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
3911 - Defining a SUV decrease cut-off in PET/CT response monitoring after one cycle of preoperative breast cancer chemotherapy
Presenter: Marcin Kubeczko
Session: Poster Display session 2
Resources:
Abstract
1849 - Effect of thioredoxin 1 quantity detection to complement the mammography in breast cancer diagnosis
Presenter: Younju Lee
Session: Poster Display session 2
Resources:
Abstract
2221 - Identification of ultralow risk breast cancer patients (probable overdiagnosis)
Presenter: Salvador Gamez Casado
Session: Poster Display session 2
Resources:
Abstract
5291 - Prevalence of Vitamin D3 deficiency among women with early breast cancer receiving chemotherapy in an oncology dayward.
Presenter: Warner Finstad
Session: Poster Display session 2
Resources:
Abstract
4247 - Changes in ER pathway activity score during neoadjuvant letrozole to assess therapy response and predict disease free survival (DFS) in ER positive breast cancer patients
Presenter: Arran Turnbull
Session: Poster Display session 2
Resources:
Abstract
568 - Second primary malignancies in patients with breast cancer.
Presenter: Carlos Erasun Lecuona
Session: Poster Display session 2
Resources:
Abstract
1428 - Phase II randomized trial of neoadjuvant trastuzumab and pertuzumab (TP) with either palbociclib + letrozole (Pal+L) or paclitaxel (Pac) for elderly patients with estrogen receptor & HER2 positive (ER+/HER2+) Breast Cancer (BC) (International Breast Cancer Study Group IBCSG 55-17, TOUCH)
Presenter: Laura Biganzoli
Session: Poster Display session 2
Resources:
Abstract
1479 - Neoadjuvant HER2-targeted therapy with or without immunotherapy with pembrolizumab (neoHIP): an open label randomized phase 2 trial
Presenter: Heather McArthur
Session: Poster Display session 2
Resources:
Abstract
1481 - A randomized phase 2 study of peri-operative ipilimumab, nivolumab and cryoablation versus standard care in women with residual, early stage/resectable, triple negative breast cancer after standard-of-care neoadjuvant chemotherapy
Presenter: Heather McArthur
Session: Poster Display session 2
Resources:
Abstract
4334 - ALEXANDRA/IMpassion030: A phase 3 study of standard adjuvant chemotherapy with or without atezolizumab in early stage triple negative breast cancer.
Presenter: Michail Ignatiadis
Session: Poster Display session 2
Resources:
Abstract