Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells.
Tianyu CaiAgnès GoubleKathryn L BlackAnna SkwarskaAmmar S NaqviDeanne M TaylorMing ZhaoYuan QiMayumi SugitaQi ZhangRoman GalettoStéphanie FilipeAntonio CavazosLina HanVinitha KuruvillaHelen MaConnie WengChang-Gong LiuXiuping LiuSergej KonoplevJun GuGuilin TangXiaoping SuGheath Al-AtrashStefan CiureaSattva S NeelapuAndrew A LaneHagop M KantarjianMonica L GuzmanNaveen PemmarajuJulianne SmithAndrei Thomas-TikhonenkoMarina Y KonoplevaPublished in: Nature communications (2022)
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN ® nucleases. In this study, we examine the antitumor activity of UCART123 in preclinical models of BPDCN. We report that UCART123 have selective antitumor activity against CD123-positive primary BPDCN samples (while sparing normal hematopoietic progenitor cells) in the in vitro cytotoxicity and T cell degranulation assays; supported by the increased secretion of IFNγ by UCART123 cells when cultured in the presence of BPDCN cells. UCART123 eradicate BPDCN and result in long-term disease-free survival in a subset of primary patient-derived BPDCN xenograft mouse models. One potential challenge of CD123 targeting therapies is the loss of CD123 antigen through diverse genetic mechanisms, an event observed in one of three BPDCN PDX studied. In summary, these results provide a preclinical proof-of-principle that allogeneic UCART123 cells have potent anti-BPDCN activity.
Keyphrases
- dendritic cells
- induced apoptosis
- cell cycle arrest
- stem cell transplantation
- bone marrow
- regulatory t cells
- nk cells
- immune response
- stem cells
- gene expression
- cell death
- randomized controlled trial
- clinical trial
- mouse model
- type diabetes
- signaling pathway
- dna methylation
- crispr cas
- high throughput
- oxidative stress
- mesenchymal stem cells
- weight loss
- high dose
- endothelial cells
- genome wide
- cell therapy
- low grade
- study protocol
- phase iii