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
3330 - Tumour-infiltrating lymphocytes and BRCA-like status in stage III breast cancer patients treated with intensified carboplatin-based chemotherapy
Presenter: Leonora De Boo
Session: Poster Display session 2
Resources:
Abstract
3971 - Unravelling the biological characteristics of MammaPrint extreme risk subgroups
Presenter: Rajith Bhaskaran
Session: Poster Display session 2
Resources:
Abstract
5871 - Residual Cancer burden as a prognostic factor in a large series of Neoadjuvant chemotherapy. Subgroup analysis per molecular surrogated subtypes
Presenter: Catalina Falo
Session: Poster Display session 2
Resources:
Abstract
5014 - Clinical validation of CanAssist Breast in a Spanish cohort
Presenter: Manjiri Bakre
Session: Poster Display session 2
Resources:
Abstract
2787 - Meta-analysis on association of pathological complete response with long-term survival outcomes in triple-negative breast cancer
Presenter: Peter A. Fasching
Session: Poster Display session 2
Resources:
Abstract
4301 - Immune infiltrate composition across intrinsic subtypes in hormone receptor (HR)+/HER2- early breast cancer (BC) enrolled in the prospective LETLOB trial
Presenter: Gaia Griguolo
Session: Poster Display session 2
Resources:
Abstract
3205 - Frequency of germline mutations in women's cancer susceptibility genes in a large cohort of Chinese breast cancer patients
Presenter: Ning Liao
Session: Poster Display session 2
Resources:
Abstract
4091 - Triple blinded Prospective Study assessing the Impact of Genomics & Artificial Intelligence Watson For Oncology (WFO) on MDT’s Decision of Adjuvant Systemic Therapy for Hormone Receptor Positive Early Breast Carcinoma-
Presenter: Somashekhar Sampige Prasannakumar
Session: Poster Display session 2
Resources:
Abstract
4359 - Prognostic significance of Progesterone Receptor levels in luminal-like Her2- early Breast Cancer patients. A retrospective single Cancer Center analysis.
Presenter: Anna Diana
Session: Poster Display session 2
Resources:
Abstract
1369 - PAM50 HER2-enriched subtype and pathological complete response in HER2-positive early breast cancer: a meta-analysis
Presenter: Francesco Schettini
Session: Poster Display session 2
Resources:
Abstract