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October 13, 2022 by Ania Wronski 13 min read

The Hills and Valleys of Precision Medicine with Aaron Llanso

In the latest episode of On the Drop, Ania Wronski, PhD, sat down with Senior Director of Clinical Applications, Aaron Llanso. Here, Aaron discusses his untraditional career path, his personal experience with cancer, and how truly impactful the Tapestri scMRD Assay for AML can be for a patient’s journey.

Ania Wronski: Hi everyone and welcome again to On the Drop. Today I’m joined today by Aaron Llanso who is our Senior Director of Clinical Applications. Welcome, Aaron.

Aaron Llanso: Thank you, Ania. Great to be here.

Ania: So Aaron, you’ve been working with Nicole Ovadia who in our last episode discussed the new Tapestri scMRD Assay for AML. So, can you tell us a little bit just to remind people what MRD is?

Aaron: Sure. So, MRD stands for measurable residual disease. The term has sort of evolved. It used to be minimal residual disease, but I think the field is really moving towards a more accurate representation of the ability to detect cancer cells that may be persisting after the completion of therapy. So when a patient has been treated for cancer, whether it’s chemotherapy, radiation, or other types of treatments, can we detect residual cells that would be the harbinger of relapse, and that’s really what MRD is referring to.

Ania: It’s a little scary. Generally speaking, how many patients who become MRD positive end up relapsing?

Aaron: It’s an interesting question. It depends on the indication, of course. The statistics vary a little bit, and of course by type of treatment, intensity of treatment, age, stage of disease, etc. But cancer is genetically heterogeneous and we know that that drives evolution of the disease and perhaps subsequent risk for relapse. As we are good at killing most clones or most cells indicative of disease, but it’s what we leave behind that can drive that relapse – the MRD cells.

As far as how many patients will receive an MRD positive determination that will go onto relapse, I think it’s fairly high, it’s a fairly strong predictor. But the point is, is I think where we are in the field today is there’s a number of methodologies to detect MRD. Again, it’s sort of indication-specific, or sample type specific. There are false positives and there’s false negatives, and that creates a lot of obvious problems.

But from a patient’s perspective, to be told that you’re MRD positive is obviously a terrifying thing to hear, because you start imagining what options do I have left? What are the next steps? Does this mean more therapy? So to have that not play out, obviously there’s some good things to that. There’s upside, you don’t want to have a relapse, but there’s a lot of psychological impact to receiving a false positive or a false negative of course, because if you receive a false negative, the inverse can be true. All of a sudden you’re thinking that you’re doing quite well, and some of these patients do become symptomatic and ultimately relapse again.

I think one of the biggest goals that we have in trying to move the field forward and improve on this paradigm is really to improve the accuracy or the comprehensive detection of MRD cells for more accurate prognostications for patients.

Ania: Absolutely, it’s incredibly important. Can you talk a little bit about your background and how you come to this slightly differently than most researchers?

Aaron: So I have a slightly non-traditional background, I guess. I started out in high school working in a couple different lab positions doing internships, and I was lucky enough to do a stint at the NCI in doing some skin cancer research, but I didn’t really enjoy the lab work originally, and so I changed directions. I wasn’t sure what I was going to do, but ultimately I found myself more on the business side after college.

So I’ve been more on the commercial side of the industry and I have really enjoyed doing that in the last 15 years, although I’ve sort of transitioned to more product management-focused developmental opportunities working with thought leaders in the field to build on new assay concepts and things. But I think I have a slightly different perspective, and certainly I’m not unique by any stretch, but I, like many others in the field, am a survivor of lymphoma as well.

So having gone through that experience and also having been working in the field, I sort of have perspective on both sides of the coin. Developing products that hopefully will impact patient care, but I’ve also been the patient on the receiving end of what our current system has to offer. I try in everything that I do to connect those perspectives and make sure that the end justifies the means, that there’s going to be an impact for what we’re doing.

That’s what I love about so much of the work that we’re doing at Mission Bio, is that we really are focused on not just precision medicine as a buzzword, but how can we actually change the world for some patients out there and empower doctors to make better treatment and care decisions for these patients that change outcomes. So that’s obviously a huge aspiration, and there’s many, many groups and companies out there that want to do that, but that’s a huge motivator for me in my approach to the work.

Ania: We’re very truly lucky and blessed to have you,  and bringing that energy and that perspective, because I think it’s easy when you’re in the grind to forget that there are real patients behind this, and so I always value your perspective and the way that you lead, because it is really important to keep that goal in mind, especially when things might be a little bit challenging. So, you work a lot as well with different patient advocacy groups. Can you talk a little bit about your work there?

Aaron: Yeah, so over the last several years since my own diagnosis, which was in 2015, I’ve always been involved to some degree, more sort of on the philanthropic side, but I’ve been trying to get more involved actively in some of these community-based organizations. Obviously, my own experience impacted that and really ignited a drive me to participate more.

I’d be remiss to not mention the Leukemia & Lymphoma Society right off the bat. I mean, they’re one of the biggest organizations out there. They do tremendous work in the field, and it’s been a real pleasure to spearhead some of the initiatives that we’ve done internally at Mission Bio to support Light the Night and Big Climb and those types of things. I’ve participated in the executive challenge and tried to really drum up more support for the organization at large.

But in a more direct patient impact setting, I also have been volunteering with the Lymphoma Research Foundation, and that’s more in a capacity of peer-to-peer sort of patient engagement. So when there’s a newly diagnosed patient with lymphoma, this organization, among many other things that they do of course, but they will connect survivors with experience of what is it like to be on chemotherapy? What is it like to get radiation therapy? How did you deal with all of the psychological gymnastics that you have to learn to do in that kind of setting?

So, that’s been an interesting opportunity to rely on my own experiences to help coach someone who’s just walking into it through those initial sort of dark days, and really just understand what lies ahead and how to conceptualize what they’re going to be facing. That’s been pretty rewarding work and stuff that I’ve done some of, but have really found that to be quite rewarding.

Ania: Absolutely, I’m sure. They’re very lucky to have you as well. I can’t imagine how much easier that makes the already tremendously difficult process and time in people’s lives to have someone like you to help them through that, because I can imagine it’s terrifying to say the least.

Aaron: Yeah, well, when I was first diagnosed, I didn’t reach out to those groups, I wasn’t exactly aware of them. So, I think it’s an interesting opportunity for someone like me on the other side, so to speak, that I’m incredibly fortunate to be here. But in those days and weeks following my own diagnosis, I was scouring the internet for experiences.

Obviously, there’s just way too many people that have come before me in this kind of experience, but they’ve blogged and put up websites of their own experience. Just reading through all of that really helps you to put into perspective what am I facing? What does the day-to-day look like? I really appreciated the ability to find those resources, and then to be able to channel that through an organization in a more formal process was excellent. I mean, I was really happy to be able to get involved that way.

Ania: Absolutely. So if we go back to the MRD work that you’re doing, how does that dovetail with what you’re trying to do from a patient perspective?

Aaron: Yeah, so I won’t take credit for MRD by any stretch, it’s not my idea, this has been in the field for a long time. I think it wasn’t even necessarily my idea to focus Mission Bio’s technology towards this application, but I’m privileged to help carry the torch a little bit in channeling some of our developmental resources and application development towards this area.

The goal here I think is really to improve on the accuracy of an MRD assay. Again, I sort of rely on my own experience and why I’m so engaged and really passionate about this particular project at Mission Bio is that in my own experience, in lymphoma and I had Hodgkin’s Lymphoma, the primary readout of complete remission is a PET/CT. So, they’re looking for metabolic activity that would be indicative of perhaps residual cancer.

PET/CT scans are incredibly sensitive. They can find very minute differences, but they’re not specific at all. That’s a problem that I see across many different tool sets that we have in the industry. So in my own experience, I actually never achieved a PET negative response, so I was always considered to be MRD positive, and that set off a flurry of tumor board reviews and getting second and third opinions.

There’s just a lot of anxiety that went into that, ultimately to find out that you know what? PET/CTs can report out a positive area in the lymph nodes that were treated due to inflammation in response to the actual killing of tumor cells. So in some sense, it’s a positive. If I’m not mistaken, I believe that actually correlates with better outcomes if you have that inflammation positivity, but it wasn’t reported that way.

All of a sudden we were talking about increasing amounts of therapy, which has its own risk for secondary malignancies. So there’s more impact than just the anxiety and the psychological aspects, but it often leads to more aggressive treatment plans, which can increase a patient’s risk for later in life toxicities and secondary myeloid malignancies and so on.

So, I always think about that when I’m talking about the strategy behind an MRD assay that we want to build. PET/CT is one example where you’re measuring the metabolic rate of these cells. Other approaches rely on sequencing or flow cytometry, but they’re all individually single-analyte assays that measure one attribute of the cells that could be or could not be malignant.

I think that that’s sort of akin to looking into the spotlight, whereas we could probably improve on the specificity or more comprehensive disease detection if we have a couple defining attributes of disease.

Ania: How is our approach and the use of Tapestri different in that aspect?

Aaron: We’ve gotten through some technical validation that’s really supportive of the multi-omic approach in proteogenomic assessment specifically where we’re measuring surface protein expression from these cells and integrating that information with the genotypes or the clonotypes of those cells. So, that can help us to uncover disease that can masquerade by changing its protein signature and appearing normal, but inside the cell we find the disease-defining mutations indicating that it is in fact residual cancer.

Of course, we know that there’s evolution in disease, and so the actual mutations can be different cell to cell. Even if some of the variants are the same, we might see different combinations of mutations. So, we’re learning to correlate these protein signatures with these genotype signatures and more comprehensively map out malignant signatures.

But ultimately, I think the goal here is to more comprehensively define what disease looks like and so that we can whittle away at the false positive and false negative margins. We’re not there yet to make any astronomical claims, but we’ve got a lot of data to generate. But the early proof of principle studies that we’ve done have been extremely encouraging, so we’re very optimistic about the opportunity here.

Ania: It sounds incredibly exciting and I know we’re all very excited entirely about this as well. I think there was a lot of excitement just when we held the scMRD Assay for AML Summit in New York City where you were joined by academic collaborators, other academics, as well as pharma groups. Can you tell us a few highlights and things that happened there?

Aaron: Yeah, so that was really exciting for me and for the team at large. This idea has been in the works for probably at least the last two years, and about a year, year and a half ago or so, we started kicking off the initial collaborations that generated the first proof of principle demonstration of this new MRD assay that we’re developing.

This was really a milestone event for us to actually get everybody in a room from different perspectives, from industry, from academia, from clinical pathology, to share ideas, perspectives, all with the goal of moving the field forward. This wasn’t just a Mission Bio event, this is about what does this assay need to accomplish? What are the needs that are unmet right now in this workflow?

We were really privileged to have Dr. Ross Levine from Sloan Kettering, who’s been one of our lead collaborators together with Wenbin Xiao, Troy Robinson and Dr. Misha Roshal, all from Sloan Kettering to share some of the first data and insights from their proof of principle studies with this approach. So, that was really exciting and stimulating.

We had a great panel discussion afterwards sort of debating the pros and cons of existing technologies, and how can we improve on what we’re doing today with novel assays. Especially as we’re in this developmental phase, that it’s hugely valuable for us as a company to get that feedback and incorporate that into the roadmap that we’re executing on.

Ania: Yeah, absolutely. Was there anything that really stood out to you as highlights of that meeting?

Aaron: I think there were some great highlights around how this can be used not only in clinical practice, which had initially always been my primary target, because obviously I’m sort of bringing that patient perspective as we talked on. But there’s also immense interest in the clinical trial space from our pharma partners, and so it was really great to have Christina Guttke from Janssen speak a little bit on the industry perspective and share some of the impact consortium’s views on how they’re approaching more of a systematic analysis of what’s available out there. How do we move this forward in the clinical trial space to hopefully achieve what’s called a surrogate biomarker for overall survival?

The idea there is really instead of waiting five years to see if we’ve improved patient survival compared to the existing standard if they’re testing a new drug, can we perhaps use an MRD assay to show that we’ve eliminated disease comprehensively, and therefore use that information as directional or reliable efficacy data and hopefully maybe one day even source FDA approval based on that information.

We’re not there today, but that would bring drugs to market faster that hopefully would be more efficacious and would impact patient care for the better. So, I think it was a great highlight to hear the clinical trial perspective from our pharma partners on how this could be a game changer for them too.

Ania: I really like the way that all of the panel members kind of discussed MRD as such an interesting diagnostic tool. I think Chief Medical Officer Dr. Todd Druley says it really well, in that we’re so focused on diagnosing cancer as early as we can, which I think is obviously very important, but it’s usually for surgical intervention, when we’re now so much more sophisticated from a pharmaceutical perspective.

I think something like the Tapestri platform can really help show that tumor so much earlier on, where it’s easier to treat something that’s smaller than it is larger and you don’t have to go through the surgical margins and a lot of the complications that go with surgery. So I think it’s a really exciting time, where in addition to the cost of genomics coming down, something we talked about on the last episode, we’re seeing this introduction of these new much more sophisticated tools that can really help combine with some of these newer technologies and newer drug approaches as well. So, I think it’s really exciting.

Aaron: Yeah, definitely. We know that outcomes improve the earlier we can detect cancer, and Tapestri has actually revealed that we can detect a lot of the rare sub-clones that we select for particular therapies that drive a more aggressive-resistant relapse later on.

I spoke briefly about this in my talk at the scMRD Summit, but I also have this vision of one day being able to use a multi-omics single-cell assay like Tapestri to actually detect and intercept precursors to disease prior to actually becoming an C2 tumor, or in perhaps a high-risk stage where we know that these cells are likely to transform, but they haven’t actually become a cancer yet. I think moles are an easy classic example, is do you have a dysplastic mole that the dermatologist wants to remove and they say, “It’s a good thing we got this one, it didn’t look like it was on a good path,” right?

We’re starting to see companies come out with that intention specifically to develop targeted therapies, as you mentioned, the complexity of our pharmacologic capabilities have really advanced dramatically. The more that we can shed light on the dynamic features of these tumors that might be druggable or targetable. That pertains also to that precursor environment. I could imagine improving the annual blood tests, where instead of catching things in stage one, stage two, we’re catching it before it actually becomes even necessarily a stage zero, if you will. That’s, I think, really exciting potential for the field.

Ania: I completely agree. Now, one thing that I’m very passionate about is accurate science communication to the community. So can you tell us very openly, I guess, how long is this going to take to actually impact patients? Because we always say we’re going to cure cancer, but it is a very long road to develop some of these things and to get clinical approval. So, how long do you think this is going to take?

Aaron: That’s where I put my patient hat on and say it’s never fast enough. But realistically I think that’s a good question, because there’s important hurdles in place that we need to clear to show that this is reproducible, that it’s actionable, that there’s clinical utility for this approach, and that we’re not just doing fancy science for the sake of fancy science, it needs to actually impact how we do things and for the better.

So, where we are today really is that we have, I think, a robust technical demonstration of the workflow and we have a lot of the data points that we’re connecting now to show that we’re very likely to impact the way we want it to and the way we’re all hoping it will. But that’s what has to come next is many, many more samples have to be run with clinical outcome correlation to show that with the information that we can reveal using this approach, something would’ve been done differently by the clinician. Or perhaps as new therapies are being developed, had we known that this feature was present on this cell, we could have actually used a different drug or a combination of drugs to more effectively treat that patient.

We don’t have that data yet, but I’m optimistic that we should have that probably within I’d say the next I’d say six months to a year. There’s a lot of folks in our early access program that are focused exquisitely on that problem ahead. So, we’re getting all of our ducks in a row to align across multiple sites and standardize the protocols so that we can build a larger clinical dossier that demonstrates the utility of this platform and this approach.

So, the assay’s available now for research use and we need that to be available for researchers to generate these data sets. But ultimately in clinical practice, we’re probably I’d say a year or two off from that. That’s probably on the optimistic side, because it always takes a little bit longer than you hope, but that’s, I think, what we’re looking at.

Ania: Yeah, absolutely. Well, thank you for highlighting that. I know we’re nearly at time, so I want to ask my final question, which I ask everyone, which is what is your favorite ice cream flavor?

Aaron: Ah, I got involved in this one on the last comment thread in LinkedIn when you had Todd Druley on. I’ve got to say green tea.

Ania: Green tea, okay, interesting. I would not have guessed that one from you. Maybe not matcha, but green tea like the-

Aaron: Either way, either way. I like both. They’re hard to find, so I’ll take what I can get. But yeah, I don’t know when I discovered it, but if it’s out there, I’ll go to it every time.

Ania: All right, good to know. We’ve got to stock some green tea ice cream in the office then next time you come.

Aaron: There you go.

Ania: Well, thank you so much for joining me. This has been a pleasure!

Aaron: Absolutely, thank you for having me on.

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