TY - JOUR
T1 - CD28/4-1BB CD123 CAR T cells in blastic plasmacytoid dendritic cell neoplasm
AU - Bôle-Richard, Elodie
AU - Fredon, Maxime
AU - Biichlé, Sabeha
AU - Anna, François
AU - Certoux, Jean Marie
AU - Renosi, Florian
AU - Tsé, Frédéric
AU - Molimard, Chloé
AU - Valmary-Degano, Séverine
AU - Jenvrin, Alizée
AU - Warda, Walid
AU - Pallandre, Jean René
AU - Bonnefoy, Francis
AU - Poussard, Margaux
AU - Deschamps, Marina
AU - Petrella, Tony
AU - Roumier, Christophe
AU - Macintyre, Elizabeth
AU - Féger, Frédéric
AU - Brissot, Eolia
AU - Mohty, Mohamad
AU - HoWangYin, Kiave Yune
AU - Langlade-Demoyen, Pierre
AU - Loustau, Maria
AU - Caumartin, Julien
AU - Godet, Yann
AU - Binda, Delphine
AU - Pagadoy, Maïder
AU - Deconinck, Eric
AU - Daguindau, Etienne
AU - Saas, Philippe
AU - Ferrand, Christophe
AU - Angelot-Delettre, Fanny
AU - Adotévi, Olivier
AU - Garnache-Ottou, Francine
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85081313030
U2 - 10.1038/s41375-020-0777-1
DO - 10.1038/s41375-020-0777-1
M3 - Article
C2 - 32111969
AN - SCOPUS:85081313030
SN - 0887-6924
VL - 34
SP - 3228
EP - 3241
JO - Leukemia
JF - Leukemia
IS - 12
ER -