Abstract 1428: Allogeneic CRISPR/Cas9 gene-edited CAR-T cells targeting CD33 show potent preclinical activity against AML cells

Acute myelogenous leukemia (AML) has a high mortality rate and remains difficult to treat, making new treatment approaches critical. Chimeric antigen receptor T (CAR-T) cell therapies have shown impressive clinical responses in B-cell neoplasia. However, comparable successes have not been reported to date in myeloid malignancies, potentially due to difficulty in manufacturing efficacious CAR-T cells from AML patients and lack of a suitable tumor antigen for AML. To address these issues, we have developed allogeneic CAR-T cells from healthy donors targeting the CD33/Siglec-3 antigen, a protein expressed on most AML cells and subpopulations in the majority of AML patients at presentation and relapse. Allogeneic anti-CD33 CAR-T cells were produced from healthy donor-derived T cells using CRISPR/Cas9 gene editing. In these cells, the TRAC locus was disrupted to reduce the risk of graft versus host disease (GvHD). At the same time, a CAR construct targeting CD33 was inserted site-specifically into the TRAC locus. In addition, the beta-2-microglobulin locus was disrupted to prevent clearance of the allogeneic CAR-T cells by the host immune system. These allogeneic anti-CD33 CAR-T cells showed potent effector activity in vitro against human AML-derived cell lines, as measured by both tumor cell lysis and effector cytokine secretion. The allogeneic anti-CD33 CAR-T cells also potently reduced AML tumors in vivo in xenograft mouse models.Citation Format: Brigid McEwan, Zinkal Padalia, Ashley Porras, Jason Sagert, Jonathan A. Terrett, Tony Ho, Demetrios Kalaitzidis. Allogeneic CRISPR/Cas9 gene-edited CAR-T cells targeting CD33 show potent preclinical activity against AML cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1428.