The cell therapy space is still very hot with numerous products and almost as large of a variety of cell types in development. While CAR-T (chimeric antigen receptor) therapies are still the main players, multiple CAR-NK therapies are making their way through development. Developing an “off-the-shelf” allogeneic therapy remains a significant interest in the field that is reflected in the distribution of allogeneic and autologous therapies in development. We had a chance to catch up with Steve Kanner, CSO at Caribou Biosciences. Caribou Biosciences is developing multiple allogeneic therapies and working on their first clinical candidate currently in Phase 1.

Thank you so much for taking the time to speak with us. We’re very excited to hear more about Caribou. To start, how would you describe the work you’re doing and what you’re hoping to achieve?

Thank you for inviting me. Caribou is a clinical-stage CRISPR genome-editing biopharmaceutical company developing allogeneic cell therapies for treating patients with different types of cancer. We have two different platforms to generate our cell therapies: One is for allogeneic, genome-edited CAR-T cells that are derived from healthy donors. The other platform utilizes induced pluripotent stem cells (iPSCs), also genome-edited, that we differentiate into natural killer (NK) cells. They are engineered to express a CAR, so we call them CAR-NK cells.

So far, we have been using the CAR-T cell platform to target hematologic malignancies and CAR-NK cells to target solid tumors, and we believe each of these platforms has the potential to target additional pathologies.

It is very interesting how you are treating these platforms as flexible. Maybe you could speak a little more on that aspect?

I believe that genome editing is the key for driving both product efficacy and safety. Our platforms allow us to apply safe and effective edits to a wide variety of cell types. This enables us to go after cell surface targets that are applicable to the hematologic or solid tumor space using the best cell for the job, whether that is a CAR-T or CAR-NK cell therapy.

The other possibility is that these cell products could be combined in the future. If you think about how our immune systems function, all these immune cells participate in preventing us from getting cancer. It's not inconceivable that in the future, one might be able to implement, either in sequence or in combination, both the CAR-NK and the CAR-T platforms for any type of malignancy.

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So, you are moving away from the idea of a single type of product and more towards the concept of the platforms being deployed versatilely to meet the unique demands of different diseases. To follow that up, the CAR-T space is very crowded right now. How do you think Caribou differentiates itself?

Caribou has a number of different approaches that are differentiated in the space. The first approach is our genome editing platform. We have a technology that we call CRISPR-hybrid RNA-DNA (chRDNA, pronounced “chardonnay”), in which the guides of the CRISPR-Cas system have been modified to increase specificity and precision of edits.

The platform uses natural enzymes with our modified guides, primarily Cas12a chRDNAs, to produce high specificity. This means they can perform multiplexed genome edits at the sites of interest but aren’t plagued by the off-target edits that unmodified CRISPR Cas9 and Cas12a systems often experience. That leads to a reduction in the likelihood of translocations that may occur if you're inducing both on-target and off-target edits.

We have the ANTLER Phase 1 clinical trial ongoing now for our first product candidate CB-010, an anti-CD19 allogeneic CAR-T cell therapy being investigated in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). CB-010 includes three edits, the main differentiator being a knockout of PD-1, a major checkpoint that is important in r/r B-NHL because many tumors, as well as the lymph nodes where these tumor cells reside, express the ligand PD-L1. This means there is opportunity for the CAR-T cells to become exhausted through the inhibitory effects of the PD-1/PD-L1 pathway. We've shown pre-clinically that it makes a big difference when CAR-T cells with a PD-1 knockout face a tumor expressing PD-L1. CAR-T cells that still express PD-1, that is the cells without the PD-1 knockout, become exhausted quicker and don't have the same durability of anti-tumor activity as CB-010.

We are finding this remains true in a clinical trial with CB-010. Initial results from our Phase 1 trial show that CB-010 may be resulting in enhanced persistence of anti-tumor activity in a higher percentage of patients than what has been observed with other CD19 CAR-T therapies.

When we dosed the first six patients in the trial with the lowest dose where we initially were evaluating safety, we weren't expecting dramatic efficacy. The exciting element really was that all six patients had a complete response at some point in the trial and 50% of the patients remained in complete response at their six-month evaluations. This is truly outstanding in the field. Whether you look at autologous CAR-T or other allo-CAR-T programs that are advancing in the clinic, it's definitely a unique outcome at this low dose. These results are giving us hope that we can identify the recommended Phase 2 dose in the dose escalation portion of this trial and continue to advance this off-the-shelf therapeutic and potentially make it an option for more patients with r/r B-NHL.

Do you see your technologies as platforms that are more broadly available to the field for collaborations or partnerships?

Yes, the Cas12a chRDNA genome editing platform is quite flexible and could be used across a wide range of applications. It's certainly not restricted to CAR-T and CAR-NK cells. We have been focusing our energy and using it for these ex vivo approaches, but it has the potential to be used across the board. One could apply them to iPSCs for differentiation into many different types of cells. They could have applications across a wide range of diseases.

In addition, it could be used as a direct therapy, which is also known as in vivo therapy, where one directly delivers the CRISPR reagents to organs to make edits on the affected tissue and have an impact on disease in a direct way. Also, they could be used in non-therapeutic applications such as in agriculture.

There are a number of companies interested in developing “off-the-shelf” allogeneic therapies. Do you feel like this is the natural evolution of the field?

There are patients who have been through many therapies and by the time they're ready for CAR-T cell therapy their T cells may not be in sufficient shape to be used for an autologous therapy. For them to undergo leukapheresis is a burden and then they must wait for their product to be made, and they often require a bridging therapy to survive until they receive the CAR-T therapy. At the end of all of that, there is still a risk that the cells may not have performed well either in the manufacturing process or post-infusion to make a robust product.

The natural evolution for the field is to use cells from healthy donors. This ensures healthier cells as a starting material and eliminates wait times because the allogeneic therapy would be previously prepared, frozen, and ready for the patient as soon as they undergo their lymphodepletion regimen, which happens to all patients ahead of the CAR-T cell infusion. Cost is another advantage because we can generate multiple doses per batch from a single donor and have enough material for many patients.

I think a higher level of this concept would be the platform that we're currently using for our CAR-NK cell therapies. These cells are derived from iPSC cells that have been genome modified and are used to make a master cell bank of the modified clone that has all the desired edits. This would provide for a truly uniform ‘off-the-shelf’ product because it has the potential to generate a supply of cells ad infinitum without having to repeatedly rely on healthy donors. You have that master cell bank forever, so that's kind of another level of evolution, if you will, for the field.

Given that the anti-CAR immune response for allogeneic CAR-T or NK cell therapies is still something happening, how is Caribou handling this? Do you think it is a solved issue in the field?

There are many potential elements in allogeneic cells that could be immunogenic. That’s why we're focusing on developing product candidates that are what we like to call “one and done.” You give an infusion and that takes care of the cancer. Your immune system is designed to remove the allogeneic cell therapy. The trick is addressing persistence through genome edits to generate the highest level of anti-tumor activity right at the beginning. In that first month or two, when the cells are proliferating and inducing their anti-tumor activity, that's when they need to do their job. After that, the immune system will clear them out.  

For many of our products we address the potential anti-CAR response by using either humanized or fully human sequences for the antibody portion of the CAR to minimize immunity. Additionally, we are deploying several product-specific methods for increasing persistence. In CB-010, the PD-1 knockout reduces CAR-T cell exhaustion. Our next program, CB-011, which is an anti-BCMA allogeneic CAR-T cell product candidate, is edited to evade the immune system through modified expression of HLA proteins, which help the body identify self from non-self. We are developing armoring and cloaking strategies for CB-020, our CAR-NK cell program, as well.

Regarding your two platforms, what do you think are the big advantages of NK cells over T cells? Do you think you'll eventually see NK cells displace T cells or do they both have their role?

While NK cells have some distinguishing features compared with T cells, I think both have a place in the armamentarium of therapies for cancer patients.

NK cells perform functions in the body that don't require education against antigens. T cells become educated by being presented with antigens and then respond to that engagement by proliferating in response. NK cells are part of the innate immune system, so they recognize stress antigens that are expressed on cells that may be infected, are malignant, or are dying. They're a first line of defense before T cells get fully engaged.

The other nice element about NK cells is that they don't induce a significant amount of cytokine expression and because of that you don't see some of the adverse events in the clinic that are associated with CAR-T cell therapies such as cytokine release syndrome. That makes NK cells an attractive platform in a system where you may want to administer multiple doses.

For example, we plan to implement the CAR-NK platform in the solid tumor setting. Solid tumors are harder to tackle than hematologic malignancies because they exist in spaces that are hard for the cells to get to and thrive in immunosuppressive microenvironments that prevent anti-tumor immune cells from functioning properly. Evidence suggests these barriers may lead to a necessity for multiple doses of cell therapies, and we believe armoring the NK cells will help them overcome multiple solid tumor challenges.

That said, I don't think NK cells are going to replace CAR-T cells. There are going to be challenges, and there may be a possibility in the future of combining NK and T cell therapies together or in sequence for a particular patient or different types of cancer. I don't see them as interrupting each other's progress if you will, but complimentary depending upon what cancer they're used for, how they're used, and what modifications one makes to them.

What do you think are the biggest challenges in CAR T / NK cell therapy development right now?

I believe that compared to autologous cell therapies, the time of manufacturing for the patient can be overcome by allogeneic cell therapies. Also, using CAR-NK cells can prevent some of the adverse events with respect to safety.

I also think that the technology that we're implementing to try to improve activity could enable a better therapeutic index for the product candidate of interest. What I mean by that is if one can improve the anti-tumor activity of the therapeutic, potentially one could administer a lower dose, which has the potential to correlate with a reduction in adverse events. Both the improved efficacy and safety may thereby improve the therapeutic index. That's certainly a challenge that we're taking head on. I think once manufacturing is locked in, allogeneic cell therapies are going to be more robust and reproducible than autologous CAR-T products.

Are there any manufacturing difficulties currently? You can just speak on this generally if you want.

I think there's significant complexity to generating these cell products. You have to be prepared to solve issues that may arise when generating a living therapeutic. It's something that I think is inherent in the therapeutic type because the product is alive. Manufacturing the cells takes special care and attention, and you want to generate products in a way that is both stable and reproducible. I think these are elements that every company is probably challenged with and will improve upon with time as expertise and experience increases.

To address these challenges at Caribou, we have invested in both in-house process development and analytical teams. We believe that building the expertise directly is critical to the success of our programs and have seen the progress as we moved CB-010 into the clinic. The process development team develops the process, scales it, optimizes it, and transfers the entire process to contract manufacturing organizations (CMOs). The CMOs then make the clinical material for us.

Putting that all together, what's next for Caribou? What should we expect to see going forward?

For CB-010, our plans are to share additional data from cohort 1 in the ongoing Phase 1 ANTLER trial before the end of this year. CB-011 is also progressing towards the clinic and being developed for relapsed or refractory multiple myeloma. Our plan is to submit an IND application in the fourth quarter of this year.

Then we also touched on our NK platform. Our plan is to announce the target for CB-020 in the fourth quarter of this year. We will also share some of the armoring strategies that we're developing for the CAR-NK platform that could improve CAR-NK anti-tumor activity.

Thinking into the future, we have another CAR-T cell program called CB-012 that targets an antigen called CLL-1, also known as CD371. Our intent is to investigate CB-012 as a treatment for patients with relapsed or refractory AML. The plan is to submit an IND application for that program in 2023.

Sounds like it's going to be a very busy year for Caribou!

Yes, much more to come, and it's really exciting.

That's great. I'm certainly very excited to hear how it goes and I'll be following your developments closely.

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