Abstract 4331
Background
Esophageal adenocarcinoma (EAC) is a lethal disease with poor prognosis due to the limited treatment options. STING is a transmembrane protein that activates transcription of type I IFN genes, resulting in stimulation of APCs and enhanced CD8+ T cell infiltration. Recently, STING agonists have demonstrated not only potent efficacy against the primary tumor but also in the distant metastasis and recurrences. Interestingly, combining the STING agonist with radiotherapy and immune checkpoint inhibitors has demonstrated durable anticancer activity in solid tumors. Hence, the aim of the study was to specifically evaluate the efficacy and immunologic regulatory effects of STING agonist +/- radiation in an established EAC model.
Methods
Esophagojejunostomy was performed on rats to induce gastroduodenojejunal reflux leading to the development EAC. At 32 weeks post operatively, rats received either 50μg STING (ADU-S100) +/- 16Gy radiation or placebo (PBS) +/- 16Gy radiation. Drug or placebo control was delivered intratumorally twice via endoscopy, 3 weeks apart. Drug efficacy was evaluated by pre- and post- treatment MRI, serial biopsies, histology and RT-PCR. Additionally, IHC was performed using CD8 and PD-L1 antibodies.
Results
There was no difference in observed mortality among the groups (p = 0.3). Mean MRI tumor volume decreased by 19.7% and 18.6% in ADU-S100 and ADU-S100 + radiation animals and increased by 34.7% and 90.3% in placebo and placebo + radiation animals, respectively (P = 0.0006). Downstream gene expression, pre- to on- treatment, demonstrated upregulation of IFNγ (p = 0.0003) and TNFα (p = 0.02) in the treatment groups vs. placebo. The most remarkable change was observed in ADU-S100 group (5.5X IFNγ and 10.9X TNFα; p < 0.01). On- or post- treatment, radiation alone, ADU-S100 alone and ADU-S100 + radiation groups demonstrated significantly elevated densities of CD8+ T cells and PD-L1+ tumor and immune stromal cells compared to placebo (p < 0.01).
Conclusions
ADU-S100 exhibits potent antitumor efficacy and a promising immunomodulatory profile in a de novo EAC model providing the rationale for clinical strategies, likely in combination with immune checkpoint inhibitors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
A.H. Zaidi: Shareholder / Stockholder / Stock options: Array Biopharma; Research grant / Funding (institution): Eli Lilly & Co. All other authors have declared no conflicts of interest.
Resources from the same session
1452 - RBP-Jκ in colon cancer cells facilitates tumor associated macrophages (TAMs)-induced cell metastasis by secreting CXCL11
Presenter: Meng jie Liu
Session: Poster Display session 2
Resources:
Abstract
2786 - Development of a living organoid biobank derived from colorectal cancer patients: towards personalized medicine
Presenter: Federica Papaccio
Session: Poster Display session 2
Resources:
Abstract
3351 - Microsatellite Instability Detection in Colorectal Cancer: 44-Center Comparison between the Idylla MSI Assay and Routine Molecular and Immunohistochemistry Tests on Formalin-Fixed Paraffin-Embedded Tissue
Presenter: Xavier Matias-guiu
Session: Poster Display session 2
Resources:
Abstract
4901 - Expression profile of EPHB3 and its prognostic significance in colorectal cancer progression (Running head: Prognostic value of EPHB3 in colorectal cancers)
Presenter: Bogun Jang
Session: Poster Display session 2
Resources:
Abstract
5030 - A pan-ErbB family inhibitor, AF8c, promotes apoptosis by DR5/Nrf2 activation via ROS in colorectal cancer cells
Presenter: Soyeon Jeong
Session: Poster Display session 2
Resources:
Abstract
5053 - Frequent BRAF, GNAS and SMAD4 mutations identified in Colorectal Mucinous Carcinomas
Presenter: Sun Mi Lee
Session: Poster Display session 2
Resources:
Abstract
5220 - Impact of CCL4 knockout using CRISPR Cas-9 technology on colorectal tumor progression
Presenter: Roba Barakat
Session: Poster Display session 2
Resources:
Abstract
5330 - Independent clinical validation of a gene expression profile to predict benefit of 5-FU in metastatic colorectal cancer
Presenter: Ida Buhl
Session: Poster Display session 2
Resources:
Abstract
5515 - WRN mutated Colorectal Cancer (CRC) is characterized by a distinct molecular and immunological profile
Presenter: Andreas Seeber
Session: Poster Display session 2
Resources:
Abstract
5716 - Mutation analysis of B2M gene in colorectal cancer patients with microsatellite instability
Presenter: Ivana Kašubová
Session: Poster Display session 2
Resources:
Abstract