Abstract 2560: Preclinical efficacy of allogeneic anti-CD123 CAR T-cells for the therapy of blastic plasmacytoid dendritic cell neoplasm (BPDCN)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with historically poor outcomes and no established standard of care. Nearly 100% of patients with BPDCN overexpress CD123, and targeting CD123 emerged as an attractive therapeutic target given its differential expression on BPDCN cell surface. UCART123 product (Cellectis) uses genetically modified allogeneic T-cells (derived from healthy donors, so-called “off the shelf”) containing an anti-CD123 CAR and a RQR8 depletion ligand that confers susceptibility to rituximab. The expression of the T-cell receptor (TCR) is abrogated through the inactivation of the TCRα constant gene, using Cellectis' TALEN® gene-editing technology. We have previously reported the selective in vitro anti-tumor activity of UCART123 cells against CD123+ primary BPDCN samples using cytotoxicity assays, T-cell degranulation assay and the secretion of IFNγ and other cytokines (IL2, IL5, IL6, IL-13 and TNF-α) by UCART123 cells when cultured in the presence of BPDCN cells (Tianyu Cai, 2017 ASH). However, UCART123 had minimum toxicity against normal bone marrow cells. To evaluate in vivo anti-tumor activity of UCART123 cells, we established two patient-derived xenografts (PDX1-2) from patients with relapsed BPDCN in NSG-SGM3 mice. In PDX-1 model, all mice in vehicle-treated group died by D53, with high tumor burden in peripheral blood, spleen and bone marrow. Three out of 9 (33%) mice treated with 3×106 UCART123 and Six out of 9 (67%) mice treated with 10×106 UCART123 were alive and disease-free at the end of the study (D299). In PDX-2 model, while UCART123 similarly extended survival of the mice (D104-241), relapses occurred in all treatment cohorts at D90-155. Flow cytometric analysis showed that all of the relapses were associated with emergence of CD123- BPDCN clones (95-96% CD123-). To understand the molecular basis for loss of CD123 surface expression, we isolated RNA from two CD123 positive samples from vehicle group and two CD123 negative samples from 1×106 UCART123 group. RT-PCR and RNA-seq detected the presence of full-length transcripts containing exons 1-12 in both CD123 positive samples. In one of the two CD123 (-) samples, CD123 transcripts were completely absent, along with loss of transcripts of neighboring genes. In another CD123 (-) sample, CD123 transcripts containing only exons 1-9 were detected, indicating the presence of a truncation. Interestingly, if translated, this transcript would produce a protein isoform lacking the transmembrane domain (Ex 10). In summary, UCART123 therapy results in BPDCN eradication and long-term disease-free survival in a subset of primary BPDCN PDX models. However, loss of CD123 through diverse genetic mechanisms could lead to escape from UCART123 therapy and cause relapses. A phase I trial of UCART123 in BPDCN is opened for enrollment (NCT03203369). Citation Format: Tianyu Cai, Kathryn L. Black, Ammar Naqvi, Roman Galetto, Agnès Gouble, Julianne Smith, Antonio Cavazos, Lina Han, Qi Zhang, Vinitha Kuruvilla, Sergej Naumovich Sergej Konoplev, Sattva S. Neelapu, Andrew A. Lane, Monica L. Guzman, Hagop Kantarjian, Andrei Thomas-Tikhonenko, Naveen Pemmaraju, Marina Konopleva. Preclinical efficacy of allogeneic anti-CD123 CAR T-cells for the therapy of blastic plasmacytoid dendritic cell neoplasm (BPDCN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2560.