Exploring VISTA and LRIG1 Interactions: Cancer Immunotherapy

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics program and co-director of the Cleveland Clinic Sarcoma program.

Today I'm happy to be joined by Dr. Lily Wang, staff of the Department of Translational Hematology Oncology Research here at Cleveland Clinic Cancer Institute. She's here today to talk to us about targeting VISTA and LRIG1 interactions. So welcome Lily.

Lily Wang, PhD: Thank you, Dr. Shepard.

Dale Shepard, MD, PhD: To start out, give us a little idea, what's your role here, what do you do here at Cleveland Clinic?

Lily Wang, PhD: We came to Cleveland Clinic in 2019, and I moved my laboratory and myself here. So we're studying basic immune mechanisms in the context of cancer. Mostly we use pre-clinical models and also study human specimens, correlative studies, and also trying to understand the basic mechanism.

Dale Shepard, MD, PhD: Okay, excellent. We're going to talk about something called VISTA, we're going to talk about this LRIG1 and T-cell. So let's start really basic. A lot of different people with different backgrounds listening in, what are each of those?

Lily Wang, PhD: Yeah, so VISTA has a long name. It's called V-domain Suppressor of T cell activation, and we call it next generation immune checkpoint protein. So we actually spent a decade working on this molecule understanding how VISTA regulate immune response, particularly in the context of cancer. And we founding, at least in animal models, if we block VISTA, we can induce protective immune response. And there's still significant knowledge gap on how VISTA functions, so that's how our current study shows.

Now LRIG1, it also has a long name. It stands for leucine-rich domain IG-like protein 1. LRIG1 has been studied previously in cancer biology and stem cell biology, but its function in immune cell biology is completely unknown, until our current study that discovered this surprising connection between these two molecules.

Dale Shepard, MD, PhD: So why don't we just go ahead and jump into that. When you did a study to look at the interaction of these two, and what did you find?

Lily Wang, PhD: Yeah, so we initially found that it's through protein interaction assays and basically through the interaction because both the cell surface proteins and through the interaction VISTA activates LRIG1, which is an inhibitor receptor that has a function in T cells to impair the T cell activation, and consequently the cytotoxic T cell cannot kill tumor cells anymore and the tumor will grow undeterred. So that's essentially one line explanation of how VISTA and LRIG1 works to promote tumor growth by suppressing the immune response.

Dale Shepard, MD, PhD: So when we think about a lot of other things we use to treat cancers, there's a lot of duplication of mechanisms and things work by different pathways. Is there any indication that this is something that works on T cells? Is it something that there may be other either pathways it's work through or any other sort of things, because sometimes that's what leads to side effects and things maybe not working as well as we'd like?

Lily Wang, PhD: Couple of different questions embedded here. So first, this pathway is T cell-centric. It's a ligand-receptor interaction, sort of like a lock and key. So VISTA is a key and it goes into LIG1 and activate LIG1 T cells. The implication here is the T cell response is augmented. Now this is cancer type agnostic, meaning it's broadly applicable to many cancers where an immune system play a role.

Now mechanisms, we spent quite a few years and we still hasn't completed the entire study. Our first study was just initial door opener, and we don't fully understand yet that the basic molecular mechanism level, how this whole interaction works and what's the signaling adapters downstream of this axis and what kind of T cell subsets it will affect most and what kind of a cancer type that it will affect the most.

So these require many more years to really stepwise, painstakingly study different cancer type, et cetera. But basically in the mouse model it's pretty clear. Now this axis is quite independent and non-redundant to the other, quote-unquote, "immune checkpoint pathways" such as PD-1 or CTLA-4 that people are mostly familiar with, mostly because the mechanism is so different. For example, the expression pattern of these two molecules are entirely different, very distinct from other known checkpoint pathways. And at the molecular level, the receptor LRIG1, it does not contain a similar signaling domain as the other PD-1 or CTLA-4 protein.

So the mechanism of action we envision is very distinct, and distinction bring the synergy when you combine two. So we envision that combined blockade of these multiple different checkpoint could potentially really synergize and maximize their clinical output. So that's the overall idea here, and that's the reason the study is very exciting because it open a door for many years to come.

Dale Shepard, MD, PhD: So when you think about, you mentioned things we're maybe more familiar with like PD-1 and CTLA-4, and you said that this mechanism, the new mechanism is likely to be effective in cancers that we think about immune therapies being useful. How might this be different from those two mechanisms in terms of do we think that there might be some cancer types that we'd be able to treat through this mechanism that we aren't currently able to? PD-L1 we have 17, 18 different tumor types, but we still have limitations. Can this maybe overcome that?

Lily Wang, PhD: Based on the mouse studies, we have a very high expectation that because it's so distinct that this may be one of the mechanism resistance to the current immune therapies. As you well know, the PD-L1 therapy as well as the CTLA-4 therapy, either of them only cover certain percent of a patient across a broad range of cancer types.

And of course there are many other resistance mechanisms, but we think that this VISTA-LRIG1 pathway is one of the reason that some of these patients don't respond. And how do we know that? Because in the LRIG1 knockout mice and versus wild-type mice, we can treat with, for example, CTLA-4 inhibitors and PD-L1 inhibitors and the wild-type mouse, the tumor just continue to grow, but the LRIG1 knockout mice tumor can regress, which tell us that if we were to use pharmacological inhibitor to block LRIG1 to mimic the genetic deletion effect, then we potentially can really get synergistic outcome.

Dale Shepard, MD, PhD: Talk about using things to block these responses. Is there anything that looks promising yet in clinical trials?

Lily Wang, PhD: There are a couple clinical stage reagent and companies are testing the VISTA-specific inhibitors. The results has not coming out yet, so we look forward to see that. We don't know how any of these reagent, their effect will be on specifically targeting this particular axis because those reagent has been developed a few years prior.

Also, that's one of the challenges actually targeting VISTA in the past decade, because the initial discovery of VISTA was 2011 when we published the first paper, but it's been more than a decade now. And I think there are a couple of challenges on this, which, for example, it's really ambiguous in terms of how VISTA function in vivo. And this axis will answer some of the questions, long-standing questions, but potentially there are other aspects we haven't uncovered.

So without knowing the precise mechanism, it's really hard to pinpoint how the drug was action-wise, how does it work. And if it's not working, is it because it missed this axis? And the second challenge is VISTA has several other binding partners in addition to this receptor we discovered. And it is not clear whether it's possible to target all of those simultaneously or whether it's even necessary to do so. Potentially too toxic if you want to completely take on VISTA every single aspect of it and potentially it's really not necessary. A partial blockade like this, just targeting LIG1, LRIG1 axis may be effective enough.

So these are the long-standing questions. And I think finally now we have this very precise mechanism to look into. So we look forward to the next few years of study to try and really answer these questions to see how we can better target this VISTA in general and this particular pathway to benefit cancer therapy.

Dale Shepard, MD, PhD: So I guess you're suggesting that there are drugs that are maybe targeting VISTA, but maybe it would be better to be targeting specifically LRIG1 and that VISTA connection?

Lily Wang, PhD: Certainly that's one of the hypothesis, because in the animal model we see very similar outcome if we knock out LRIG1 versus if we knock out entirely the VISTA protein, therefore indicating LRIG1 may be the dominant axis where the other VISTA binding partners doing other different aspects may or may not be critical, and maybe even preserve some of the immune functions, so that can prevent overt systemic inflammation, which has the side effects we see in general by blocking immune checkpoint, because these immune checkpoint is being installed there have a good reason to prevent overall systemic inflammation that can be really damaging to a person's house.

So that's one of the downfall many times for immune checkpoints inhibitor therapy, many patient cannot go on with the therapy if there's a too severe side effects.

Dale Shepard, MD, PhD: Yeah, the inflammatory part. So the thought is that targeting VISTA, LRIG1 maybe not only could be effective and people have resistance primarily to the tumor, but intolerances from a toxicity standpoint as well.

Lily Wang, PhD: Possibly. Yeah, we're testing that in animal models and see if that's indeed the case, so minimizing.

Dale Shepard, MD, PhD: Yeah, makes sense. When you're looking at tissue interactions and things, what have you primarily been focusing on in terms of tumor types?

Lily Wang, PhD: Previously we did extensive modeling on melanoma. So from there we gained some understandings and really encourage us to branch out. For example, looking to other solid tumor space where we know there's a high level of VISTA presence, and the LRIG1 is new, so we don't have too much data yet, so we're looking into that.

So we established extensive amount of collaborations with the colleagues here at Cleveland Clinic looking to multiple solid cancers, for example, breast cancer, head and neck lung cancer, et cetera. Try to understand this landscape of the expression first. Also utilizing the specimen to see if we can block on these because we're developing laboratory-grade inhibitors, and if we can block at least we can rejuvenate some of these patient-derived immune cells, and that will be more encouraging for the future clinical translation.

Dale Shepard, MD, PhD: When we think about your comment on looking at expression and getting a sense for essentially what ultimately we hope would be tumor types that this could be effective toward. Have there been tumors that you've seen good expression where we wouldn't ordinarily think about using, say, PD-L1 or CTLA-4?

Lily Wang, PhD: That's a good question. We haven't looked into this of a tumor type only because the study was new and then we try to start with a tumor model that's more sensitive or responsive to some level of immune modulation. And the situation you're describing, there are a couple of tumor models that's really resistant to the murine mouse version of these checkpoint inhibitors. And these are the next level of study that we're also planning to do to see if those resistance could be partially because of this mechanism, so we do combinations. So that's the second level of study we also plan to do.

But definitely those are the goal because the resistant tumor are really the target for these kind of combinations, therapeutic strategies.

Dale Shepard, MD, PhD: And then I guess you mentioned combinations, is there a thought that perhaps these VISTA or LRIG-1 mediated therapies could ultimately be used in combination with the traditional checkpoint inhibitors for instance?

Lily Wang, PhD:

Very likely, yeah, yeah, because still I think the PD-1, PD-L1 access and the CTLA-4 are really the first level of the gates or the break, so to speak. But in addition to that, so the VISTA, LRIG-1 level maybe is accessory, the primary break is out and the secondary break in terms of the analogy to a car. So combinations more likely to be more effective and solving the current problem, because the field is already advanced enough that there's many patient can be already having a good survival benefit with a single monotherapy regimen. So we should take advantage of that and then try to do the combination.

Dale Shepard, MD, PhD: So a lot of interesting work, really, really interesting area. What are we looking forward to having you back and hear about next?

Lily Wang, PhD: Definitely the translational potential. So we are working hard right now. We have a couple of screening strategies based on our previous studies so we can screen inhibitors, and so we're developing that laboratory grade and we'll translate that to testing in preclinical models. Hopefully soon enough this will be giving a promising hint that can be tested in patient population, which we hope Cleveland Clinic will be the first to test these.

Dale Shepard, MD, PhD: I guess just as we close, you've mentioned it a couple of times, but I just want to make sure people have a grasp of this. This is not easy work and it's not rapid work. And so how long has it taken to get to this point? Because I think this is actually an important point that sometimes people think these are these quick things that we find and get a drug, we move on. So this has been a long effort.

Lily Wang, PhD: Very long. I'm glad you asked. I have to say the initial discovery was made in 2015 in the laboratory, so it's been nine years, but from the concept we need on developing two experimental models and create de novo reagents, and not everything's commercially available as a kit. And so we created a lot of de novo reagents, antibodies, mouse, and many years of figuring out in the dark initially. And also takes a lot of twists and turns because we're not experienced initially about the biology taking the other receptor like the PD-L1. PD-L1 as a poster boy, but the biology is different. So it took quite a detour, and I'm really happy that we did not give up.

Dale Shepard, MD, PhD: Yeah.

Lily Wang, PhD: Yeah, perseverance.

Dale Shepard, MD, PhD: Well, it appears the labor of love, and it looks like you're starting to get some good rewards here, so...

Lily Wang, PhD: Thank you, thank you.

Dale Shepard, MD, PhD: ... appreciate everything you've done and your insights, and we'll look forward to hearing more.

Lily Wang, PhD: Yeah, yeah. We look forward to that too. So all the trainees are very excited, and we have a renewed and revived energy now because finally we see that this is the right direction.

Dale Shepard, MD, PhD: Very good. Well, thanks for being with us.

Lily Wang, PhD: Thank you so much.

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