Electrochemotherapy as in situ vaccination therapy

BASIC DATA OF THE RESEARCH PROJECT

• ARRS code: Z3-2651
• TITLE: Electrochemotherapy as in situ vaccination therapy
• PROJECT LEADER: Katja Uršič, PhD
• DURATION: 1.9.2020 - 31.8.2022
• APPLICANT RESEARCH ORGANISATION: INSTITUTE OF ONCOLOGY LJUBLJANA
• FINANCING: Slovenian Research Agency

Electrochemotherapy is a well-established ablative therapy in Europe with 60-90% response rate, depending on the tumor type. Despite high local effectiveness of electrochemotherapy, a systemic antitumor effect has not yet been observed in clinics. The importance of ablative therapies, such as electrochemotherapy, has been recently re-evaluated in the light of the new era of cancer immunotherapy. In situ vaccination seeks to enhance tumor immunogenicity, generate tumor infiltrating lymphocytes and drive a systemic antitumor immune response (abscopal effect) directed against untreated distant tumors. It is known that irradiation induces in situ vaccination. Conversely, it is not yet known if electrochemotherapy with bleomycin, cisplatin or oxaliplatin induces in situ vaccination and to what level. The main goal of the project is to describe and compare the timeline of the immunologically important biomarkers after electrochemotherapy with bleomycin, cisplatin or oxaliplatin. Moreover, the project will primarily seek the answers to the question: “Does electrochemotherapy induce in situ vaccination?”.

In the project, immunologically “cold” tumor cell lines B16F10 murine melanoma and 4T1 murine mammary carcinoma will be used. Electrochemotherapy will be tested, whether it can turn an immunosuppressive tumor to a tumor highly recognizable by the immune system. Three specific aims of the proposed project are:

1) to evaluate specific types of cell death after electrochemotherapy with bleomycin, cisplatin or oxaliplatin,

2) to describe the differences between cytotoxic and immunomodulatory actions of the chemotherapeutic drugs used in electrochemotherapy and most importantly,

3) to prove if electrochemotherapy is sufficient in accomplishing effective in situ vaccination. 

The aims of the project will be implemented through Work Packages (WP) divided into Specific Tasks (ST).

WP 1: Electrochemotherapy with bleomycin, cisplatin and oxaliplatin in vitro: cytotoxicity and the type of cell death

• ST 1.1: Cytotoxicity of electrochemotherapy with three different chemotherapeutic drugs in vitro
• ST 1.2: Detection of different types of cell death and other immunologically important biomarkers after electrochemotherapy with bleomycin, cisplatin or oxaliplatin
• ST 1.3: Electrochemotherapy induces maturation and activation of and antigen uptake by dendritic cells

WP 2: Electrochemotherapy in vivo and in situ vaccination

• ST 2.1: Equieffective electrochemotherapy with bleomycin, cisplatin or oxaliplatin
• ST 2.2: Immunohistological analyses of tumors treated – staining for type of cell death and immune cell infiltration

WP 3: Proof of principle: electrochemotherapy as an in situ vaccine therapy

• ST 3.1: Electrochemotherapy in athymic NUDE mice
• ST 3.2: Mouse model of systemic disease

The description of the timeline of immunologically important effects of electrochemotherapy with bleomycin, cisplatin or oxaliplatin are important for the combined treatment with other immunotherapies. Specifically, the timing of the combined treatment is important. Therefore, the results of this project would allow us to design more effective combinatorial treatment protocols that would include electrochemotherapy and immunotherapies targeting immunosuppression or immunostimulation.