127P - Combining chemotherapy and checkpoint inhibitors with an engineered oncolytic adenovirus encoding a human vIL-2 cytokine to treat pancreatic ductal adenocarcinoma

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.