A Conversation with UCSF Innovators Max Krummel and Michael Kattah
In a recent discussion, we sat down with two esteemed UCSF professors, Max Krummel and Michael Kattah, to explore their collaborative work in the field of immunology. We also discussed the ambitious initiative at UCSF – Autoimmunoprofiler (AutoIPI), an academic-industry consortium focused on autoimmune disease, aiming to unlock the mysteries of the human immune system. Together, they are shedding light on the intricacies of the immune system and paving the way for innovative therapeutic strategies.
Here are some highlights from this discussion:
Professor Max Krummel, a renowned immunologist at UCSF, is known for using state-of-the-art technologies to study the mechanisms of immune system regulation with the goal of understanding and applying the immune system to improve human health. In the course of his career, he has made discoveries that have led to some critical advances, including co-discovering the anti-CTLA4 checkpoint blockade drug, the first approved immunotherapy for cancer, while earning his doctoral degree at UC Berkeley, as well as the next-generation immuno-oncology therapies through Pionyr Immunotherapeutics. Max shared with us the origin of the immunoprofiling initiatives at UCSF.
Max Krummel: "...the origin story of that obviously starts with the observation that some of the immunotherapies we were making at the time worked in some people, and didn't work in others. So you knew that you had in the world at least two classes of a thing you called the same disease, whether it was melanoma or ovarian cancer. So you had some biology about some people that was different from the biology about other people."
Among many people who work with Prof. Krummel is Prof. Michael Kattah, a gastroenterologist who earned his medical and doctoral degrees in immunology at Stanford University School of Medicine. Prof. Kattah is currently working as a physician-scientist at UCSF. He cares for patients with inflammatory bowel disease (IBD) and other disorders involving the digestive tract, and his research focuses on ways to better treat patients with IBD. Prof. Kattah brings a critical clinical perspective to this research, and he shared his frustration with the unpredictability of treatment responses in IBD patients.
Michael Kattah: "I often tell that story of a patient that we saw and tried multiple different therapies over the course of two years, I think three or four advanced therapies before we tried one that we really didn't think was going to work. And he responded beautifully and was in a deep remission, off of steroids, like thriving after we tried this sort of, I think fourth- or fifth-line agent. And it would be great if we could know upfront who's going to respond to what and just start off with that medication."
Immunoprofiling initiatives at UCSF
These two researchers are collaborating on Autoimmunoprofiler, a project that's transforming how we understand and approach autoimmune disorders. This initiative is an extension of Immunoprofiler, a cancer focused consortium aimed at collecting and analyzing flow cytometry, RNA-seq and imaging data from fresh human tumor samples across a wide range of tumor types. What was the motivation behind the Immunoprofiler consortium?
Max Krummel: “So, ultimately, Immunoprofiler was an attempt to say, look, let's take apart this thing that we call cancer. We know it has some distinctions in its immune states. Let's figure out how many there are. Because you can't treat it as if it's one thing. This is like your IBD problem. You know that patients are going to, with some statistical probability, respond to drug A better than drug B, but you don't know which is which until you do what you're doing right now…"
Autoimmunoprofiler, on the other hand, uses single-cell omics to profile freshly collected tissue samples with matched peripheral blood samples from select clinically well-annotated patients with autoimmune diseases, including Sjögren’s Disease, Type 1 Diabetes, Scleroderma, Ulcerative Colitis, Crohn’s Disease, Lupus Nephritis, and Cutaneous Lupus. So, why did the UCSF team decide to tackle autoimmune diseases in this way, and how are the two consortia related?
Max Krummel: “I think that our hope with Autoimmunoprofiler was to understand autoimmune diseases and that pattern, that class with the idea that then the matching of what's in the tumor space versus what's in autoimmune space actually would help us let cancer people cure autoimmune people and let autoimmune people cure cancer people.”
For Prof. Kattah, this detailed profiling across multiple autoimmune diseases allows for several unique avenues of research that could lead to a better understanding of how the human immune system works.
Michael Kattah: "I think what I really like about the kind of work that was done as part of the AutoIPI consortium is that we have the snapshot of the biology at the moment when we collect the sample…. a snapshot of the immune system in that state, in the tissue. And then when we bank the samples and we're able to grow the epithelial cells in culture and we can actually grow the fibroblasts also from that tissue and start to try and reassemble these in vitro, now we can look and see how they react to stimulations.”
“It's great in terms of you can learn more I think about inflammatory bowel disease by comparing and contrasting to all these other disorders and vice versa than just by being in a silo and saying, well, we're just going to look at IBD. But I mean, there are important differences. For example, the anti-IL17 works great for psoriasis in the skin but makes Crohn's worse. And so why is that, even though IL23 works in both?
Max Krummel: “And they're both called autoimmunity. So you would think that tamping down the immune system in one system would tamp it down in the other. But no”
Michael Kattah: "So I think the idea of looking in the blood and the tissue in inflammatory disorders that affect all these different tissue types, you can really start to see what the immune pathways are that are abnormal in all these types of patients versus just certain types of patients.”
Max Krummel: “I think one of the things you're getting at that I think is a trend in immunology right now is that it used to be thought of as hot or cold, like a binary, or your immune system is either super active or it's inactive…. But I think when you start to think what you're describing with the IL17, here's a drug that works in some autoimmunities and doesn't work in other ones, both of those we thought were cold. But if you actually change your thinking and say, well, it's not about coldness, it's about identity, about what's going on in each of those...”
The Sharing of Resources, Expertise and Research findings in Academia-Industry Partnerships
Through his work on the two initiatives, Prof. Krummel and his colleagues have forged multiple partnerships with pharmaceutical companies. One of the questions we hear often from faculty is how to engage with industry. How did industry partners come into the Immunoprofiler story?
Max Krummel: "Industry came in because I gave a talk at a company and I told them what we would do with this, I guess maybe devious but pitchy kind of thing, saying this isn't just a question that is academic. This is a question that is really important for pharma because if you want to make the drugs, because that is their role in the world, they make the drugs that treat some of the biology that we understand - if you want to do that, you should be asking this question. You should be wanting to know this question. And from everything from an investment standpoint to just a pure success standpoint, if you are putting the right drugs in the right patient, you're going to get better results. So, there was just a slide or two that I put at the end of a talk where I was telling them what we were doing fundamentally, and then we got a call.”
Years of collaborative work with industry partners have provided valuable experience and key lessons about what it takes to foster successful collaborations. What tends to work well? What are the greatest advantages for UCSF faculty?
Max Krummel: “I think it works really well when you can come to a two-sided discussion about what needs to be done. Because the motivations are somewhat different ... And I think the thing that we've sort of seen that has been the best is when both sides of that are conversing and coming to the same need of let's say data, but that relies on pretty strong partnerships and it relies on people that are innovators on the pharma side that want to come across and say, we want to support that data and it needs to have the following functionalities to it. And then you need to make sure that both sides put value into that. And when you do that, it works really well.”
Michael Kattah: “I have to say, I think one of the big advantages for us is the rigor. Because I think in industry when they're used to running clinical trials, it's like the term that Steph Targan at Cedars-Sinai has used is reagent grade patients, strict enrollment criteria, and you have everything really documented very well, the enrollment, the follow up, all of the clinical metadata, and putting all of this together in a way that another party, like the industry sponsor can then download the data and interact with it. If something's not clear, you find out quickly. And I think for us, having to synthesize everything in a very straightforward way has elevated the way that we do it. It's also raised the bar in terms of the goals.”
Ambitious collaborative efforts come with many challenges, some of which are logistical, and others require a large investment in time and money to execute. In that regard, industry partners were critical in enabling both of these consortia.
Max Krummel: “The biggest question about that was how to share. Because typically, pharma companies and even academics hoard their data until they're ready to make a product or write a paper or something like that. So the biggest thing around that was to figure out how to get it so that multiple groups would say, Look, let's all collect the data. We all have our own questions. Is there a way that we can share this cost and the effort to collect all that data? And it worked really, really well… And one of the things that allowed us to do that is also to put a lot of effort into trying to get really high-quality data. It's super hard…”
Michael Kattah: “I think I remember you telling me that the traditional funding mechanisms, when you sort of pitch this to some of those, the budget that's required to do this massive kind of transformational project, it just wouldn't have been possible without this innovation in the way that you structured it.”
Max Krummel: “I think the thing that I had to learn about was that, of course, this is obvious, but the conversation with the patient, the consent process, and sometimes they aren't going to give their consent, so you have a failure rate associated with that. It's not failure, it's just choice. And so all of those things are costs. You put value on them, they have a cost, and the cost has to be taken up, or you can't do it. And so many of us, I think, on the other side were like, it should be easy. And for good reasons, it’s not. I mean, there are a lot of good ethical and process reasons, and patient care, those are not trivial things. And they have to be paid for, and we didn't know how to do that before….”
The Next Big Thing
Looking ahead, Professors Krummel and Kattah expressed excitement about the potential of perturbational experiments, where cells from patient samples are cultured and exposed to various stimuli to understand disease mechanisms and identify potential therapeutic targets and appropriate therapeutics.
Max Krummel: “The thing that Mike and I are thinking and have been talking about recently has been this idea that you kind of want to be able to take a bunch of different scenarios and perturb them in real-world ways. And that is to perturb in the sense is put a little pressure on them chemically a drug, a molecule, and then ask how each one behaves so that you can learn the principles of how healing happens. That is to say, when you cut yourself first, you bleed, and then it forms a crust, and then that starts to fill in, and then you get cell proliferation, where your skin cells and some muscle pull it all together, and then eventually you've got new skin. That's phases, and with any chronic disease, I think we all think that that's probably the right answer, too, is that it has to go through phases. How are we going to learn those phases if we don't perturb every system and see if it is moving in the direction I want it to go, or where it is going? And so I think a lot of what we've been thinking about is collecting that sort of data set…(that) would be the kind of thing that we could really learn, then sequences of drugs to give to patients to walk their disease back to health. And it requires us to collect the things like Mike has been doing, and then again to apply increasingly diverse sets of drugs to them and perturbations to them.”
Michael Kattah: “…the idea of having a set of primary cells from patients from the affected tissue and being able to look in culture and add stimulations and then try and block with a panel of potential therapeutic targets, I think that's really appealing to try and accelerate the preclinical phase. Most of the preclinical testing is done in mouse models. And I mean, there's nothing wrong with doing mouse research. We do a lot of mouse work, but having primary human cells, which behave a little bit differently, if you can set up good in vitro assays, either using epithelial monolayers or assembloids or these different things, that you can then try and prioritize certain candidates over others in terms of drug development. I think that's certainly something that a lot of people are very excited about.”
To listen to the entire conversation with Prof. Max Krummel and Prof. Michael Kattah and hear more of their thoughts on cancer, autoimmune disease, Immunoprofiler and Autoimmunoprofiler initiatives, please visit….