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
4653 - Impact of Pembrolizumab (pembro) Versus Paclitaxel on Health-Related Quality of Life (HRQoL) in Patients With Advanced Gastric or Gastroesophageal Junction (GEJ) Cancer That Has Progressed After First-Line Chemotherapy (KEYNOTE-061)
Presenter: Eric Van Cutsem
Session: Poster Display session 2
Resources:
Abstract
5063 - Does Nutritional Status Affect Treatment Tolarability, Response and Survival in Metastatic Gastric Cancer Patients? Results of Prospective Multicenter Study
Presenter: Senem Karabulut
Session: Poster Display session 2
Resources:
Abstract
2717 - Ramucirumab use in patients with Advanced Gastric Cancer (AGC) or gastro-oesophageal junction (GEJ) adenocarcinoma in Spain: RAMIS observational study
Presenter: Federico Longo Munoz
Session: Poster Display session 2
Resources:
Abstract
3187 - Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor: Exploratory analysis in the patients who were enrolled in JCOG0705/KGCA01 phase III trial (REGATTA) and could continue chemotherapy
Presenter: Takaki Yoshikawa
Session: Poster Display session 2
Resources:
Abstract
4765 - A prospective observational study on the optimal maintenance strategy in HER2-positive advanced gastric cancer treated with trastuzumab based therapy
Presenter: Qian Li
Session: Poster Display session 2
Resources:
Abstract
3500 - Randomised phase 2 trial of first-line docetaxel, carboplatin, capecitabine (CTX) and epirubicin, oxaliplatin, capecitabine (EOX) in advanced esophagogastric adenocarcinoma (SEED)
Presenter: Peter Petersen
Session: Poster Display session 2
Resources:
Abstract
5197 - Ramucirumab in the treatment of refractory metastatic gastric cancer: results from the RamSelGa trial.
Presenter: Alexey Tryakin
Session: Poster Display session 2
Resources:
Abstract
2011 - Regorafenib in combination with Paclitaxel for beyond first-line treatment of advanced esophagogastric cancer (REPEAT): a phase Ib trial with expansion cohort
Presenter: Mohammed Khurshed
Session: Poster Display session 2
Resources:
Abstract
2117 - The relationship between the survival and fixed dosing of S-1 in advanced gastric cancer patients by pooled analysis using individual data from four Japanese randomized phase III trials
Presenter: Wataru Ichikawa
Session: Poster Display session 2
Resources:
Abstract
2669 - A Phase 1b Study of Oraxol in Combination with Ramucirumab in Patients with Gastric or Esophageal Cancers who failed previous chemotherapy
Presenter: Ming Huang Chen
Session: Poster Display session 2
Resources:
Abstract