRNA expression profiling was done in sequential biopsies of liver metastases at baseline and prior to IRE.
ResultsTreatment was safe, but the trial terminated early due to futility. The response rate in eight patients was 0%, tumor growth was exponential, while median progression-free and overall survival were 1.8 and 2.0 months, respectively. A drop in circulating plasmacytoid dendritic cells after immunotherapy and an increase in monocytic myeloid-derived suppressor cells and neutrophils immediately after IRE was observed. In liver metastases, gene expressions indicated upregulation of immune stimulatory genes and downregulation of immune suppressive genes after pembrolizumab, while direct markers of effector T-cells were unchanged.
Conclusions: PD-L1 inhibition followed by IRE of a liver metastasis was safe but showed no clinical efficacy in PC. Immunotherapy induced a mostly immune permissive tumor microenvironment but with no detectable increase in effector cells.
Trial Registration: The protocol was registered at EudraCT (2020-004536-22) and clinicaltrials.gov (NCT04835402).
Patients and Methods: In this phase II study, patients with PC received pembrolizumab 400 mg intravenously and, on day 10, percutaneous IRE of a liver metastasis. Blood samples were analyzed by multicolor flowcytometry for immune cell subsets. mRNA expression profiling was done in sequential biopsies of liver metastases at baseline and prior to IRE.
ResultsTreatment was safe, but the trial terminated early due to futility. The response rate in eight patients was 0%, tumor growth was exponential, while median progression-free and overall survival were 1.8 and 2.0 months, respectively. A drop in circulating plasmacytoid dendritic cells after immunotherapy and an increase in monocytic myeloid-derived suppressor cells and neutrophils immediately after IRE was observed. In liver metastases, gene expressions indicated upregulation of immune stimulatory genes and downregulation of immune suppressive genes after pembrolizumab, while direct markers of effector T-cells were unchanged.
Conclusions: PD-L1 inhibition followed by IRE of a liver metastasis was safe but showed no clinical efficacy in PC. Immunotherapy induced a mostly immune permissive tumor microenvironment but with no detectable increase in effector cells.
Trial Registration: The protocol was registered at EudraCT (2020-004536-22) and clinicaltrials.gov (NCT04835402).
| Originalsprog | Engelsk |
|---|---|
| Udgiver | SSRN: Social Science Research Network |
| Antal sider | 19 |
| DOI | |
| Status | Udgivet - 2023 |