The microenvironmental shield of multiple myeloma against immunotherapy

Lisa Charrèl Holthof

    Research output: PhD ThesisPhD-Thesis - Research and graduation internal

    98 Downloads (Pure)

    Abstract

    Scope of the thesis: Immunotherapy has emerged as a promising, yet incurable, therapeutic approach in MM. Mechanisms of immune escape distinct from immunosuppression, immune exhaustion or target antigen downregulation entail the development of intrinsic resistance mechanisms against the cytotoxic killer machinery of MM-reactive cytotoxic T cells (CTLs) through the intensive cross-talk between MM cells and bone marrow mesenchymal stromal cells (BMMSCs), a phenomenon that was previously only acknowledged as a mechanism of drug resistance. In this thesis we first explored the significance of this mode of immune escape for the FDA approved anti-CD38 antibody daratumumab. In chapter 2 we investigated the capacity of BMMSCs to protect MM against daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). To modulate these resistance mechanisms, we analyzed the combinatorial effects of daratumumab with an inhibitor of anti-apoptotic proteins. In chapter 3, we investigated the therapeutic anti-MM activity of a novel small molecule, FL118. This camptothesin analogue, that inhibits multiple anti-apoptotic proteins, showed impressive activity against multiple drug-resistant solid tumors. We analyzed its potential to modulate the apoptotic pathway in MM cells and its capacity to induce MM cell death. Additionally, we addressed the potential of FL118 to modulate BMMSC-induced drug resistance. Chimeric antigen receptor (CAR)-transduced T cell-based therapy is highly appealing for MM treatment. Nonetheless, absolute eradiation of tumor cells by CAR T cells in vivo is still not possible. Therefore, in chapter 4 we addressed the potential negative impact of BMMSCs on CAR T cells. To gain a broad insight on this matter, we tested CAR T cells with various antigen specificities, target cell affinities, and co-stimulatory domains. To circumvent the BMMSC-induced immune resistance against CAR T cells, MM-reactive CTLs and daratumumab-mediated ADCC, we tested the combinatorial effects with FL118. In continuation of our investigation into the impact of BMMSCs on immune therapies, we explored in chapter 5 the effects of BMMSC-mediated immune resistance against a model NK cell line KHYG-1 and death receptor 5 (DR5)-agonistic antibodies. Subsequently, we tested the combinatorial effects of these two distinct modalities with FL118. Additionally, we assessed whether the BMMSC-mediated immune resistance against the KHYG-1 NK cells could be overcome by improving its cytotoxic machinery though the introduction of a MM-reactive CAR or an optimized TRAIL-variant. In the final chapter 6 we extended our research on the pathological interactions between MM cells and BMMSCs and investigated the role of Notch signaling in the induction of immune resistance against CTLs and CAR T cells. Using three different inhibitors, we examined Notch as a possible target for therapy. In chapter 7 the most important results of this thesis are summarised and discussed.
    Original languageEnglish
    QualificationDr.
    Awarding Institution
    • Vrije Universiteit Amsterdam
    Supervisors/Advisors
    • Mutis, T., Supervisor, -
    • Zweegman, Sonja, Supervisor, -
    • Groen, R., Co-supervisor, -
    • van de Donk, N.W.C.J., Co-supervisor, -
    Award date15 Nov 2021
    Place of PublicationAmsterdam
    Publisher
    Print ISBNs9789493197794
    Publication statusPublished - 15 Nov 2021

    Keywords

    • Multiple Myeloma
    • Microenvironment
    • Immunotherapy
    • Immune resistance
    • Apoptosis
    • FL118
    • Notch
    • Survivin
    • CAR-T cell
    • Daratumumab

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