Abstract 127P
Background
Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis due to its late detection, high stromal content, and high relapse rate. Immunosuppressive tumor microenvironment creates a major challenge for PDAC immunotherapy requiring novel therapeutic approaches. Ad5/3-E2F-d24-vIL2 (vIL2-virus) is an engineered oncolytic adenovirus (OAd) encoding a variant IL-2 cytokine. vIL-2 expression leads to preferential stimulation of natural killer cell and effector lymphocyte expansion over T regulatory cell proliferation. We propose to combine vIL2-virus to nab-paclitaxel, gemcitabine, and anti-PD-L1 to formulate an effective immunotherapeutic treatment for the traditionally therapy-resistant PDAC.
Methods
PDAC cell lines treated with vIL2-virus, normal IL-2 virus, and unarmed virus were studied in mono- and co-cultures with macrophages and fibroblasts with flow cytometry profiling. Ex vivo experiments with real time cell killing assays were performed with clinical PDAC samples with concurrent flow cytometric and cytokine analysis. In vivo antitumor efficacy and safety of the combination were tested using an immunocompetent hamster model.
Results
Increasing doses of gemcitabine, paclitaxel, and virotherapies led to increased PD-L1 expression on PDAC cells. Different OAds showed lower levels of PD-L1 upregulation on cancer cells when co-cultured with macrophages or fibroblasts, while macrophages and fibroblasts expressed PD-L1 considerably more than cancer cells after IFN-gamma stimulation. Macrophages upregulated PD-L1 and PD-L2 only around virus producing normal human IL-2. Experiments with clinical PDAC samples showed efficient cancer cell killing and cytotoxic immune cell changes by the combination therapy. In vivo, the triple therapy showed significantly improved tumor growth control and survival compared to chemotherapy with anti-PD-L1 or chemotherapy alone. Moreover, animals cured by the triple treatment showed increased resistance to tumor re-challenge.
Conclusions
A combination of vIL2-virus, chemotherapy, and anti-PD-L1 is a promising strategy to overcome therapeutic limitations and effectively improve outcome in patients with PDAC.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
J. Clubb, J. Santos: Financial Interests, Personal, Full or part-time Employment, Employee of TILT Biotherapeutics: TILT Biotherapeutics Ltd; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics Ltd. L. Haybout: Financial Interests, Personal, Full or part-time Employment, Employee of TILT Biotherapeutics: TILT Biotherapeutics Ltd. D.C.A. Quixabeira: Financial Interests, Institutional, Full or part-time Employment: TILT Biotherapeutics. V. Cervera-Carrascon: Financial Interests, Personal, Full or part-time Employment: TILT Biotherapeutics Ltd; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics Ltd. A. Hemminki: Financial Interests, Personal, Financially compensated role: TILT Biotherapeutics Ltd; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics Ltd, Circio Holdings ASA; Financial Interests, Personal, Stocks or ownership: Aeruginosa Oy; Non-Financial Interests, Institutional, Research Grant: Helsinki University Hospital Research funds, Cancer Foundation Finland, Jane and Aatos Erkko Foundation, Red Cross Blood Service, Sigrid Juselius Finland, European Commission. All other authors have declared no conflicts of interest.
Resources from the same session
146P - Neoadjuvant adebrelimab combined with chemotherapy for adenocarcinoma of esophagogastric junction: A single-arm, single-center, phase II clinical trial
Presenter: Jinqiang Liu
Session: Poster Display session
Resources:
Abstract
147P - Serplulimab combined with chemotherapy in the neoadjuvant treatment of resectable oesophageal squamous cell carcinoma: A single-arm phase II trial
Presenter: Zixiang Wu
Session: Poster Display session
Resources:
Abstract
148P - Neoadjuvant camrelizumab plus metronomic chemotherapy in patients with advanced esophageal squamous cell carcinomas: A randomized phase II trial
Presenter: JIE LIU
Session: Poster Display session
Resources:
Abstract
149P - Toripalimab and chemotherapy as first line combination in advanced thymic carcinoma: A prospective, single-arm, phase II trial
Presenter: Kai Zhu
Session: Poster Display session
Resources:
Abstract
150P - Interim results of the multicenter phase II study on induction pembrolizumab plus chemotherapy followed by radiotherapy in locally advanced head and neck cancer
Presenter: Tatiana Antonova
Session: Poster Display session
Resources:
Abstract
151P - Anti-tumor T cell response and immunoselection under combined GARP:TGF-?1/PD-1 blockade
Presenter: Grégoire de Streel
Session: Poster Display session
Resources:
Abstract
152P - TACTI-003 Cohort B: Eftilagimod alpha (Soluble LAG-3) and pembrolizumab in first-line recurrent or metastatic head & neck squamous cell carcinoma with PD-L1 negative
Presenter: Martin Forster
Session: Poster Display session
Resources:
Abstract
153P - Combination of Tim-3 blockade TQB2618 with PD-1 blockade for patients with immunotherapy-resistant recurrent/metastatic nasopharyngeal carcinoma (R/M NPC): Preliminary results from a phase II study
Presenter: Cheng Xu
Session: Poster Display session
Resources:
Abstract
154P - Casdozokitug (casdozo, CHS-388), a first-in-class IL-27 antagonistic antibody, as monotherapy in treatment-refractory non-small cell lung cancer (NSCLC)
Presenter: Aung Naing
Session: Poster Display session
Resources:
Abstract
155P - Tarlatamab for patients with small cell lung cancer: 6-8 hour outpatient vs 48 hour inpatient monitoring in cycle 1
Presenter: Anne Chiang
Session: Poster Display session
Resources:
Abstract