Caribou Biosciences Selects ROR1 as the Target for CB-020, an iPSC-Derived Allogeneic CAR-NK Cell Therapy

Caribou Biosciences, Inc. recently announced target selection for CB-020, an induced pluripotent stem cell (iPSC)-derived allogeneic anti-ROR 1 (receptor tyrosine kinase like orphan receptor 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 was presented at the 12th American Association for Cancer Research and Japanese Cancer Association (AACR-JCA) Joint Conference.

“ROR1 has been selected as the target for CB-020, Caribou’s first off-the-shelf iPSC-derived CAR-NK cell therapy, and the preclinical data presented at AACR-JCA shows that ROR1 may be a promising target for several solid tumor indications,” said Steve Kanner, PhD, Caribou’s Chief Scientific Officer. “We are leveraging our chRDNA genome-editing technology across our allogeneic CAR-T and CAR-NK cell programs to address disease-specific challenges. For solid tumors, we are exploring several armoring strategies for our allogeneic CAR-NK cell therapy platform, including a CBLB knockout, a B2M knockout with a B2M–HLA-E fusion protein insertion, and a membrane-bound IL-15 insertion/IL-15RA fusion protein to help overcome the complex tumor microenvironment that has challenged previous cell therapies.”

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 (Casitas B-Lineage lymphoma proto-oncogene-B), 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.

The full poster is available on Caribou’s Scientific Publications webpage.

CRISPR genome editing uses easily designed, modular biological tools to make DNA changes in living cells. There are two basic components of Class 2 CRISPR systems: the nuclease protein that cuts DNA and the RNA molecule(s) that guide the nuclease to generate a site-specific, double-stranded break, leading to an edit at the targeted genomic site. CRISPR systems are capable of editing unintended genomic sites, known as off-target editing, which may lead to harmful effects on cellular function and phenotype. In response to this challenge, Caribou has developed CRISPR hybrid RNA-DNA guides (chRDNAs; pronounced chardonnays) that direct substantially more precise genome editing compared to all-RNA guides. Caribou is deploying the power of its Cas12a chRDNA technology to carry out high efficiency multiple edits, including multiplex gene insertions, to develop CRISPR-edited therapies.

Caribou Biosciences is a clinical-stage CRISPR genome-editing biopharmaceutical company dedicated to developing transformative therapies for patients with devastating diseases. The company’s genome-editing platform, including its proprietary Cas12a chRDNA technology, enables superior precision to develop cell therapies that are specifically engineered for enhanced persistence. Caribou is advancing a pipeline of off-the-shelf CAR-T and CAR-NK cell therapies for the treatment of patients with hematologic malignancies and solid tumors. For more information, visit www.cariboubio.com.