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How Senti Bio Plans to Use NK Cells to Revolutionize Cancer Therapy

What Do You Do At Senti Bio?

As a scientist, people often ask me  “what do you do?” and while I’m tempted to answer, “I’m democratizing cell therapy for cancer patients,” I know that not everyone at the dinner party will know what I mean. So what do you do at Senti then Alba? At Senti, we are engineering smarter medicines which we hope will enable access to cell therapy to all patients who need it. And this is how we plan to democratize cell therapy. We just came back from this year’s Innate Killer Summit, where we were invited to present on Senti’s novel technology applied to NK cells for the treatment of tumors. It was incredible to finally meet in person in San Diego with leaders in the NK cell therapy space. 

Our team was particularly energized by the open and collaborative spirit where all the researchers at different companies are brainstorming together on how we can potentially solve the scientific challenges in this space to develop powerful new therapies. From my workshop on the use of synthetic biology as a therapeutic strategy for solid tumors and chairing a panel discussion on gene-editing of innate cells, to our CTO Philip Lee’s roundtable session on improving GMP manufacturing of cell therapies to our Director of Research Brian Garrison’s presentation on using NK cells for logic gated therapeutics and his panel discussion comparing the safety of cell therapy to CAR-T therapy, Senti was well represented as part of this growing community.

At the conference we learned about multiple sources of cells, different engineering and manufacturing approaches, as well as some promising results in early clinical trials. But we also learned there is still a lot of progress that needs to be made and unanswered questions around efficacy in challenging tumor indications, such as solid tumors. To try to address some of these challenges, I presented during the solid tumor workshop Senti's approach to engineering NK cells with complex gene circuits to enable improved tumor homing, antigen targeting, and avoidance of immune suppression. 

 

How Senti Bio is Addressing the Challenges of NK Cell Cancer Therapeutics 

It is clear from all the presentations that we attended that NK cells are a promising therapeutic candidate for oncology. Clinical data has sparked interest in this cell type due to anti-tumor activity with a much more favorable safety profile compared to T cells. However, NK therapies have not yet translated to the solid tumor field, mainly due to key barriers that industry is trying to address: 

• NK cells need to better infiltrate solid tumors
• Tumors are heterogeneous and the antigens we are targeting are often also expressed by healthy cells
• NK cells need to show persistence, in order to survive long enough to do their job 
• NK cells need to overcome the multiple suppressive mechanisms that are present in the tumor microenvironment. 

 

We believe Senti is uniquely positioned to make an impact by applying sophisticated gene circuits to NK cells. For example, we can help address the tumor heterogeneity and lack of unique antigens by using logic-gated circuits, in which we will incorporate a safety mechanism that prevents the NK cell from killing healthy cells that also express the targeted antigen. Another area where we can deliver a more potent product is by applying multi-arming mechanisms. By expressing multiple cytokines on our gene circuits, we can sustain the growth and keep the NK cells alive, but also engage and activate the host immune cells to hopefully provide successful and durable antitumor responses. By using our gene circuit technology platform, we are aiming to improve on the properties of these powerful cells, trying to solve some of the big challenges in the field such as persistence, potency, harnessing the patient’s own immune cells, and utilizing controlled release to ensure safety. 

 

How NK Cells Will Help Senti Democratize Cell Therapy

So how do we democratize cell therapies so they can be more readily available to the many patients that could benefit from them? One approach is to focus on developing allogeneic cell therapies, which enable patients to receive cells from a healthy donor instead of having to wait for medicines to be made autologously, or from the patient’s own cells.

At Senti Bio, we chose to take advantage of NK cells since, as their name suggests, they have that killer capacity and their natural function is to patrol the body and prevent cancer. Cell therapy treatments in cancer still have some hurdles to overcome and our hope is that our allogeneic NK cells will enable us to do that in a way that’s optimal for the patient. The tricky part about tumors is they continue to evade NK cells, or anything they deem as a threat really, which is why we are going even further to help NK cells identify the tumor cells and decide, using logic, how to do their job better and kill them. This is where we apply our proprietary gene circuit technology platform.

Even in cell therapies engineered to maximally kill the tumor, there remains the issue of also killing healthy cells. This “off-tissue” effect results in toxicities that patients experience when the antigen on the tumor cell we are “chasing” is also expressed by normal non-malignant cells. We believe that by adding logic, or gene circuits, into NK cell therapies, we can help NK cells recognize and find the tumor so they can kill it, while sparing the healthy cells. Gene circuits may also help to give NK cells extra energy, so they may survive and thrive for longer, thereby becoming more efficacious and able to coordinate with other immune cells to help in the killing of tumor cells. Essentially, I view NK cells as the body’s “first responders” against cancer, and if we can build NK cell therapy to be stronger, faster and have less toxicity than we have seen with other cell therapies, we’ll be achieving our mission of outsmarting complex diseases with more intelligent medicines.

 

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