CAR T-Cell Pioneer Takes Aim at Where No Campus Has Gone Before

In this episode of the CU Anschutz 360 podcast, Terry Fry, MD, the inaugural executive director and Charles C. Gates Endowed Chair of the Gates Institute, explains how the institute is heading toward new frontiers of targeted cell and gene therapies for cancers and other rare diseases. Fry talks about the latest advances in chimeric antigen receptor (CAR T) cell therapies, which he helped pioneer at the National Institutes of Health. He talks about how the Gates Institute, which connects and centralizes campus resources into a seamless translational pathway, offers an incredible opportunity to help patients facing serious health issues. Thomas Flaig,  MD, CU Anschutz vice chancellor for research, co-hosts the discussion.

Transcript

Thomas Flaig:

So Terry, very much looking forward to the conversation today. This is a rapidly changing and fun topic and before we jump into it though, let me just ask you a few things. So what's motivated you to work in this field, work with gene and cell therapies? What's the driving part behind that for you?

Terry Fry:

In many ways it was somewhat serendipitous. I got into pediatrics not really knowing exactly where it was going to end up. I was always interested in science. I was a biology major, did a little research in college. When I got into pediatrics I was attracted to the field of immunology really as a science, and so ultimately I ended up in oncology because I saw that that was the place where immunology was being applied in a way that I found interesting. But at the time, we were doing cancer vaccines, most of which were not particularly effective.

And I made a joke recently that when you think back to my first (conferences) – we just had last week the American Association for Cancer Research meetings – and I remember the first meetings literally being relegated to the back room because largely immunotherapy was viewed to be a fringe specialty in the field of oncology. And the serendipity part was I was at the NIH when CAR T-cell that ultimately became Yescarta was being developed by Steve Rosenberg (MD, PhD) and Jim Kochenderfer (MD) two floors up from me. And we were running cancer vaccine trials, and ultimately we applied it to pediatric leukemia and that's kind of how it all started.

Thomas Flaig:

Just one quick follow-up on that. So you think about where this started – being in the back room of the meeting. You guys are now at the podium at every meeting, appropriately. What do you think the potential is here, are we just scratching the surface in this therapy? Where do you think the future of this is going?

Terry Fry:

I think there's a huge potential. I think that we as a community, the immunotherapists, have been humbled by the fact that replicating the results with CD19 CAR T-cells and BCMA (B-cell maturation antigen) now in myeloma has been challenging when you get into things like solid tumors. So I think the enthusiasm was driven by the huge success of CD19. I think there's enormous potential there, but I think we have to constantly check ourselves and realize that this is going to be hard when we try to apply this to other areas.

Chris Casey:

Terry, could you explain to us just a little bit more about your background? You were at the NIH and that's where some of the pioneering CAR T therapies began. How did you make the transition from there to out west out here to CU?

Terry Fry:

I was happy at the NIH. I was very content. We had run the CD19 CAR T-cell trials and implemented an alternative CAR targeting another antigen in B-cell malignancies – that was seeing success in patients for whom the CD19 CAR had failed – and was leading the CAR T-cell program there. And I got a call from Lia Gore (MD), who leads the pediatric oncology program here and asked me to come out and take a look. And I wasn't really looking. What happened was I came out here and what I saw was just an enormous opportunity because of where this institution was at, biomanufacturing facility already in place, an adult and children's hospital world-class at the same campus, a world-class immunology program and I just saw an opportunity to come and maybe help try to put all that together.

Thomas Flaig:

So Terry, maybe you want to say a little bit about your impact on what's been done here at CU Anschutz. This area is dramatic and obviously there's a team that’s been the driving force behind that. So why don't you tell a story about what's really transpired the last few years from that initial introduction to the campus community to where we are today, with several trials ongoing across two hospitals and so forth.

Terry Fry:

Yeah, I guess I had lived the experience at the NIH of trying to implement the first CAR T-cell trials and execute on the manufacturing and try to put all the regulatory structure together. And so (here), expected that it was going to take a little while to piece all that together. When I got out here the programs were pretty far along and in the hematology side, on the adult hematology side and trying to implement a CAR T-cell program. But I anticipated that there were going to be some connections between groups on campus that weren't used to working together, all very good at what they did, but just not used to working together.

And so I think a lot of the time, the couple of years it took to get from that, those first meetings to actually treating the first patients, was really just figuring all that out. And what's been great is that as we got into the second CAR T-cell program, it went a lot smoother. And that's usually the case – once you figure these things out. And so I think we're just sitting on the cusp of a huge opportunity to really do a lot more.

Thomas Flaig:

Yeah, I couldn't agree with you more. I think the foundations that you put in place, yourself and the team, are really starting to yield a lot of fruit now. Can you tell us a bit more about cell and gene therapy and how they're different from other therapies to treat cancer as you think about this whole field?

Terry Fry:

It is the case that CAR T-cells, the field that I've been involved in, it was the first FDA-approved gene therapy because the cells themselves are gene modified. So on the one hand it's a cell therapy, but it is a gene therapy in that sense. Obviously, recently we've seen this field of gene therapy just explode in lots of areas, including non-oncology, but particularly in the oncology space when you think about immunotherapy in general. Really, in the last decade, there have been two areas that have been transformative in terms of immunotherapy. One is the field that involves immune checkpoint inhibitors. Jim Allison was awarded the Nobel Prize. And that field, as you know, has been hugely impactful in a lot of adult cancers, epithelial cancers.

And in that field with that therapy, essentially what happens is that you take the brakes off the immune system and you get regression of cancer. That works great if the immune system is capable of seeing the cancer, recognizing the cancer. I was at the NCI when we ran some of the first trials with these checkpoint inhibitors in pediatric cancers, and we saw nothing. And that's been true, as you know, even in a number of adult cancers as well. And so it is certainly the case that not all cancers are seen effectively by the immune system in the natural state. And so the CAR T-cell field is essentially a field where the gene modification educates the immune system to now see the cancer cell. And so what you have is really the parallel development of two immunotherapies that have both been effective but in really largely non-overlapping fields of oncology.

I think what's been interesting is watching how after a long time where the paradigm in cancer was surgery, radiation, cytotoxic chemotherapy, maybe with some of the small molecules being developed in the latter part of that. Now, with the opportunities in immunotherapy – it's a very different treatment in the sense that it really relies on the patient's immune system. And although it can be combined with those other modalities, obviously, it combines very differently than the way that traditional oncology therapies come together. And so I think it's really changed in many ways the treatment paradigms in oncology a bit on its head.

Chris Casey:

Terry, when you mentioned you came out to CU and the campus here initially, you mentioned the Gates Biomanufacturing Facility was here. Could you recount the story of it was like a two-year effort to get the product made at the facility and then transferred over to Children's to be put into a patient?

Terry Fry:

Yeah.

Chris Casey:

Could you explain that story for us?

Terry Fry:

Yeah, it hearkens back a little bit I think to the question that Tom was asking me earlier about all of the challenges in connecting entities on campus that weren't used to working together. It wasn't long after I got here that the biomanufacturing facility was making CAR T-cell products, taking it from that point, which is making products, but not having structure in place to deliver those products to patients over at the hospital really required a lot of connectivity. And one of the jokes was there were all of these insurance aspects that we had to navigate – to actually transport the cells from across Montview over to the hospitals. So the joke I typically make is that moving the cells, whatever that is, a quarter of a mile or less, was one of the hardest things I've ever done, but we got there.

Thomas Flaig:

So Terry, if we just think about the trials open on campus right now, I think there are three trials using two different compounds, both are still in progress, results haven't been released yet, but do you want to make any just comments about what trials are open here right now?

Terry Fry:

So the first trial that we opened was CAR targeting CD19, which is very similar to the CARs that are commercially available, but it turns out that a lot of patients don't have access to those commercially available CARs. And so that trial has turned out to be very useful to Manali Kamdar (MD) and the team in terms of something that they can offer patients that don't have access to the traditional commercially available CD19 CARs. Thus far, the outcomes look quite good. A number of patients that were treated early in the trial remain in remission, still ongoing and we're in the process of finishing that trial up. We've used that same CAR product at Children's Hospital, so manufactured the same way, essentially the same drug under the same IND (investigational new drug), but a second trial that allows us to treat pediatric patients at Children's. Similarly ongoing, we've seen good activity –  and they've also used that quite a bit to treat patients that otherwise wouldn't have access.

So the second product is, and the third trial right now, is really a truly novel CAR construct that targets not just CD19 but CD19 and a second target on the same cancer cells called CD22. And what we know is that about half of patients with lymphoma won't achieve a complete remission. And although the response rates in leukemia are about 90%, out of all the kids who go in remission about half of those patients will ultimately relapse. And one of the mechanisms that drives that relapse is that CD19, the antigen that's being targeted by the CAR, ends up being lost by the cancer cells. And so the concept with this truly novel product is that if we target both antigens simultaneously, that the cancer cells will be less likely to evade the CAR T-cell and we'll have a higher remission induction rate and durability, but (it’s) obviously early. We'll wait and we're looking forward to see how that plays out.

Thomas Flaig:

Just to think about the setup then. So basically with the Gates Institute, you've got the biomanufacturing capacity, you've got the clinical partners in this campus, UC Health, Children's Hospital Colorado, you've got the investigators, you've mentioned Dr. Kamdar and other people. So you've got this essentially manufacturing through sponsorship, through treatment of patients here, which is really a pretty remarkable capacity that you've led. Can you talk to us a bit about your vision for that institute and where it's going in the future?

Terry Fry:

In many ways it links back to the conversation we had earlier about that first trial and I made a comment that in some ways wasn't surprised that it took a lot of work and time to be able to overcome many of the barriers that ultimately led to a lot of promising ideas (from campus labs) never making it into patients. And so my vision with the Gates Institute and the vision really of the Gates family, Diane Wallach and the Gates family and campus leadership – Chancellor Elliman, Dean Riley – has really been that what we want to do is remove some of those barriers – to be able to make it possible for more of the ideas on this campus, the terrific ideas that are coming from the labs across this campus make their way into patients. And so that's really the vision at the institute.

Chris Casey:

Switching a little bit back to the CAR T therapy, I was curious about how the side effects could be pretty severe, and you've alluded to that already, when patients get the infusion of the CAR Ts. Can you share a little bit about the side effect issue with patients receiving this therapy? Has there been any progress made in helping to mitigate those?

Terry Fry:

It's a great question. In many ways, I think the side-effect profile, much of it was predictable, meaning that the cells that we ultimately educate to recognize the cancer are known as T-cells. These are the cells that are responsible for fighting viral infections, so what they do normally is they destroy virally infected cells or other cells in the body. And if you think about what happens when you get a virus, you can envision what the CAR T-cell toxicity looks like. It's high fevers, it's shaking, chills, etc. And a lot of that was pretty predictable. There were some other aspects of the toxicity that were maybe less predictable, which is that there are some neurologic side effects that emerge from some of that early experience. In its most severe form, it actually can be fatal. And in fact, one of the stories that I'll tell, and this is a public story, is that one of the first patients, pediatric patients treated at the University of Pennsylvania CHOP, she was a young girl at the time, her name was Emily Whitehead, and she's public and has spoken out about this.

She had refractory leukemia, had been through a bone marrow transplant, ultimately was one of the first children to receive CD19 CAR T-cells and ended up in the intensive care unit with this inflammatory toxicity – essentially in the ventilator and thinking that she wasn't going to survive. And again, in conversation between a number of the physicians taking care of her, one of them brought up the fact that there was a drug called tocilizumab that was used for inflammatory side effects in rheumatoid arthritis. They decided to try it and she completely responded and is still alive and probably cured. Bottom line is, as the field evolved, we've learned quite a bit and I think, although I wouldn't say that the toxicity risk is completely gone – for sure it's still there – I think we've gotten a lot better at managing it.

Thomas Flaig:

So we talked a little bit, Terry, about some of the very early initial, sometimes dramatic successes, there's some challenges as we move into different disease sites and then the toxicity issues. So there's this great promise and then as you point out, we're learning new techniques and ways to address this. Think about that, the response and the toxicity, what do you think are the biggest challenges out there now broadly in the CAR T field and how are you going about addressing this through the institute and other activities?

Terry Fry:

A couple things I'll say. I mentioned earlier that it was somewhat serendipitous. I think that the first experience was CD19 CAR T-cells for a number of reasons. One, it appears that leukemias, lymphomas, tend to be very responsive to this therapy. The second is that the target, the protein itself that the CARs go after, CD19, is restricted in terms of its expression, meaning it's on the cancer cells and it's on B cells. When we give these cells, the CAR T-cells, we eradicate the cancer, we also eradicate the B cells for some period of time. That turns out to be a toxicity that patients can tolerate and you can manage through administration of immunoglobulin antibodies. What I think is challenging is that there aren't going to be a whole lot of CD19s out there, number one.

And the second thing is that it appears, and we know this even from immunotherapy, other immunotherapies for solid tumors, that particularly in solid tumors, there are lots of mechanisms that the tumors evolve to sort of evade the immune system sort of naturally. They exclude these sorts of cells from their microenvironment. When the T-cells get there, they shut them down, et cetera. So I think it's, as we get into other tumors there's going to be a problem finding good antigens. There's probably some promising antigens out there, but then there's also going to be these other things we're going to have to grapple with. But the other challenge is that – and this is really kind of, I think, where the institute fits in – is that I've been humbled across all of my experience in this area.

When you get into the clinic, you only know so much. The animal models get you so far, hopefully get you to a point where you see something that looks promising and you think there's value in trying it in patients, but it's not the case that we know what's going to happen when you make that jump. In order to really understand this, what you really have to have is the mechanism to fairly nimbly take these promising ideas and run what ultimately, quite frankly, is a clinical experiment and see. And so, hopefully with the institute, we're going to be able to do that more efficiently and really generate the type of early stage clinical data that's really going to help us understand if we're onto something.

Thomas Flaig:

So here we are, a couple of oncologists talking about this field. We talked about the liquid tumors of the blood tumors. Do you see a future for CAR T beyond oncology in other diseases, and how do you see that moving forward?

Terry Fry:

It's been in the rumblings of people talking about this field for quite a while and that there were potential opportunities in other areas. What's happened is that very recently, within the last one to two years, there's been now published data demonstrating that CAR T-cell – remember I mentioned that the antigen, the target is CD19, that, and when you give these cells it leads to not just eradication of cancer but complete eradication of B cells, meaning that when you look in multiple places you can't find a single B cell. So it's very, very deep depletion of B cells. Those are also the cells that manufacture the antibodies that lead to autoimmune diseases, lupus, etc. And we know that antibodies targeting those, targeting B cells, are effective, but there's also data that suggests that the depth of that depletion can be important in how well a patient responds.

And so a number of centers began using CAR T-cells in refractory lupus patients largely with kidney manifestations. And quite frankly, the results have been pretty dramatic. I think it remains to be seen how that's going to play out when you get into larger clinical trials entirely focused on lupus. I think there's some rumors out there that it continues to look good, but remains to be seen. So I think certainly autoimmune disease with the CD19 CARs makes a lot of sense. The other thing I think is really important, and this probably also links, it does link to our opportunities on this campus, is as a field a number – there were probably five, six – academic centers that were involved in some of those early CAR T-cell trials. They were all academic centers. We were working with the FDA on how to approach valuation and approval of these gene therapies.

Remember I said it was the first gene therapy that was approved. There was a lot of back and forth. The FDA was learning, the clinical sites were learning, the scientific teams were learning, and the aftermath of that really created a foundation for gene therapy, cell and gene therapy more broadly. And so since that time now beyond the approvals for CAR T-cells in oncology, we've seen approvals for gene therapy for adrenoleukodystrophy. We've seen approvals for gene therapy in hemoglobinopathies, thalassemias. There are likely going to be some approvals with sickle cell anemia. The foundational work from the CD19 CAR T-cells has certainly extended beyond not just oncology, but beyond CAR T-cells in general, and I think that you're going to see a lot more of these types of therapies in many other diseases.

Thomas Flaig:

And I sometimes think ahead and say in 20 years when we look back or 30 years at the end of our careers and say, what are those critical times that we were a part of? Seems to me that the last bit of time as we've gained this experience and engaged pharmacy companies and academics over, it's going to be a special time. People are going to look back at the foundation that's been set here and really where that goes.

Terry Fry:

I think that's right. And I also think that something you alluded to is important, which is I think a lot of the early foundational work and the discovery work is going to continue to happen within academic institutions. A lot of the foundational, so the connection to the basic science, etc. I similarly think that there's a lot of reason why that early translation into human patients is – not everybody would agree with this – but I think there are reasons why it may be best done in academic institutions. And I say that because I think that there are – you have that collection of the scientific teams that develop the therapy – the clinical teams that are implementing the therapy, and a lot.

I gave the example of the decision to give tocilizumab. I mean, that's literally a bunch of people who were treating the patient – but also who developed the drug – sitting around and talking about it and coming up with those ideas. And I think that's really important in all of this. That said, though, the other thing we've learned is that these are expensive trials, they're expensive drugs, and none of these are going to be commercialized without partnerships with industry. And I think that relationship between academia and industry has always been one that can be challenging. And I think that one of the things that we're hopefully is emerging from this is that we've recognized it that's going to require those partnerships really to make sure that we see the full development of these.

Chris Casey:

That reminds me of a question I wanted to ask you, and that is, you've straddled both sides. You've been in academia, you've been in private industry. Could you talk a little bit about how, and currently I believe you have a role still in private industry. Could you talk about how those synergize and help with the Gates Institute's efforts?

Terry Fry:

Maybe the story I'll tell is really I mentioned earlier that when I was at the National Cancer Institute I had the privilege really of being involved in the early development of a CAR that became Yescarta, but then also a second CAR targeting another protein called CD22 that we initially opened as a phase one, an early phase safety feasibility type trial. We began treating children and young adults with leukemia and recognized that it was very effective in children who had received CD19 CARs and then relapsed about, remember I said about 50% of those patients will ultimately relapse. The problem was that at that point in time we hadn't really considered what we were going to do with it if it worked.

And so we were running that phase one study and we hadn't really thought through partnerships or development beyond we were doing at the NIH. The NIH is not going to commercialize the drug. The outcome of that was that that quote phase one study, usually a phase one study is 12 patients in a safety phase and then maybe an expansion into a few other patients, and then eventually you transition into your later stage trial. We ended up treating over 80 patients on that study because it was successful. We couldn't close it because we hadn't really figured out how to develop it commercially.

Hopefully my experience in industry, I realized through some of that work with (industry) – eventually we did partner – I had very little understanding of what the process of drug development and industry was all about. I was a lab researcher who took things into early stage clinical trials and so part of this experience for me, has really been a lot more of an understanding of what that process looks like. And so hopefully what it means is that as we develop things within the Gates Institute, we can do that constantly aware of when might be the most opportune time to think about partnering these to make sure that they get developed beyond the University of Colorado.

Thomas Flaig:

Terry, it's been a great conversation and again, I'm just struck by this idea of how far we've come in a short period of time, and really as you think of where this could go and what places in medicine that could touch is pretty remarkable. Do you have any sort of last thoughts about what keeps you optimistic about the future and this very broad area?

Terry Fry:

When I think back to, as I said, I was, sort of came into this somewhat serendipitously. I wasn't a gene therapy person. I was largely an immunologist. And along the way I've learned a lot about the technologies, gene editing technologies, CRISPR, etc., and have even begun to work on those in some of the programs that I've been involved in. I would say that if I reflect back to the early days of the CAR T-cell space, I remember sitting in the NIH biomanufacturing facility and transferring the process of manufacturing CAR T-cells from my lab to the manufacturing facility, bunch of scientists with a bunch of lab notebooks and manufacturing folks trying to figure out how to take what we were doing in the lab and turn that into something that the FDA was going to allow us to do for patients. And we went through that whole process and one of the very experienced GMP (good manufacturing process) manufacturing folks in one of those meetings sort of sighed and said, "This is really cool, but this is never going to be possible outside the NIH."

And fast-forward, the drug actually got commercialized, and I don't think anybody at that point thought that that was going to be figured out. So what makes me optimistic is that there's one example, and I can tell you when I look at what's possible with a lot of the technologies that are out there in cell differentiation and gene editing, etc. Honestly, when I first got in this field, I never would've thought any of that stuff was possible. So what keeps me optimistic is that I continue to be surprised by how the innovation out there is really leading to capabilities that I think really ultimately will be transformative in many diseases.

Thomas Flaig:

A hundred percent, and I think it's exciting, Terry, your leadership, the team that you developed and you nurture, and really where this could go.

Terry Fry:

Thank you very much. It's been a pleasure talking to you today about my favorite topic.