ID: 2168

  • Title:
    Electrochemotherapy as in situ vaccine

    Uršic Valentinuzzi, Katja - Institute of Oncology Ljubljana; University of Ljubljana
    Kešar, Urša - Institute of Oncology Ljubljana; University of Ljubljana
    Kamen?ek, Ur?ka - Institute of Oncology Ljubljana; University of Ljubljana
    Kranjc Brezar, Simona - Institute of Oncology Ljubljana; University of Ljubljana
    ?ema?ar, Maja - Institute of Oncology Ljubljana; University of Primorska
    Ser?a, Gregor - Institute of Oncology Ljubljana; University of Ljubljana

    Besides direct cytotoxic effects, electrochemotherapy (ECT) can also trigger indirect antitumor

    effects via induction of immune system responses. Namely, elevated expression of immunologically

    important molecules on tumor cells as well as induction of immunologically recognizable types of cell

    death, accompanied with the release of tumor-associated antigens and accumulation of damage-

    associated molecular patterns (DAMPs), can induce in situ vaccination effect. Lately, ECT is frequently

    combined with immunotherapies. To improve responses and outcomes, the timing of the therapies

    in combination is of utmost importance. Therefore, the main goal of this study was to describe and

    compare the timeline of the immunologically relevant biomarkers after intratumoral ECT with

    bleomycin (BLM), cisplatin (CDDP) and oxaliplatin (OXA). We considered cytotoxic and

    immunomodulatory actions of the ECT and investigated if it is sufficient in accomplishing effective in

    situ vaccination.

    The immunologically important effects of ECT with equieffective doses of BLM, CDDP or OXA were

    investigated in three immunologically distinct murine tumor models (B16F10, 4T1 and CT26) in in

    vitro and in vivo setting. Specifically, in vitro, the type of cell death and the expression of MHC-I,

    MHC-II, PD-L1 and CD-40 were evaluated. In vivo, the antitumor effect of ECT was compared in wild-

    type mice and immunocompromised (NUDE) mice and the background immune-related mechanisms

    as cell death and infiltration of tumors by different immune cells were compared. For the latter,

    cytometric and histological analyses were performed. To assess systemic antitumor effect, the ECT

    was also performed on metastatic model established through induced lung metastases.

    We showed that the three tumor models are differently sensitive to ECT with the three drugs used;

    ECT was more effective in more immunogenic tumors in vivo (CT26 > 4T1 > B16F10). The involvement

    of the T cells in the antitumor effect of ECT with CDDP was confirmed by using immunocompromised

    mice. Moreover, histological analyses showed that ECT also attracted other immune cells

    intatumorally. Furthermore, ECT modified the tumor expression of MHC I, MHC II, PD-L1 and CD40

    and induced immunogenic cell death-associated DAMPs; however, the kinetics were cell line- and

    drug-specific. Finally yet importantly, ECT with CDDP and BLM also resulted in the abscopal effect.

    The study was initiated to systematically evaluate the effects of ECT with CDDP, BLM or OXA in three

    tumor models. We showed that the three models are differently sensitive to ECT, i.e., immunogenic

    tumors responded better with all the three drugs used. Additionally, we confirmed the involvement

    of the immune system in the response. The degree of immune system activation depended on the

    type of drug and the type of tumor model. Therefore, the selection of the drug in ECT should be

    predominantly based on the tumor immune status. The data obtained in this study will allow us to

    design a combinatorial treatment protocol more effectively.

    Electrochemotherapy, mouse models, immune response


    Topic 1:
    12. Biomedical applications

    Topic 2:
    6. Cancer treatment and tumor ablation

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