Scientist Stories: Carl June, Curative Cell Therapies for Cancer & Beyond

Well, good morning. I'm really excited to be able to start the meeting with such an important conversation with Dr.

Carl June.

I could take the next 30 minutes, and I've been internet stalking him, so I have a lot to say, but I'm going to omit the embarrassing parts. We're going to talk about The concept of what Carl said in his interview for this meeting, which is—

and I got to make certain I say it right— that we're at the end of the beginning as far as immune oncology. And I absolutely agree with him. When you think about discoveries of major breakthrough approaches to the treatment of cancer, certainly immunology has probably been the biggest and certainly the most effective breakthrough So we're going to spend the next 30 minutes kind of hearing his perspective on where we're at, where we're going.

And I'm particularly intrigued by his experiences that led up to this kind of successful period of—

it's always been successful, but the publicly acknowledged success of his contributions to the field. He's currently the Richard Vague Professor of Immunotherapy in the Department of Pathology at the University of Pennsylvania. He's also the site director for the Parker Institute for Cancer Immunotherapy at Penn. He serves as the director of the Leonard and Madeleine Abramson Family and Cancer Research Institute and is the head of translational research at the Abramson Cancer Center at UPenn.

So that's just what he— that's his day job.

He discovered in 1980 the T-cell positive signaling receptor CD28. And since then, he's been best known as one of the contributors to the invention of the CAR T-cell, first publishing on this approach in 2011, and the details of which his work has led to approved— the first approved gene therapy for the treatment of cancer in August of 2017. He has 400— as of last night, 490 articles in PubMed. And he's actually listed as a co-inventor on 66 patents as of last night.

So you can find a lot out on the internet if you try.

So be careful what you post out there. He's won a zillion awards, including the ACR/CRI Lloyd Old Award in Cancer Immunology in 2015. He's won the Luminary Award here at this meeting. And he also, as of last year, year was on the Time 100 Most Influential People in the World list. So he got to mingle with the stars. He is board certified in internal medicine, medical oncology, and he completed his MD and then his training and went on to join the University of Pennsylvania in 1999. He's actually on the scientific advisory board for 9 companies, as far as I can tell from the internet, and is the co-founder or the chief scientific advisor in two companies that have primarily focused on the use of the immune system for the treatment of cancer dating back to— I hope I have this right— 1996.

Yeah.

The first of these companies being Excite Therapy, which was acquired by Cyclocell Pharmaceuticals in March of 2006. And he currently serves as the scientific founder for Tumunity Therapeutics. Which is also working on developing immunotherapies for cancer, infectious disease, and autoimmune disease. The company, I believe, is based in Philly. At least that's what the internet says. So with that introduction, I'd like to offer a round of applause for Carl June joining us for today's fireside chat.

Okay, now that we got that out of the way, um, so he has no, um, knowledge of what I'm about to ask, so you're very brave. So here we go. I wanted to focus a little bit on the past, and kind of— I just read A Cure Within. For those of you who haven't read it, it's just a tremendous insight into the people that have gotten this field, and you have your own chapter in that, and it describes some of your early efforts in infectious disease, in particular working in the late '80s, early '90s, I think. Or even before that, on some of the viral infectious diseases including HIV. And I was just curious, we'll start, we're going to start way back but we're going to move forward here in a minute. Um, was there one or two things that you learned, and I'm going to have you narrow like 10 years of work down into little tidbits for the audience today, but was there one or two things that you learned working in that field that really contributed to your thinking about how we could harness the immune system for the treatment of cancer?

You know, we— it was a— there's a story there of just plain serendipity. Because I didn't plan it that way, but it turned out to make a big contribution to the cancer therapy. So I was actually Admitted to Stanford in 1971, and then I got a draft number of 50. Ended up going to Annapolis so I wouldn't have to go to Vietnam. And then went to medical school, and then the Navy trained me to do bone marrow transplants, and that's where I became a leukemia specialist. And because the Navy had issues with potential radiation casualties through their submarines. So that's how I got trained in as a cancer physician and got interested in the immune system. And then with the Navy, though, there had been in 1971 a law passed where all cancer research comes to the NCI, as you probably know, through DHHS. And all the research in the armed forces was— and I had a 12-year obligation— was for infectious disease. So for 10 years, I worked on HIV and malaria and learned a lot about the virus. It allowed us to do the engineering of the CAR T cell. But also, we did the first human T cell transfusions with CD4 cells for patients with late-stage AIDS. And that gave us a lot— we saw dose-dependent responses. And then used the first lentivirus, which is really just a politically correct name for HIV. It's a gutted-out virus that becomes a tool. And we did the first transfusions with that in the '90s. And they were patients— and this was done ethically because there were risks, perhaps, with the virus. So it was done in patients with HIV. We found it was safe, and we got long-term engraftment. So then I went to the University of Pennsylvania with that in 1999, with that background of having done adoptive transfer in HIV. And it allowed us— basically, I'd had my feet in two camps, one as a cancer doc. But then I couldn't work on cancer, and so I moved to Penn in 1999. But that HIV background was critical.

All right. So I have kind of a pessimistic question and I have an optimistic question. So we'll start with— which one do you want to start with?

Okay.

Probably the optimistic, but we'll see. Yeah. Yeah. So, you know, when my background's working in the field of antibody drug conjugates, and if you hear how the story was told, one of the things that really cracked the ADC world was being able to discover linkers and understanding the biology of the lysosome and the and how things get degraded within the cell, which were completely opposite of our preconceived notions of how they actually do. So there was this aha moment in the field of ADCs where the lysosome and its environment was cracked. Was there 1, 2, or 3 aha moments in particular in your recent years working in the cancer field that, you know, just really turned the tide and, you know, monumental leap forward in what you were trying to do?

I think there were several. I mean, the major one was, you know, CAR T cells had been given in the past and they just basically failed. They lasted a day or two in patients. And that first trial was done in ovarian cancer patients by a group at the National Cancer Institute with a group also now in Australia. And that was an ovarian cancer, and the cells didn't last more than a week. And in the Netherlands, trials were done in renal cell cancer, and they didn't work as well. In fact, they were toxic. But those were so-called first-generation CAR T cells. They didn't have a hardwired co-stimulatory domain. Whereas in HIV, we had found actually that they worked. Single domain like that. So that the lesson there probably is that the immune environment in cancer patients is more toxic to T cells than it is in HIV patients, which was not immediately obvious. But then we did our first patient with a so-called second-generation CAR T cell that had this 4-1BB signaling domain in addition to the zeta chain. Which had been used in the past. And for the first time, I mean, we saw what had been the Holy Grail, which is the cells went in and then proliferated in the patient. And they proliferated much better, in fact, than they had in mice. So it was one of the very few times where it worked better in humans than it did in our preclinical mouse models. So I mean, we just— we had— it was, you know, we didn't know if we were really lucky or— but then, you it was reproducible. And it turns out that proliferation of the CAR T cells— so it's engraftment, and then they divide very rapidly with a doubling time of 0.78 days, is our recent data— that correlates with the response.

And when was that that you— just to kind of put the time—

So that was— so our patient was on the front page of The New York Times. I can say his name. He was a retired Marine sergeant, a prison warden. Now, 8 years out, seems to be cured with chronic lymphocytic leukemia. Still has his CAR T cells. And we infused him July 31, 2010. We had no idea what would happen. We had never even thought of the word cytokine release syndrome. And so in our informed consent document, it said, we're giving you this first— it was a phase 1 trial. It was a safety thing. We had this CAR. It was really surprising that it actually engrafted because it is a mouse hybridoma. And all the history is when you give mouse antibodies to people, they reject them. And so we put in our consent form that these cells will probably last a few weeks at most, then you'll reject them. And we thought that would be a safety feature. And then lo and behold, the cells went in and they proliferated and they killed off all the leukemia cells, but they also killed the cells that would reject the CAR, the mirroring part. They killed the B cells. So it was one of these lessons of who shoots first in a duel. And the immune system, the CAR T cells won. And this patient now has— 8 years later now, he still is engrafted with CAR T cells.

Wow, that's great. So I'll ask the— this could be a yes or no answer to the pessimistic question, but reading your story and thinking about all the things that you probably weren't successful at, was there a moment either when you were in the Navy, when you were working Armed Forces, before you joined Penn, after you joined Penn where there was a moment that you really thought this is just not gonna work?

Well, that—

It's just too complex. Maybe you think that every day, I don't, but you know, is it? Was there this moment where you really had to—

I mean, oh, for sure. I mean, so first of all, you had to be— I didn't know the difference really between the word persistence and stubborn. And you had to have both because no one thought it would ever work really. They kind of tolerated us. And there are only like 3 groups. There was my group at the University of Pennsylvania, Michelle Sadeline's group at Sloan Kettering, and Stanford and Phil Greenberg working. In Seattle on this. And no one thought it would ever be anything other than some boutique treatment, even if it did work. And no one really thought it would work because there's such a long history of immunotherapy not working. And, you know, so in 2010, when we got that response, that was just as ipilimumab was coming out. So no one believed in cancer immunotherapy. And, um, so what happened was I could not get funding to do the clinical trials. I mean, we got continuous funding from the National Cancer Institute to develop T-cell culture systems and so on and do studies in mice. But I never was able to get— and I got rejections 3 times from study sections— to do the trial. And so it was initially funded by philanthropy. But then, you all remember the 2008-2009 financial collapse. Well, then all the philanthropy went away as well. I had to fire most of my team. And I mean, I almost gave up and just was going to just go back and do— it's pretty easy to get funding for basic science experiments. So in 2009, I had to really, unfortunately, trim the workforce a lot. And we almost threw in the towel. And then we treated that first patient with the remaining funds funds we had and saw a response, but then ran out of money. So we published a case report on one patient because we didn't have any more money to actually finish the study. And then, then we got the arrangement with Novartis and we could finish the study.

Wow, that's not in the book, by the way. So that's a really amazing—

it was a breakfast I had with David Porter, who was a clinician. So I, you know, I made the lab side of this and the IND And David treated the patient. We saw this astonishing response. We didn't know if we were lucky, but we didn't have any funds to continue the study. So we sat down one morning, it was February, and it was freezing snow outside, and we decided we'd just publish our one patient and see what happened. And it got a firestorm of attention.

Wow, that's a great story. That really leads me to my next question, and then we'll hear your predictions for the second half of our fireside chat. And, you know, the thing I like about this meeting is it really is a unique meeting in that it's got industry, it's got academics, it's got foundations, it's got diagnostics. And, you know, I believe it's going to take a community to move this field forward. I just joined Lilly 6 months ago, having lived in the academic realm for 27 years. And I— one of the things that's really impressed me in, in in your career is that towards the end especially, and it's part of it's resource-driven, is that you've been able to maintain kind of this foot in academics and bench research, not necessarily for a commercial endpoint, and also having a vision for how do you deliver your scientific findings into the clinic. And maybe you could help us just kind of for people in the audience that are sitting on one side of the fence and thinking about going to the other side of the fence— and it shouldn't be a fence to begin with, but I'll just use it as a fence, you know, or someone that's sitting in industry thinking I might go back to academics, or someone that's trying to do what you've done, you know, found some companies, thinking about founding a company. Do you have some hints, or what do you think's, you know, really enabled you to kind of think about commercialization of your project, other than venture capitalists and people approaching you with money?

You know, it's complex. I mean, I have a very strong feeling that ethically we need to do everything we can to accelerate and do the same thing you're doing, which is, I mean, we finally have the toolset to talk about curing cancer. And I went back and read recently the You know, when the war on cancer started in 1971 with Nixon. And back then, it's really interesting when you go back and look at the congressional testimony. So, I mean, there was Sidney Farber and Mary Lasker pushing to have a major national cancer institute. But all the scientists who testified said we shouldn't do this. It's premature because we don't know what's causing cancer. And I hadn't— so that was, you know, I think now it's very different. I mean, we talk about the moonshot, but now we actually have science behind it and understand, you know, what really causes many cases of cancer. And so I think there is reason to have optimism that we can, by putting together the different tools— I mean, last night we had like CRISPR technology, you know, awarded.

It's—

that is really very much synergistic with immunotherapy. And, you know, it seems like something out of the blue, but it's an amazing orthogonal approach. And so we have this ethical imperative to have— and I get emails every day, and I'm sure you do, you know, from desperate patients. And how do we make this happen? It's frustratingly slow. Biotech has, in my experience, is the most nimble way to move things. You know, I've had 5 years of great association of artists. It's a big aircraft carrier, to use an analogy back to the Navy. It's hard to turn a big ship and, you know, it takes miles and miles. So the biotechs are more rapid and innovative, I think, but we need Big Pharma to be able to deploy and scale out. So So I think that's what we have to do now is have this partnership. And the one thing that I've learned now is the cell therapy and immunotherapy in general, unlike for instance, where I've worked with Novartis, I mean, they had Gleevec, imatinib, they then could make drug compounds. It didn't really need to go back to academia. Once they had that initial target of BCR-ABL. It's very different with cell therapies. Because in immunotherapies, with immunotherapies, you learn how they succeed or fail at the clinic by biopsy. And that really means there now has to be a partnership because it can't be done out there in the wild by pharma or something. It needs close partnership with academia. It's very different than making new drug lead compounds, I think. So immunotherapy now to move forward with targeted therapies has to be partnered. And really, we need to make sure that everyone has biopsies because we learn how we succeed or fail there. I was talking once to Bill Sellers, who ran our initial alliance with Novartis. And he was— we found now 3 different mechanisms, molecular mechanisms of resistance to CAR T-cell therapy. And then that leads us to ability to then engineer around those. Bill told me, he says, this is really remarkable. He says, we've been studying Taxol resistance for 20 years, and we still don't have any idea how to overcome it. So immunotherapy is because you can interrogate it, and I think there's hope at least that we can find the mechanisms of resistance and then engineer around them.

Yeah, well, I think your story really is a convincing one for when academic and industry partnerships work. Patients definitely benefit. And the toolbox on both sides of the fence has way more tools than it had 25 years ago when I started my career as an oncologist. So I think you're absolutely correct.

OK, so we have a few more minutes.

And I'm going to ask the question that everyone is probably here to hear you answer, which is, what is the next big breakthrough in immuno-oncology? If you had to put your money down on an approach— and I'm sure one of your answers will be improving the use of adaptive cell therapies for the treatment of cancer. But if you just had to predict, no insider information, Where do you think we've made the most recent progress and what are you excited about, I think is really the gist of my question.

So I'm really excited about synthetic immune systems. And so I mean CAR T cells are just one example of those. And we have now much more potent ones in preclinical studies than the ones that are FDA approved. That is going to move ahead at a cycle of advancement that's much more rapid, I think, than the pharmaceutical industry has ever seen because of this. Now there's a lot of research in the space. And so we'll see that. But the T cells are just one part of the immune system. We'll see engineered natural killer cells, dendritic cells, stem cells. We have an investigator at Penn, Sargill, who had a paper in Cell sometime last year where you can take CD33. For AML, really, the treatments for most patients are no different than when you and I were in medical school.

7+3.

7+3. And unless you're— it's one of the most awful things you've ever seen, the toxicity that has. I mean, you know. Unfortunate, but it's the only choice for most patients right now. And one antibody-based therapy is the Wyeth CD33 antibody and an ADC, as you know. So, and the problem with most CAR T-cell therapies for AML is that they will also hit stem cells and give you aplastic anemia. So unless you do it as a bridge to a to transplant, it's a nonstarter. So Sar had this idea that you could engineer around that by taking the stem cells and knocking out CD33, the Wyeth CD33 target. And then if you give a dual product, so stem cells plus T cells, so the stem cells have a CRISPR-ed out CD33 target. We knew there are patients that it's a tolerable immune deficiency because people can be born without CD33 and they're fine. So now, that's a trial that's going to start sometime later, we hope this year, in AML, giving a dual product, so engineered stem cells and CAR T cells. And I think we'll have the same things with NK cells and macrophages, et cetera.

Yeah. Well, I mean, I think that's what everyone's very excited about. What do you think about solid tumors? What has really— I know you get asked this every day, and I mean, my love is— my, not my love, my hate is breast cancer. But, you know, and we were talking about it before the session started, that every day patients are faced with a disease that will quickly take their life, and we have very little to offer them. What, what do you think we're going to need to do to take the successes you've learned through these, you know, cellular adaptive therapies and apply them to solid tumors? Because The science is probably close to there. I mean, is it that it's a lack of a target? Is it the immune suppression that is necessary for a solid tumor to develop? We just can't figure out how to turn that aircraft carrier around. What do you think it is?

You know, I think— so I'm optimistic it's going to be a problem solved. The timescale of how long it will take, I don't know.

Yeah.

I mean, we have examples that, you know, particularly with neoantigens where people have had remarkable responses, sometimes following an infection or whatever. And when you go back and dissect what happened, you can show that there were responses of T-cell-based usually against the tumor. And if it hits a driver oncogene I mean, it can be game over for the tumor. So I'm optimistic in that if we take out— and we have from our tissue banks at the University of Pennsylvania many surgically resected, for instance, ovarian cancer, pancreatic cancer, and lung cancer. Those, if you make a CAR T cell or engineered T cell in vitro, they will kill the tumor. So it's not that there's intrinsic resistance to most tumors to the immune system. It's targets. And then the complexity, as you know, there's subclonal complexity. There is the tumor microenvironment's more toxic. And sometimes, like pancreatic cancer, the collagen and tumor stroma and so on. So all of those can be, in principle, targeted and overcome. So it is more complex than in a bone marrow-derived tumor where T cells normally travel through more and there's a lot higher trafficking. So I'm optimistic it will be solved, but it's going to, you know, for instance, there's data from several groups now that if you combine an oncolytic virus with an immune-based approach and other, you know, I think we'll see it's going to not be a single bullet. But it's going to require multiple modalities to do this.

Well, I think we'll end on that. You heard it here first, or second, or third, that he's optimistic we'll crack the solid tumor dilemma here, at least hopefully soon, because patients are needing it. And I just want to congratulate you on your Luminary Award from this meeting, all the recognition that you've received. And certainly the patients that you've helped are incredibly grateful for your persistence and resilience and stubbornness.

So thank you very much for joining us this morning.

Thank you.

Thanks.