Caribou Biosciences selects ROR1 as target for CB-020

Caribou Biosciences announced target selection for CB-020, an induced pluripotent stem cell derived allogeneic anti-ROR 1 CAR-NK cell therapy. Preclinical data on the selection of the CB-020 CAR construct and armoring strategies for Caribou’s CAR-NK cell platform will be presented today at the 12th American Association for Cancer Research and Japanese Cancer Association Joint Conference. iPSC-derived NK cells innately exhibit potent antitumor activity against solid tumors. CB-020 is being engineered using Caribou’s Cas12a chRDNA genome-editing technology to express a ROR1-specific CAR, which can enhance the innate NK cell antitumor activity by increasing specificity and function. ROR1 is a cell signaling receptor that is overexpressed on the surface of several solid tumor types and has been shown to drive tumor cell growth, survival, and metastasis. Preclinical data to be presented at AACR-JCA show that a single dose of iPSC-derived anti-ROR1 CAR-NK cells, administered in a tumor xenograft model, significantly reduced tumor burden compared to iPSC-derived NK cells without an anti-ROR1 CAR. Multiple armoring strategies are being developed for Caribou’s CAR-NK cell platform to enhance tumor targeting, allogeneic CAR-NK cell survival, and persistence of antitumor activity. Results from the company’s preclinical studies suggest iPSC-derived NK cells with a knockout of CBLB, a ubiquitin ligase that negatively regulates NK cell function, results in reduced tumor burden and increased overall survival in an in vivo solid tumor xenograft model, compared to unedited iPSC-derived NK cells. Additionally, results show that iPSC-derived NK cells were not killed by donor-derived T cells and NK cells when harboring a knockout of B2M and an insertion of a BM2-HLA-E fusion protein. This strategy may induce more potent NK activity and help prevent CAR-NK cells from killing each other, which is a common problem with NK cell therapies. In addition, results from iPSC-derived NK cells with an insertion of membrane-bound IL-15/IL-15RA fusion protein, which is shown to enhance NK cell antitumor activity, demonstrated high cytotoxicity against tumor cells compared to unedited iPSC-derived NK cells. Together, these preclinical data demonstrate Caribou’s genome-editing technology has the potential to be used to implement a variety of armoring strategies in iPSC-derived CAR-NK cells to address many of the challenges associated with treating solid tumors.