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
Heather Lin,
Vivek Subbiah,
Siqing Fu,
Aung Naing,
Courtney Nicholas,
Shubham Pant,
Chad Tang,
Michael A Curran,
David S Hong,
Ying Yuan,
Sarina A Piha-Paul,
Jordi Rodon Ahnert,
Timonthy A Yap,
Apostolia M Tsimberidou,
Daniel D Karp,
Anupallavi Srinivasamani,
Coline Couillault,
Genevieve P Hartley,
James Dai,
Ecaterina E Ileana Dumbrava,
Paola Guerrero,
Sarah Dhebat,
Theresa Proia
Affiliations
Heather Lin
Biostatistics
Vivek Subbiah
Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Siqing Fu
Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Aung Naing
MD Anderson Cancer Center, Houston, Texas, USA
Courtney Nicholas
Aff1 grid.240145.60000000122914776Department of ImmunologyUniversity of Texas MD Anderson Cancer Center Houston TX USA
Shubham Pant
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Chad Tang
Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Michael A Curran
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
David S Hong
Division of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Ying Yuan
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Sarina A Piha-Paul
Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Jordi Rodon Ahnert
Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Timonthy A Yap
8 University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Apostolia M Tsimberidou
Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Daniel D Karp
Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Anupallavi Srinivasamani
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Coline Couillault
1The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Genevieve P Hartley
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
James Dai
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Ecaterina E Ileana Dumbrava
Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Paola Guerrero
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Sarah Dhebat
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Theresa Proia
Oncology R&D, Research & Early Development, AstraZeneca PLC, Waltham, Massachusetts, USA
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.
