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Transcription Inhibitor Lurbinectedin and Oncolytic Peptide LTX-401 Trigger Immunogenic Cell Death and Synergize with Immune Checkpoint Blockade Wei Xie

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Transcription Inhibitor Lurbinectedin and Oncolytic Peptide LTX-401 Trigger Immunogenic Cell Death and Synergize with Immune Checkpoint Blockade Wei Xie Transcription Inhibitor Lurbinectedin and Oncolytic Peptide LTX-401 trigger Immunogenic Cell Death and Synergize With Immune Checkpoint Blockade Wei Xie To cite this version: Wei Xie. Transcription Inhibitor Lurbinectedin and Oncolytic Peptide LTX-401 trigger Immunogenic Cell Death and Synergize With Immune Checkpoint Blockade. Cancer. Université Paris-Saclay, 2020. English. NNT : 2020UPASL072. tel-03186843 HAL Id: tel-03186843 https://tel.archives-ouvertes.fr/tel-03186843 Submitted on 31 Mar 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. INDEX ABSTRACT ............................................................................................................... 1 RESUME.................................................................................................................... 2 ORIGINAL PAPERS ................................................................................................. 3 ABBREVIATION ...................................................................................................... 4 INTRODUCTION ..................................................................................................... 7 Cancer and anticancer immunity ............................................................................ 7 Cancer epidemiology .......................................................................................... 7 Cancer immunology ............................................................................................ 8 Immunogenic cell death in cancer therapy ...........................................................13 Major DAMPs of ICD .......................................................................................16 Methods to detect ICD ......................................................................................25 ICD inducers .....................................................................................................27 Induction of ICD sensitize cancers to immune checkpoint blockade ...............31 Transcription inhibitor Lurbinectedin ..................................................................33 Oncolytic peptide LTX-401 .................................................................................36 AIMS OF THE THESIS ..........................................................................................38 RESULTS ................................................................................................................39 Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity .............................................................................................39 Tumor lysis with LTX-401 creates anticancer immunity ....................................41 CONCLUDING REMARKS ...................................................................................42 ACKNOWLEDGEMENT .......................................................................................45 REFERENCES .........................................................................................................46 ANNEX 1: SCIENTIFIC PUBLICATIONS ...........................................................66 ANNEX 2: PAPERS NOT INCLUDED IN THIS THESIS (INSERTED IN PDF) ..................................................................................................................................69 ABSTRACT Cancer is the second leading cause of death worldwide, despite the existence of standard treatment, innovative therapeutic strategies and drugs are still in urgent demand. The combination of immunogenic cell death (ICD) inducing drugs and immune checkpoint blockade (ICB) seems to be a promising modality. In this thesis, we demonstrated Lurbinectedin, a transcription inhibitor newly approved for relapsed lung cancer treatment, triggers hallmarks of ICD in four different human and murine cell line in vitro. Vaccinated with Lurbinectedin-treated fibrosarcoma cell protects immunocompetent mice from rechallenge of syngeneic tumours. Lurbinectedin restrains transplanted fibrosarcoma growth in an immune dependent manner. Both transplanted MCA205 cancer and hormone/carcinogen induced breast cancer were sensitized by Lurbinectedin to PD-1 and CTLA- 4 double ICBs. Of note, long-term immunological memory was generated in cured mice. Further, we evaluated the anticancer capacity of LTX-401, an oncolytic peptide designed for local immunotherapy. Sequential intratumoral injections of LTX-401 dramatically retards subcutaneous MCA205 and TC-1 tumour growth in immunocompetent host, yet shows limited therapeutic effect on abscopal syngeneic tumours. Single LTX-401 administration boosts the efficacy of anti-CTLA-4 or anti-PD-1/anti-CTLA-4 ICBs. Moreover, sequential LTX-401 treatment with double ICBs exhibits systemic antitumor immunity to both treated and abscopal tumour. In conclusion, lurbinectedin and LTX-401 induce cancer cell immunogenic cell death and enhance the anticancer effects of immune checkpoint blockade. These results lay the experimental foundation of combination regiments and may facilitate the clinical trial designs. Key words: cancer, immunogenic cell death, immune checkpoint blockade, transcription, oncolytic peptide 1 RESUME Le cancer est la deuxième cause de mortalité dans le monde. Malgré l’existence des traitements standards, le développement et la recherche de stratégies thérapeutiques innovantes et de médicaments est toujours nécessaire. La combinaison des médicaments, induisant la mort cellulaire immunogène (ICD) et l’inhibition des points de contrôle immunitaire (ICB), semble être un protocole prometteur. Dans cette thèse, nous avons démontré que la Lurbinectédine, un inhibiteur de la transcription nouvellement approuvé pour le traitement du cancer du poumon récidivant, déclenche les caractéristiques de l’ICD dans quatre différentes lignées cellulaires humaines et murines in vitro. Vaccinée par des cellules de fibrosarcome traitées par la lurbinectine, les souris immunocompétentes sont protégées lors du rechallenge des tumeurs syngéniques. La lurbinectédine limite la croissance du fibrosarcome transplanté d'une manière immunodépendante. Dans les souris, le fibrosarcome murin (MCA205) transplanté et le cancer du sein, induit par des hormones en combinaison avec des cancérigènes, ont été sensibilisés par la lurbinectédine aux deux ICB : PD-1 et CTLA-4. Il convient de noter que la mémoire immunologique à long terme a été générée chez des souris guéries. En outre, nous avons évalué la capacité anticancéreuse de LTX-401, un peptide oncolytique conçu pour l'immunothérapie locale. Les injections intratumorales séquentielles de LTX-401 retardent considérablement la croissance des tumeurs sous-cutanées MCA205 et TC-1 chez un hôte immunocompétent, mais montrent un effet thérapeutique limité sur les tumeurs syngéniques abscopales. Une seule administration de LTX-401 augmente l'efficacité des ICB anti-CTLA-4 ou anti-PD-1 + anti-CTLA-4. De plus, le traitement séquentiel avec LTX-401 et les deux ICB présente une immunité antitumorale systémique à la fois contre la tumeur traitée et la tumeur abscopale. En conclusion, la lurbinectédine et le LTX-401 induisent la mort cellulaire immunogène des cellules cancéreuses et renforcent les effets anticancéreux des inhibiteurs de points de contrôle immunitaires. Ces résultats jettent les bases expérimentales de traitements combinés et peuvent faciliter les conceptions d'essais cliniques. Mots clés: cancer, mort cellulaire immunogène, inhibiteur de point de contrôle immunitaire, transcription, peptide oncolytique 2 ORIGINAL PAPERS This thesis is based on the following papers: Paper I. Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity. Xie W, Forveille S, Iribarren K, Sauvat A, Senovilla L, Wang Y, Humeau J, Perez-Lanzon M, Zhou H, Martínez-Leal JF, Kroemer G, Kepp O. Published in Oncoimmunology, 2019, VOL. 8, NO. 11, e1656502 (9 pages). Paper II. Tumor lysis with LTX-401 creates anticancer immunity. Xie W, Mondragón L, Mauseth B, Wang Y, Pol J, Lévesque S, Zhou H, Yamazaki T, Eksteen JJ, Zitvogel L, Sveinbjørnsson B, Rekdal Ø, Kepp O, Kroemer G. Published in Oncoimmunology, 2019, VOL. 8, NO. 7, e1594555 (8 pages). (In agreement with the doctoral school, Paper I&II are inserted to replace chapter ‘Materials and methods’ and ‘Results’.) 3 ABBREVIATION AIDS acquired immune deficiency syndrome ATF activating transcription factor AML acute myeloid leukaemia ATP adenosine triphosphate ANXA1 annexin A1 APCs antigen-presenting cells AMPs antimicrobial peptides LfcinB bovine lactoferricin BFA brefeldin A CALR calreticulin CRC colorectal cancer CXCL10 CXC-chemokine ligand 10 CTLA-4 cytotoxic T-lymphocyte-associated protein 4 DAMPs damage-associated molecular patterns DC dendritic cell DMBA dimethylbenzantracene DOXO doxorubicin ER endoplasmic reticulum ERAD ER-associated degradation eIF2α eukaryotic translation initiation factor 2 FDA federal drug administration FPR1 formyl peptide receptor 1 GCN2 general control nonderepressible 2 Hsp70 heat shock protein 70 HCC
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