Immunotherapy and Precision Immuno-Oncology

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 Shepherd, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to welcome Dr. Timothy Chan, who is the Director of the Center of Immunotherapy and Precision Immuno-Oncology at Cleveland Clinic. Today he's going to discuss the development of the new Center for Immunotherapy and Precision Immuno-Oncology. Welcome, Tim.

Timothy Chan, MD: Great. Thanks. Thanks for having me.

Dale Shepard, MD, PhD: Absolutely. So maybe just to start, maybe you can give us a little overview of what your role is here.

Timothy Chan, MD: Sure. I'm a recent arrival at Cleveland Clinic. I come from the Memorial Sloan Kettering Cancer Center where I've worked for over a decade, and I'm a physician scientist, and an oncologist by training. And we've been here since I would say early March. And the role of why I was recruited here was to come chair this new center for immunotherapy, which is a center that is designated to forward immunotherapy developmental therapeutics and research at the Cleveland Clinic Health System.

Dale Shepard, MD, PhD: When everything's said and done, how large do you expect this effort to be?

Timothy Chan, MD: I'm still learning about the ins and outs myself, actually, because, as you know, whenever you land in a certain place, different places have different needs. My big thing is to basically, one of the things is to empower all the great people that are already here at the Cleveland Clinic, various institutes and hospitals of all throughout the system, to leverage people's passion and people's expertise, to further develop immunotherapy trial design and therapeutics.

How large it's going to be, well, I can go over the main segments of the center. It's a little bit bigger than a departmental scale, but smaller than I would say some of the clinical institutes, but it has some components that are cross institute. For instance, we have a Department of Immunologic Medicine, where we are in the process of recruiting MD, MDPhD, and PhD scientists, faculty level scientists, who are interested in a variety of different types of immunologic research, both from immune-oncology and immunotherapy design and development all the way to say viral vaccine development and auto-immunity. We have operations and faculty run laboratories in both Cleveland and also a footprint in the new FRIC or Florida Research and Innovation building down in Florida as well. So that's one component.

Another component is a joint program with Case Western as part of the NCI Comprehensive Cancer Center and the National Center for Regenerative Medicine to set up our own in-house, Cleveland Clinic centric, self-therapy program. So a developmental therapeutics program where we're going to recruit the latest, the best and brightest, folks that are interested in developing new CAR T therapies, new engineered T cell therapies, new cancer neoantigen based vaccines and so forth. This'll be in collaboration with the NCRM. I don't know if many folks know, but the NCRM is just part of our comprehensive cancer center for which Cleveland Clinic is a part of, it's really one of the very largest cell therapy production facilities in the area and in the state, definitely in the state. So we really want to very much advance the mission of immunotherapy discovery across the Cleveland Clinic enterprise.

There's a third component, which is largely research capability building. We're bringing in a team of folks that are expert computational scientists to really work with investigators at the Cleveland Clinic. This group called the immune-genomics platform is slightly different. They're very much applied computational folks. And the purpose really is to work with clinicians, both at the Taussig Cancer Center and other institutes in LRI to basically initiate correlates that will allow bench to bedside insights into how we can design our next trials and understand why people are resistant or sensitive to therapeutics.

And the last is a large initiative called the Precision Oncology Initiative. And clearly we need a sexier name here, so we need to at some point decide on what to call this, but this really is a top down enterprise where we want to expand our basket trials. And Dale, I got to talk to you about this at some point as well, because you're heading up the Phase One program.

Dale Shepard, MD, PhD: Yeah, yeah.

Timothy Chan, MD: But we really want to resource this and allow expansion of the Phase One program. We want to make molecular profiling very much available to everybody that wants this as we move forward to make precise treatment plans for our patients here in the cancer center.

Dale Shepard, MD, PhD: I guess I'll start with a question about the last initiative, which we'll get you set up with marketing on that name there.

Timothy Chan, MD: Yeah.

Dale Shepard, MD, PhD: Traditionally basket trials, we think about more of a genomic base. How are we thinking about incorporating immunotherapies into that basket trial design?

Timothy Chan, MD: Oh, that's a great question, Dale. We think right now that the question and the resources for building this are one in the same. So immunotherapies obviously are being used very widely and all over the place now for many, many cancers. And in fact, the first pan-cancer approval, i.e a indication by the FDA to use a drug based on a biomarker irregardless of disease type was really mismatched repair positivity and another one was a tumor mutation burden, both concepts really originally developed from our lab more than a half a decade ago. And so, we're very happy to be in this setting where I think that insurance approvals and so forth are really looking at these platforms, no matter if you have immunotherapy or targeted therapy as being amenable to sequencing.

So on the one hand you have readouts for tumor mutation burden or MSI or DNA damage repair, which makes you more suitable for immunotherapies that target the genetic instability and the neoantigens.
But on the other hand, on the same readouts, if you choose the right panels, you're going to get your EGFR mutations, you're going to get your ALK translocations, you're going to get your BRAF mutations profile and so forth. So it is all one in the same infrastructure, I think that we're building.

Dale Shepard, MD, PhD: What are your thoughts about maybe the future of combinations? It is kind of a you get that same information from a report and you kind of go down an immunotherapy route or a genomics route. You think there's a role at some point of combining those two approaches?

Timothy Chan, MD: Oh, yeah. I actually do. I think that teleologically, we're just looking at different qualities of the cancer genome. The readouts for immunotherapy tend to, for instance, involve a lot of how antigens are formed or specific genes that don't necessarily sensitize you to say, ETFR or kinase, signaling addiction, but perhaps towards an addiction to evading the immune system. So the biology is different, right? But we're still, I think looking at the genomic complexities of how mutations change biology. So I think that doesn't change. So at least a part of it, a big chunk of it can be captured using next generation sequencing assays that query the right mutations and the right features like tumor mutation burden.

But I think other aspects may also be needed. I think this could be married to different stainings, like PD-L1 stainings or looking at certain amplifications and so forth as part of a more comprehensive series of biomarkers that we can use. Again, I think really it's one in the same. You can take the genomic route. Now in terms of what to treat, I think the more stable a genome is, the more likely you'll find success using a targeted agent. So if you look at something like BCR-ABL, and certain leukemias, or GIST for instance, where you can get Imatinib to work there, those are relatively stable genomes. You can tell that by the genomic structure, you can tell that by the sequencing, and we'll be able to triage depending on this level of genomic stability and to determine what that patient should get based on the genomic stability.

Dale Shepard, MD, PhD: Yeah, makes sense. Thinking about one of your other components, the applied computational medicine component, do you see that as being something we're going to be working on developing absolutely new therapies, or do you see that as a way to sort of look at ongoing trials or existing therapies and optimize those? What's your vision from that standpoint?

Timothy Chan, MD: Well, I think that my thoughts on this are probably reflect the thoughts of a lot of people here at Taussig, as well as in the field, in that it's both. So I think ongoing trials right now, I think we should be learning from every patient on trial. And how we can learn most fully from them, really part of it is to understand who responds and who doesn't and when a patient stops responding, why? So that's why when we get this type of genomic data off of these precision platforms, we're able to then subsequently go from the bench to the bedside more effectively, and to basically understand why certain mutations predispose to resistance and alter our design for the next generation therapy. So I think it is both.

And in fact, from ongoing trials, if we are very judicious about it, and very careful in gathering all the data, we will then be able to actually apply that knowledge to develop the next generation of new therapies, based on what goes wrong, and what allows resistance to occur in the first place off of the ongoing trials. And this model is not new and it's not rocket science. That's how I think a lot of the lung cancer fusion targeted agents have been built. I think we're on the fourth generation now, and it successfully, very successfully, extended the lives and the quality of life as well of many patients with lung cancer.

Also EGFR, like Osimertinib and others, second, third generation EGFR inhibitors, have been dramatically beneficial in terms of improvement of how long people respond to EGFR inhibitors. So it's the same concept. We just want to do this here for Cleveland Clinic patients and allow Cleveland Clinic patients all throughout the system to really get first access to some of these new concepts and trials available.

Dale Shepard, MD, PhD: No, that's excellent. When you say all patients, what are your thoughts about being able to incorporate some of the things you're doing into our regional sites? You did mention Florida, but thinking about how we can engage people, patients, in our regional sites, what are your thoughts from that standpoint?

Timothy Chan, MD: Oh yeah. No, I do think it's very, very important. I think it's important for us to pilot and get things up and running so workflows are very smooth, but again, it is one Cleveland Clinic and there is a lot of interest now in making sure that Florida is an integral part of the precision oncology strategy. We have a lot of investments in oncology practice and research down in the Port St. Lucie and Palm Beach areas, as well as Westin and Indian River and the general facility down there. I understand that oncology services are already started in Abu Dhabi and we'll have conversations with them on how precision oncology can be rolled out. We have to be sensitive to the local practice and culture of research in each individual location and how best to apply of these precision oncology strategies in each location, also in London, presumably if, and when oncology becomes activated there.

Dale Shepard, MD, PhD: So Tim, you mentioned the cell therapy program, and you mentioned before, and I guess, so just to reiterate, we actually have capacity to make cellular therapies here and not only develop them, but make them. Where do you see that going either the near or distant future, more with solid tumors, because a lot of the cellular therapies have been far more effective in hemalignancies lymphomas. What do you see as the future in solid tumors?

Timothy Chan, MD: So, Dale, that's a great question. And it actually reflects a little bit on your point about combinations. I actually do believe that we're going to need more effective targets and combinations to effectively utilize CAR T's for instance, and engineered T cells for solid tumors. Right now CD19, liquid tumor's, very effective. So in solid tumors, much less so. And the reason is because these tumors really are able to resist entry of the T cells and if you look at a pancreatic cancer, it's almost like a shield. And so that's probably because of a couple of things, A, T cell trafficking with the right signals and integrated molecules and so forth are not attached. But secondly also because once they enter the suppressive immunologic microenvironment, the T cells become exhausted. And so it's a twofold problem.

And I think very presciently your comment about combinations, it's going to be very important here. Because here we can put multiple constructs into CAR Ts, for instance, into T cells to make CAR Ts, not only the CAR T construct itself, but also the correct signaling say integrin or other types of molecules on the surface to allow proper trafficking.

There are now a lot of very interesting trials like at the Penn and other places are running in combination with combining CAR Ts with Anti-PD-1 or other systemic checkpoint antibodies, but hopefully deal with problem number two, which is the acquired exhaustion phenotype that at one sees in solid tumors. So we want to do a lot of those trials here. I do agree with you. I think combinations are going to be very, very important. And as we've already seen in the literature and in the news, as you see, the combinations right now have been provided response rates and durability that I've never seen as an oncologist, ever.

So for instance, we just ran a trial on, and done the correlates for, the combination lenvatinib plus pembrolizumab, which is Anti-PD-1, where the objective response rate was for renal cell carcinoma, metastatic, was around 70% and overall tumor shrinkage rate of 96%. It was not that long ago that these things were rocks and the responsive, the percentage of response of tumors was more like 2%.

Dale Shepard, MD, PhD: Yeah.

Timothy Chan, MD: So, we're in a full on revolution right now with combination immunotherapeutics and I just am very excited to be at the Cleveland Clinic to be able to help folks really bring these to patients.

Dale Shepard, MD, PhD: And I guess finally not to leave any of your groups out, I guess, you mentioned the Department of Immunologic Medicine. Do you think that's going to have more of an impact initially on the basic science side or in terms of clinical science and clinical medicine, or where do you see that in terms of its development?

Timothy Chan, MD: Well, we're building all four major components of the center simultaneously right now, many of the faculty that we're recruiting for the immunologic medicine group, we're all going to be sort of immune related folks, but some of them are going to be physician scientists and will have roles in various institutes like TCI and so forth.

Some of the other components, we haven't officially launched some of the support mechanisms, but we have a human immune monitoring facility that we've just launched, that we haven't actually announced yet. This was run by Marcel Diaz and Jen Coe, both immunologists here. The sole purpose of this facility, called the IML, is to support investigators running clinical trials, to do their correlates, and to work with companies who run trials at the Cleveland Clinic. We bank, we do full suite of immunologic assays, and we look at correlates and determinants of resistance and sensitivity. So that's already up and running. It's called the IML, look forward for an announcement at the website and so forth, and other facilities that we're launching.

So I would say both Dale, we're going to sort of work on the basic sciences, but also some of the support features are here so that we can build up on current trial efforts.

Dale Shepard, MD, PhD: As you correctly noted earlier, this is certainly team science and it's a team approach and how do you think this is going to impact? It seems like it's going to have an impact in a big way our ability to collaborate with others and work with other institutions and this seems like a real great resource for us. How do you foresee moving forward from a collaboration standpoint?

Timothy Chan, MD: Very early on in my career, I've noticed that trying to help patients in this way, fulfilling our duties as oncologists and scientists to try to provide more options when options become few in number, for these patients, it is absolutely a team sport here. And the purpose of the center really is to build upon our ability to collaborate, not only internally amongst different institutions and the Cleveland Clinic for the benefit of patients, but also more widely across our NCI designated comprehensive cancer center and also with industry. And I think we all need to work together to really learn about why immunotherapies don't work for the majority of patients and to fix that.

And we see before our eyes right now the crossing of the 50% threshold and even beyond in terms of people that are responding and leading very, very high quality lives with metastatic disease. This is a critical time to be working together to breakdown silos. So that's what we're about. That's what our center, for short, we call it CITI, C-I-T-I, that's what we're about. Half of this entire enterprise is for building collaborations, breaking down barriers, so that translational scientists and trialists, such as yourself, can work together very quickly and efficiently in order to get the questions that we want from clinical trials.

Dale Shepard, MD, PhD: Well, it's outstanding work you're doing. So, any additional comments?

Timothy Chan, MD: No, other than thanks for having me on. And every day, I just am amazed at the folks here at the Cleveland Clinic and the comradery and the teamwork here. It's just an absolute pleasure.

Dale Shepard, MD, PhD: Well, great. Well, good luck as you've got great groundwork, and you continue to build the center and look forward to working with you.

Timothy Chan, MD: All right. Likewise. Thanks for having me on.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget you can access real time updates from Cleveland Clinics Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.