
Faculty, Staff and Student Publications
Publication Date
1-1-2024
Journal
BMJ Oncology
Abstract
Objective: To evaluate signal transducer and activator of transcription 3 (STAT3) inhibition we conducted a co-clinical trial testing danvatirsen, a STAT3 antisense oligonucleotide (ASO) and checkpoint inhibition in conjunction with preclinical experiments.
Methods and analysis: Orthotopically implanted pancreatic cancer (pancreatic adenocarcinoma (PDAC)) was treated with STAT3 ASO with immune checkpoint inhibition. Tumour infiltrating immune cell populations were characterised via flow cytometry. In vitro experiments evaluated STAT3 inhibition in pancreatic stellate cells (PSCs) and myeloid-derived suppressor cells (MDSCs).A phase II trial employing a Simon II stage design tested the clinical efficacy of danvatirsen and durvalumab in non-small cell lung cancer (NSCLC), PDAC and mismatch repair-deficient colorectal cancer (MRD CRC). The primary objective was 4-month disease control rate (DCR).
Results: In vivo studies identified improvement in survival of PDAC implanted mice treated with STAT3 ASO and checkpoint inhibition. Within tumour-infiltrating lymphocytes there was expansion of CD4 and PD-1+ CD8 populations with STAT3 ASO.Thirty-seven patients (29 PDAC, 7 NSCLC and 1 MRD CRC) from a single institution started treatment on trial between April 2017 and March 2020. No objective responses were observed. Four of six (66.7%, 95% CI 22.3% to 95.7%) NSCLC and 4 of 23 (17.4%, 95% CI 5% to 38.8%) PDAC patients exhibited 4-month DCR. Follow-up in vitro studies revealed an anti-inflammatory and pro-tumour effect of STAT3 ASO mediated by PSCs and MDSCs distinct from ablation of STAT3.
Conclusion: Although durvalumab and danvatirsen met the primary endpoint, no objective responses were observed. A rationale for the lack of objective responses is danvatirsen-induced myeloid immune suppression.
Trial registration number: NCT02983578.
Keywords
Pancreatic cancer, Immunotherapy, Lung cancer (non-small cell)
DOI
10.1136/bmjonc-2023-000133
PMID
39886125
PMCID
PMC11347683
PubMedCentral® Posted Date
7-30-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons