Harnessing iPSC-Derived CAR-NK Cells: A Multifaceted Approach to Combat B-Cell Malignancies

The abstract discusses the development of a novel therapeutic approach using iPSC-derived NK cells, which have been engineered to target and eliminate cancer cells while evading the host's immune response. The process involves genetic modifications to enhance the cells' persistence, functionality, and safety, including measures to reduce the risk of graft rejection and a safety mechanism that allows for cell elimination if necessary.

CNTY-101 is presented as a clinical candidate for treating B-cell malignancies, featuring six gene edits that improve the cells' performance and safety profiles. Among these edits is a strategy to avoid rejection by the patient's immune system, achieved by disrupting the beta-2-microbulin gene and introducing a transgene for HLA-E to protect the NK cells from cytotoxicity. Additionally, the class II major histocompatibility complex transactivator (CIITA) gene is disrupted to counteract CD4 T cell-mediated rejection, with the introduction of EGFR and IL-15 to aid in cell elimination and growth, respectively.

The CAR-NK cells have demonstrated potent antitumor activity against lymphoma both in vitro and in vivo, showing sustained killing capabilities and significant tumor growth inhibition with minimal doses. The EGFR-based safety switch has been validated for its effectiveness in inducing cell death in the presence of cetuximab.

In conclusion, CNTY-101 represents an innovative, engineered allogeneic CAR-iNK product candidate, designed with multiple immune evasion features and the expression of IL-15 to promote cell persistence and functionality. The manufacturing process is underway, with clinical trials planned for 2022.