Preclinical Study and Parallel Phase II Trial Evaluating Antisense STAT3 Oligonucleotide and Checkpoint Blockade for Advanced Pancreatic, Non-Small Cell Lung Cancer and Mismatch Repair-Deficient Colorectal Cancer

Authors

Chad Tang
Genevieve P Hartley
Coline Couillault
Ying Yuan
Heather Lin
Courtney Nicholas
Anupallavi Srinivasamani
James Dai
Ecaterina E Ileana Dumbrava
Siqing Fu
Daniel D Karp
Aung Naing
Sarina A Piha-Paul
Jordi Rodon Ahnert
Shubham Pant
Vivek Subbiah
Timonthy A Yap
Apostolia M Tsimberidou
Paola Guerrero
Sarah Dhebat
Theresa Proia
Michael A Curran
David S Hong

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