On December 12, 2022 Caribou Biosciences, Inc. (Nasdaq: CRBU), a leading clinical-stage CRISPR genome-editing biopharmaceutical company, reported 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 (Press release, Caribou Biosciences, DEC 12, 2022, View Source [SID1234625093]). 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 (AACR) (Free AACR Whitepaper) and Japanese Cancer Association (AACR-JCA) Joint Conference.

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"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 (Free AACR Whitepaper)-JCA shows that ROR1 may be a promising target for several solid tumor indications," said Steve Kanner, Ph.D., 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 (Free AACR Whitepaper)-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.

Details of the poster presentation at the AACR (Free AACR Whitepaper)-JCA Joint Conference are as follows:

Title: CB-020, an iPSC-derived allogeneic CAR-NK cell therapy
Speaker: Rudy Gonzalez, Ph.D., executive director of stem cell therapeutics, Caribou Biosciences, Berkeley, CA
Date and time: Monday, December 12 at 5:30 pm HST
Abstract number: B06
Location: Hyatt Regency Maui, Monarchy Ballroom

The full poster is available on Caribou’s Scientific Publications (www.cariboubio.com/technology/#pubs) webpage.