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Immunotherapy

CD28/4-1BB CD123 CAR T cells in blastic plasmacytoid dendritic cell neoplasm

Leukemia volume 34, pages 3228–3241 (2020)Cite this article

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Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is associated with a remarkably poor prognosis and with no treatment consensus. The identification of relevant therapeutic targets is challenging. Here, we investigated the immune functions, antileukemia efficacy and safety of CD28/4-1BB CAR T cells targeting CD123 the interleukin (IL)-3 receptor alpha chain which is overexpressed on BPDCN. We demonstrated that both retroviral and lentiviral engineering CD28/4-1BB CD123 CAR T cells exhibit effector functions against BPDCN cells through CD123 antigen recognition and that they efficiently kill BPDCN cell lines and BPDCN-derived PDX cells. In vivo, CD28/4-1BB CD123 CAR T-cell therapy displayed strong efficacy by promoting a decrease of BPDCN blast burden. Furthermore we showed that T cells from BPDCN patient transduced with CD28/4-1BB CD123 CAR successfully eliminate autologous BPDCN blasts in vitro. Finally, we demonstrated in humanized mouse models that these effector CAR T cells exert low or no cytotoxicity against various subsets of normal cells with low CD123 expression, indicating a potentially low on-target/off-tumor toxicity effect. Collectively, our data support the further evaluation for clinical assessment of CD28/4-1BB CD123 CAR T cells in BPDCN neoplasm.

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Fig. 1: Design and production of CD123 CAR T cells.
Fig. 2: CD123R CAR T cells induced specific cytotoxicity against BPDCN cell lines and BPDCN patient-derived xenograft cells.
Fig. 3: Functional characterization of CD123R CAR T cells in coculture with CD123+ target cells.
Fig. 4: In vivo antitumor activity of CD123L CAR T cells against CAL-1 and PDX.
Fig. 5: Evaluation of CD123 expression in normal cells compared with BPDCN cells.
Fig. 6: Evaluation of toxicity of CD123L CAR T cells against cells expressing CD123 at a low level.
Fig. 7: CD123L CAR T cells from a patient with BPDCN and induction of specific cytotoxicity against autologous BPDCN blasts.

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Acknowledgements

The authors would like to thank the animal technicians for their expertise in animal care and management. We thank Franck Monnien and the Biobank BB-0033-00024 “Tumorothèque Régionale de Franche-Comté (TRFC)” for providing tissue samples, Diaclone for collaboration for antibodies production, and Stemline for SL-401 providing. This study was supported by Programme de Recherche Translationnelle INCa (PRTK N°PRT-K-15-175), by the MiMedI project funded by BPI France (Grant No. DOS0060162/00) and the European Union through the European Regional Development Fund of the Region Bourgogne-Franche-Comte (Grant No. FC0013440), by the Region Bourgogne-Franche-Comté (IVIS Lumina Series III bioimager to P.S. #2016-0196), by the National Cancer Institute (INCa) DM/FC/sl/RT07 grant to CR and the Association Laurette Fugain (12/09) to EM.

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Authors and Affiliations

  1. Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000, Besançon, France

    Elodie Bôle-Richard, Maxime Fredon, Sabeha Biichlé, Jean-Marie Certoux, Florian Renosi, Frédéric Tsé, Alizée Jenvrin, Walid Warda, Jean-René Pallandre, Francis Bonnefoy, Margaux Poussard, Marina Deschamps, Yann Godet, Delphine Binda, Eric Deconinck, Etienne Daguindau, Philippe Saas, Christophe Ferrand, Fanny Angelot-Delettre, Olivier Adotévi & Francine Garnache-Ottou

  2. Invectys, Paris Biopark, 12 rue Jean Antoine de Baïf, F-75013, Paris, France

    François Anna, Pierre Langlade-Demoyen, Maria Loustau & Julien Caumartin

  3. Molecular Virology and Vaccinology Unit, Virology Department, Institut Pasteur & CNRS URA 3015, 25-28 rue du Dr. Roux, F-75015, Paris, France

    François Anna

  4. Service d’Anatomie et Cytologie Pathologiques, CHU Besançon, F-25000, Besançon, France

    Chloé Molimard & Séverine Valmary-Degano

  5. Department of Pathology, University of Montréal, Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada

    Tony Petrella

  6. INSERM U837, CHRU Lille, IRCL Laboratoire d’Hématologie, Centre de Biologie Pathologie, F-59000, Lille, France

    Christophe Roumier

  7. INSERM U1151, Université de Paris, Faculté de Médecine Descartes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Laboratoire d’Onco-Hématologie, F-75000, Paris, France

    Elizabeth Macintyre

  8. Université Sorbonne, INSERM U938, Service Hématologie Clinique, Hôpital Saint-Antoine, F-75000, Paris, France

    Frédéric Féger, Eolia Brissot & Mohamad Mohty

  9. TransCure Bioservices, Biopark, F-74160, Archamps, France

    Kiave-Yune HoWangYin

  10. Inserm CIC 1431, CHU Besançon, F-25000, Besançon, France

    Delphine Binda & Maïder Pagadoy

  11. Service Hématologie, CHU Besançon, F-25000, Besançon, France

    Eric Deconinck & Etienne Daguindau

  12. Service Oncologie médicale, CHU Besançon, F-25000, Besançon, France

    Olivier Adotévi

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  1. Elodie Bôle-Richard
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Contributions

EBR, MF, SB, JMC, FA, FT, MP, and AJ performed the experiments; EBR, JMC, MF, and SB analyzed data; EBR and MF performed statistical analysis; FB, JRP, and KYHWY assisted with in vivo experiments; FR, TP, CM, and SVD provided help with immunohistochemistry and transcriptomic analysis. TP, CR, EM, FF, EB, and MM provided patient samples and expertise. FR, CM, SVD, YG, PS, WW, MD, PLD, ML, JC, DB, MP, ED, ED, PS, CF, and FAD provided guidance and expertise in their respective areas of study. EBR, MF, and FGO wrote the manuscript, and FGO, OA, ED, PS, and FAD commented on the manuscript. FGO, FAD, and OA supervised the research. All authors provided input and edited and approved the final version of the manuscript.

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Correspondence to Francine Garnache-Ottou.

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Bôle-Richard, E., Fredon, M., Biichlé, S. et al. CD28/4-1BB CD123 CAR T cells in blastic plasmacytoid dendritic cell neoplasm. Leukemia 34, 3228–3241 (2020). https://doi.org/10.1038/s41375-020-0777-1

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