On April 28, 2022 Cellectis (the "Company") (Euronext Growth: ALCLS – NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies, reported the publication of two manuscripts in Nature Communications on its product candidate UCART123, currently being evaluated in the Phase 1 dose-escalation trial AMELI-01 in patients with relapsed or refractory acute myeloid leukemia (r/r AML) (Press release, Cellectis, APR 28, 2022, View Source [SID1234613110]). These preclinical data demonstrate the robust in vitro and in vivo activity of UCART123 and provide pre-clinical proof of concept for an allogenic CART cell approach to tackle AML.

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Allogeneic TCRαβ Deficient CAR T-cells Targeting CD123 in Acute Myeloid Leukemia

This preclinical study, led by Dr Monica Guzman, Ph.D., Division of Hematology and Oncology, Department of Medicine Weill Cornell Medical College, demonstrated that Cellectis’ product candidate UCART123 effectively eliminates AML cells in vitro and in vivo with improvements in overall survival and minimal impact against normal hematopoietic progenitors.

AML is a disease originated and maintained from leukemia stem cells (LSCs). CD123 is a cell surface antigen expressed on AML blasts as well as LSCs. In this study, the potential of allogeneic gene-edited CAR T cells targeting CD123 to eliminate LSCs (UCART123) was evaluated.

"While the majority of the few CD123 T-cell therapies evaluated to date rely on autologous approaches with complex clinical and logistical barriers, this set of preclinical results strongly supports the potential benefits of the allogeneic CAR T approach in AML. UCART123 exhibits unprecedented primary AML-selective cytotoxic activity and minimal effects against normal cells, which was a major drawback reported in previous preclinical studies performed with other CD123 targeted CARs" said Mark Frattini, MD, Ph.D., Senior Vice President, Head of Clinical Sciences at Cellectis.

Preclinical results showed that:

UCART123 demonstrates cytotoxic activity against primary AML samples with minimum toxicity against normal hematopoietic progenitor cells

UCART123 targets AML cells in vivo and results in improved overall survival in patient-derived xenografts (PDX) models

UCART123 selectively clears primary AML cells, without affecting hematopoiesis, in a competitive humanized mouse model harboring primary AML and normal bone marrow cells

Targeting CD123 in Blastic Plasmacytoid Dendritic Cell Neoplasm using Allogeneic Anti-CD123 CAR T Cells

This preclinical study, led by Professor Marina Konopleva, M.D., Ph.D., Department of Leukemia, University of Texas MD Anderson Cancer Center, demonstrated the antitumor activity of UCART123 in preclinical models of blastic plasmacytoid dendritic cell neoplasm (BPDCN).

BPDCN is a rare hematologic malignancy with poor outcomes with conventional therapy. Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target.

In this study, the antitumor activity of allogeneic CD123 CAR T cells (UCART123) was demonstrated by in vitro and in vivo assays using primary BPDCN samples.

Preclinical results showed that:

UCART123 cells result in specific killing of BPDCN primary samples in vitro and in xenograft (PDX) experiments in vivo

Cytokine production levels in mice correlate with tumor burden at the time of UCART123 administration

Tumor relapse was observed upon loss of CD123, through diverse genetic mechanism, in one of the PDX models

"These preclinical results support our rationale of using allogeneic CD123 CAR T cells to treat AML. Cellectis’ UCART123 is the first allogeneic product candidate to demonstrate elimination of AML and BPDCN cells in PDX mouse experiments, with significant benefits in overall survival and low impact on hematopoietic progenitor cells. This brings us one step closer to delivering these innovative therapies to patients with unmet medical needs" said Roman Galetto, Sr. Director Preclinical & Program Management at Cellectis.

Cellectis’ AMELI-01 clinical study is currently enrolling patients at Dose Level 2 (6.25 × 105 cells/kg) with Fludarabine Cyclophosphamide and Alemtuzumab (FCA) preconditioning regimen.

Articles are available on the Nature Communications website, by clicking on the links below:

Allogeneic TCRαβ Deficient CAR T-cells Targeting CD123 in Acute Myeloid Leukemia