Genome Editing Tools and Techniques for Cancer Therapies

Ryan Leahy
24 November 2021
Cell Therapy
Clinical Trials
Gene Editing
Gene Therapy
Stem Cells
For this interview, Phacilitate’s Ryan Leahy speaks with Steve Kanner, CSO Caribou Biosciences, about the tools and techniques Caribou are utilizing in their gene edited T cell and iPCS-cell investigational products, ahead of chairing the session ‘CAR-T Therapies: 10 Years On and the Future of CAR-T’ at Advanced Therapies Week 2023.
Can you please introduce yourself and describe your role within the Advanced Therapies Industry?

Hi I am Steve Kanner and I am the Chief Scientific Officer at Caribou Biosciences. I’m responsible for all of our therapeutic development, including all non-clinical R&D.

Caribou is currently working on a variety of different therapeutics. We are, in our heart, a CRISPR genome editing company, and we implement next-generation CRISPR genome editing technology to generate allogenic cell therapies for cancer.

Can you describe what Caribou is currently working on?

The platform that we use is called chRDNA, which stands for CRISPR hybrid RNA/DNA. The reason that we use guides that contain RNA and DNA in the backbone, compared to the natural form in which they are all only RNA, is that we observe very exquisite genome editing, meaning that we get very high efficiency on-target genome editing without the unintended off-target editing. What that means is that when we make a single edit we won’t see translocations occurring because there aren’t multiple breaks in the chromosome.

In our product candidates, we perform multiplex editing when we intend to make multiple genome edits. Even though we have exquisite specificity, we do also have methods that enable us to reduce the likelihood of chromosomal rearrangements asvwell. We combine these technologies to generate a variety of different therapies. Taking healthy donor-derived T cells, we implement the technology to eliminate the expression of the T cell receptor. Then at that site where we knock out the T cell receptor, we insert the CAR. So we know exactly the specific site where it’s inserted. In addition to that, we perform different edits to improve the persistence of these product candidates, because we know they’re allogenic and they can be eliminated by the host quite rapidly.

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There are a couple of different techniques that we use. One is to increase the amplitude of anti-tumor activity by knocking out checkpoints. Expression can lead to the activation of the T cell response of the patient. We play a little trick in which we insert one of the antigens back in when we knock out another to prevent the natural killer cells from rejecting it. Another approach is to enhance the time and circulation.

The first approach we’ve implemented in our first product candidate, CB-010. It’s now in the clinic being evaluated for Hodgkin’s lymphoma. The CAR target is CD-19 and the additional edit to improve persistence is a knockout of PD-1. That’s important in those patients because PD-1 helps to drive tumor growth, and so we can try to obliterate that by knocking it out and enhancing the anti-tumor activity of the CAR-T cells. The first cohort of data was presented recently and it showed that 100% of the 6 patients that were evaluated at the first dose level had complete responses, which is very exciting to see. We are currently escalating to the second dose level and all new data will be presented as it matures.

The second product candidate, CB-011, utilizes another persistence approach. It targets PCMA for multiple myeloma, and we hope that we can retain the cells in circulation longer than they otherwise would be to help promote anti-tumor activity.

The third program is called CB-012 and it targets CLL-1 for acute myeloid leukemia. We Haven’t divulged the different strategies that we’ll use to improve its persistence, but you could sort of imagine what they might be.

There is one more platform that we have built, this one uses iPCS-cells. We employ our genome editing technology to make a multitude of edits to target solid tumors. The host of different armoring strategies that may be required for the challenge of targeting solid tumors may be vaster than for liquid tumors. Consequently, we’re thinking about a variety of different strategies there. We’re going to differentiate those iPSC cells into our natural killer cells because they’ve been shown to have very high anti-tumor and anti-metastatic activity. We’re going to implement the technology there and it may give us the opportunity, because of the safety profile of iPCS-cells, to perform multi-dosing which may be required for solid tumor targeting.


What are you currently most excited about in the cell and gene therapy space?

Over the last ten years, it’s been really exciting to see the emergence of tools for genome editing to be implemented in cell therapies. As an example, there’s the use of hematopoietic stem cells to drive the improvement of various diseases, like beta-thalassemia and sickle cell disease. Folks are now using genome editing to improve the integrity and veracity of these cells to help patients with these types of blood disorders. So that’s very exciting.

Also, the implementation, as I described, of cell therapies as cancer treatments. There are a lot of challenges in targeting cancers with cells, but I think that path has been really opened up by the development of autologous CAR-T cell programs. So we’re excited that now we can really begin to address the challenges that many patients experience when trying to use their own cells and make a more universal approach. The implementation of these genome editing techniques and tools for gene therapy, mean you will be able to directly target different tissues, to address a variety of different diseases where there are mutations that need to be corrected, such as cardiac metabolic diseases and inborn errors of metabolism. There are a lot of different arenas where these various tools are going to be implemented to change the armamentarium of therapies that are available.

 What are you looking forward to about speaking at, and attending, Advanced Therapies Week 2023?

I’d say there are a few things I am excited about. One is the opportunity to hear about new technologies and new advancements in the field. The second thing is to make new connections with individuals in the industry whom maybe I haven’t yet so far. And then, thirdly, to have an opportunity to be involved and lead a panel discussion that I hope will be very interesting and informative for the attendees at the meeting!

Don’t miss Steve’s session, ‘CAR-T Therapies: 10 Years On and the Future of CAR-T’, on Thursday January, 19th 2023.

Join us at Advanced Therapies Week >>