Abstract
Abstract CD19-CAR T cells have shown antitumor activity for B-cell derived malignancies, but they also have shown limitations regarding their toxicity and development of CD19- escape variants. Given their short lifespan and potent cytolytic function NK cells are attractive candidate effectors to express CARs. The goal of this project was to devise a strategy to genetically modify NKs that express a CAR to target CD22 and secrete a CD19-specific T-cell engager (CD19-ENG) to redirect T cells to B-cell leukemias. NKs were transduced with a retroviral vector encoding a CD22-CAR and/or CD19-ENG molecules. To mimic immune escape, CD19 or CD22 knockout (ko) leukemia cells (BV173) were generated. We performed coculture and cytotoxicity assays using CD22 and/or CD19+ targets with NKs +/− T cells. In the absence of T cells, CD22-CAR +/− CD19-ENG NK cells recognized tumor cells in an antigen-dependent manner as judged by cytokine production and tumor killing. Moreover, CD22 CAR +/− NK cells secreting engager molecules efficiently redirected T cells in the presence of CD19+ targets. In vivo, CD22-CAR/CD19-ENG NK cells recognized tumor cells in an antigen-dependent manner, redirected T cells to tumor cells, and induced significant regression of leukemia in xenograft models in comparison to mice treated with CD22-CAR NK cells or NK cells targeting irrelevant antigens. We have generated for the first time NK cells that kill B-cell malignancies through a CAR and simultaneously redirect bystander T cells to a 2nd B-cell antigen to enhance antitumor effects and prevent immune escape. Genetic modification of NK cells to enhance their antitumor activity and redirect bystander T cells may represent a promising addition to current cell therapies for B-cell malignancies.
Published Version
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