Evaluating Engineered Tregs for Potential in Treating Multiple Sclerosis

Travis Drow, BS

Engineered regulatory T-cells (Tregs) are currently under investigation for the treatment of multiple sclerosis (MS) and other autoimmune diseases by the lab of David Rawlings, MD, the director of the Center for Immunity and Immunotherapies at Seattle Children's Research Institute. Travis Drow, BS, a research scientist in the Rawlings Lab, presented murine data from the lab's work at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore.

At the conference, CGTLive® sat down with Drow to learn more. He discussed the early findings and the rationale behind seeking to treat autoimmune disease with Tregs.

CGTLive: Can you give some background about your presentation at ASGCT this year?

Travis Drow, BS: I'm a research scientist in Rawlings' Lab. For a number of years now, we've sort of had a program where we've been trying to engineer Tregs from bulk CD4 T-cells using homology-directed repair. That actually started before I came into the lab; that's been an ongoing project for several years and is now part of a sponsored research agreement with Genti Bio, an early-stage biotech company that's trying to bring this engineered Treg platform to the clinic for diseases like type 1 diabetes (T1D), which I gave a talk on last year. There were other representatives from Genti Bio there last year, and I think nothing on T1D this year. But it's definitely their main program, the GNTI-122. In my role in the lab, I've been working on this Treg project and trying to apply the engineered Tregs in different models of autoimmunity, so diseases like MS, which is what I'm presenting on this time.

What were the key points you presented?

The data I presented this year was all mouse work. Essentially, we engineered myelin-specific engineered Tregs. The idea being that the T-cell receptor (TCR) that sees myelin would drive the Tregs to the site of initial T-cell priming and to the local site of inflammation. That's perfect for tissue-specific autoimmunity, like MS, where [there's a] local site of inflammation where there's demyelinating lesions, and [you have] the repropagation of these cells in secondary lymphoid organs. It's really an advantageous approach. What we saw delivering myelin-specific engineered Tregs in this mouse model of MS—when delivered before the antigen-priming, within the model, essentially, looking at the ability of engineered Tregs to suppress initial T-cell priming and sort of the background immunology before these cells actually go to the central nervous system (CNS)— but when delivered in that setting, the engineered Tregs completely suppressed, or near completely suppressed, development of symptoms in those animals. With polyclonal-engineered Tregs, those not expressing the myelin-specific TCR, there was really no effect whatsoever. So it really drove home the point that the the myelin-specific TCR was the key.

Then after those experiments, when when we delivered the cells in a setting that more closely aligns with what you would be doing in a patient, well after the initial T-cell priming, and as the cells are actually trafficking to the CNS, or whatever organ it is—when we delivered the cells 7 days post, in this sort of later stage, we did witness a reduction in disease severity across 2 different doses of cells, which was really encouraging. The next step is sort of like, what else can we do with these cells? How else can we can we look at what they're capable of in the setting of MS?

What makes Tregs a good fit for tackling autoimmune disease?

In a lot of broad autoimmune diseases, dysregulated Treg is sort of like a hallmark of the disease—it's something that's uniform across several autoimmune disease indications that you'll see that the patient has dysregulated Treg. Dysregulated Treg totally fits with an unchecked immune system. Being able to use the [engineered] Treg as sort of a band-aid for the immune system I think is a really nice approach, especially for tissue-specific autoimmunity, where you can essentially engineer the cells to go to a specific place and do a specific thing—where there is inflammation, or in the case of MS, demyelination, or in T1D, insulitis—destruction of the beta cells.

This transcript has been edited for clarity.

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