Dr. Jason Luke’s Journey in Immuno-Oncology Innovation

In this episode of OncoDaily, Dr. Jason J. Luke, a leading expert in Malignant Hematology and Medical Oncology, Associate Director for Clinical Research at Hillman Cancer Center, and Director of the Immunotherapy and Drug Development Center, joins host Dr. Ravi Kara to share his inspiring journey from music major to oncology innovator.

Dr. Luke discusses his pioneering work in melanoma and solid tumor therapies, including advancements in TILs, TCR T-cell therapy, and CAR T therapies. He highlights challenges in immunotherapy, the promise of novel therapies, and his leadership roles in SATC and ASCO. Dr. Luke also offers valuable advice for young oncologists on defining goals, seeking mentorship, and achieving excellence.

Dr. Ravi Karra, Vice President of Oncology at Advanced Clinical, is highly experienced in brain tumors, melanoma, and head and neck cancers, with over 20 years in academia, pharma, and CROs. He has led clinical trial strategies for various cancers, including rare types like glioblastoma and uveal melanoma, utilizing translational research and biomarkers. Dr. Karra has extensive experience with regulatory bodies such as the FDA and EMA, contributing to multiple successful drug launches.

Dr. Jason J. Luke, MD, FACP, FASCO, is the Associate Director for Clinical Research at Hillman Cancer Center and Director of the Immunotherapy and Drug Development Center. He also serves as an Associate Professor of Medicine in the Division of Hematology/Oncology at the University of Pittsburgh School of Medicine. Dr. Luke specializes in early-phase drug development, particularly novel immunotherapeutics and biomarkers, with a focus on solid tumors and malignant melanoma. His clinical interests include Phase I trials, cancer immunotherapy, and drug development.

Ravi Karra: Good morning, everyone, and welcome to today’s edition of Onco Influencers. I am Dr. Ravi Kara, an editor at Onco Daily. We are very excited to have Professor Jason J. Luke today as our guest. Professor Luke is an associate professor of medicine at the University of Pittsburgh School of Medicine. He is an associate director for clinical research of Hillman Cancer Center and also the director of the Immunotherapy and Drug Development Center.

Dr. Luke obtained his MD from Rosalind Franklin University of Medicine and Science, Chicago Medical School, and then he trained in internal medicine from the Boston University Medical Center. He finished his medical oncology fellowships from Memorial Sloan Kettering Cancer Center and the Bill Correll Medical Center. He is one of the foremost international investigators in the realm of immuno-oncology, having led multiple clinical trials with immunotherapies like anti-PD-1, CTLA-4, and many other secondary checkpoints.

His primary interest is in phase one clinical trials, immunotherapy of cancer, drug development for cancer, and melanoma. He is a very active member in multiple medical associations and organizations, including the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer. Professor Luke, we are very excited to have you today.

Jason J. Luke: Well, thanks very much. That’s a very nice introduction.

Ravi Karra: Let us start off by asking a personal question. Please tell us more about yourself, where were you born, where were you raised, and how did you end up where you are right now?

Jason J. Luke: Well, thanks very much. So, I was born in the Midwest outside of Chicago, a town called Hinsdale, and I have an interesting but not that interesting backstory, which was both my parents were musicians, and my father was actually pursuing a degree in conducting at Northwestern University when his mother passed away, and he decided to post back and go to medical school. So, when I was growing up, my dad was in medical school, albeit that my family was completely focused on music.

So, when I graduated from high school, I actually initially was in a music major because I didn’t know what I wanted to do, and everyone in my family is a musician, but after I realized that I was not that good, didn’t really like to practice, and was going to be very poor, I decided to switch, and I then became a, you know, pre-medical student.

But in college, what I realized was my interest actually very early on was in, you know, translational biology, and I actually worked in a lab as an undergrad all five years and basically got master’s level equivalency working in immunology and molecular biology, and as I then went to medical school and then through my training, that really kept me very focused on translational medicine, really with a focus on translational science and immunology.

And so, I think I was very fortunate to grow up at the right place at the right time, so that when I was a fellow at Memorial Sloan Kettering, as you noted, it was right when BRAF inhibition was becoming a big deal for melanoma, but that CTLA-4 antibodies were also showing this promise of curing patients with metastatic melanoma.

And while, you know, those who are listening take it probably as old hat at this point, and in the days, back in the days, 15 years ago when I was a trainee, melanoma was the kind of cancer that made cancer bad.

There was no treatment. And so, to see patients who truly got cured with ipilimumab anti-CTLA-4, that made me realize that that is the thing that I want to focus my career on, is trying to develop new immune system drugs that might cure people who have otherwise incurable cancer. And that’s really then spun forward into my faculty career and why I’ve been interested in pursuing translational immuno-oncology and drug development, and that’s led me to the place that I’m at now.

Ravi Karra: Excellent. Thanks a lot for that. I think we have a common connection that during my time at URTC almost 14 years ago, I was the lead medic on the adjuvant ipilimumab trial in a restricted high-risk stage 3 melanoma.

Jason J. Luke: Yeah, yep. That was an important breakthrough, although that was tough. Those adjuvant trials with ipilimumab, there was a lot of toxicity, so that’s, we’re welcome the fact that anti-PD-1 is so much more active to use it instead.

Ravi Karra: Absolutely, absolutely. So, that leads me to the next question, which is not the answer that why did you choose medicine, but why did you choose to specialize in oncology specifically?

Jason J. Luke: Yeah, and so that was, you know, part of that story, which was when I was training, and I was a medical student, I actually didn’t get very good grades in the courses like anatomy and physiology, because that wasn’t where my interest really lied. It was really always in molecular biology. And so, as I was a trainee then, I pursued a very clinical heavy residency at Boston University, which is the old Boston City Hospital, where you’re really looked upon to, you know, really get in there and roll your sleeves up.

And what I realized was, I really was interested in mechanisms as much as the patient’s outcomes, and so I actually considered going into transplant cardiology when I was a resident, because we saw so much heart failure. But, but as I then thought about it more, I eventually wanted to be someone that was really at the intersection of the lab and the clinic, and in oncology is really where you can do that the most. And with a background, you know, really focused on the molecular biology and immunology, that’s really what drove me to stay connected and to go into oncology.

You know, as with everyone else, you know, I have a little bit of a personal story. When I was, while I was a resident, my wife’s father was diagnosed with metastatic renal cell carcinoma, and so we went through the whole odyssey of his treatment, and that was when VEGF blockade with small molecule TKIs was evolving, but he was treated with high dose interleukin-2, and that experience also, you know, drove decision-making about why would you pursue oncology versus anything else. But in the end, I think it, you know, it’s a, it’s a high calling to take care of people who have cancer.

It can be a tough thing to do, obviously, on an emotional level, but it’s also tremendously rewarding from a scientific perspective to be actually be able to take concepts, interact from the lab all the way into the clinic and back, and there aren’t very many other medical disciplines where you can do that.

Ravi Karra: Thank you. Can you tell us more about your current role, and very specifically, what are the treatment, tumor types that you treat?

Jason J. Luke: Yeah, so I kind of have several hats at this point in my career. So on a personal level, I run our early phase clinical trials program, where we have one of the most robust phase one groups in the United States. We routinely have more than 75 open phase one clinical trials accruing actively, you know, and so that’s very robust.

Now, my personal interest is in immuno-oncology, so while I am the PI for studies of other modalities, really looking for really novel approaches to use the immune system is what I’m the most interested in. So, but beyond my clinical practice in advanced solid tumors, I’m also pretty well known as a melanoma immunotherapy person, and so I’m also helping to design and run, you know, global phase three programs for melanoma agents. So in that realm, I’m very interested in the PRAME-directed TCRT cell therapy from Immatix, as well as the previously RP1, now the virus strategy from RepliMUNE, and these are looking very promising for refractory melanoma.

So my clinical practice is really around advanced solid tumors or cutaneous malignancies, sort of from the early phase into the late phase clinical trial space. I also have a translational research laboratory that I run with my collaborator, Rir Bao, and we have an R01-funded immunogenomics lab that looks at tumor-intrinsic mechanisms of immune exclusion to try to identify novel therapeutic targets to combine with immunotherapy.

And then on an administrative level, I’m also the associate director for clinical research, which means I oversee all the clinical trials at UPMC Hillman Cancer Center, and that’s, more than 800 open clinical trials.
It’s a staff of more than 250 people, and it’s trying to keep the trains running on time to make sure that all of our clinical trials can be available for our patients and all the stuff that goes along with that.

So, you know, a lot of things to do, but it’s meaningful to participate in all these different levels from my own lab to clinical trials to governing the overall infrastructure. And so, you know, a pretty exciting time to see all these things happening in cancer.

Ravi Karra: Well, it seems like you really do have a lot of hats. Now, a follow-up question based on what you said. In melanoma, is there currently a subpopulation of patients who really have an unmet need?

Jason J. Luke: Oh, absolutely. And I think that this is a point, actually, that gets lost a little bit. You know, I mentioned earlier that 15 years ago, melanoma was the cancer that made cancer bad.

But if you fast-forward now 15 years, what you realize is that, yes, about half of our patients are being cured functionally with combination checkpoint blockade, but that means half are not, right? And so, for the people who do not go into long-term response to double-checkpoint blockade as a frontline strategy, their outcomes are very bad. They’re like the outcomes were now decades ago, right?

So, the median life expectancy for someone who does not respond to immunotherapy is like nine months, right? And so, when we think about what does that mean, there’s a huge unmet need in melanoma for checkpoint refractory patients, which is, roughly speaking, 40 to 50% of the population. So, this idea that we’ve cured melanoma is totally wrong.

We’ve made unbelievable strides in melanoma, so that even metastatic disease is something that we go into hoping to cure, and yet there’s a huge unmet need. And so, that’s where I mentioned some of the things that I’m excited about in the field, which are really novel or new mechanistic strategies to try to enhance immunotherapy responses. So, tumor-infiltrating lymphocyte therapy with lifalucel was approved in the United States as an accelerated approval earlier this year.

That gives us a totally different modality to try to treat patients with. TCRT cell therapy I alluded to, oncolytic viral therapy. And so, I’m really, really interested in the new things that can help that half the population who are not cured, right?
And I think we shouldn’t lose sight of that. I think sometimes people see all the new drugs in melanoma and think, oh, melanoma, that’s taken care of. It’s like, but it’s not.

Half the patients still pass away from melanoma in a relatively short period of time. So, we absolutely need to do better.

Ravi Karra: Okay, great. You mentioned about immune checkpoint inhibitor refractory patients, but what about the patients who respond? Do we know up front which patient may respond?

Jason J. Luke: We don’t. I would say, you know, sadly, our ability to really refine our selection of patients for different treatments has not come as far as our therapeutics have come. So, what we know is from the follow-up of the Checkmate 067 seminal study of nivolumab and ipilimumab that the 10-year melanoma-specific survival is not reached.

So, that means half the patients haven’t died from melanoma. But to your point, do we know exactly who they are? We know a little bit who they are, but not in a way that I think we should be proud of as a field given how far we’ve come.

Because I think, you know, on a translational level, we can build models using genomics and radiomics and various different, you know, things to be able to predict with very high sensitivity who is going to go into long-term response and who’s not. But we don’t really apply any of that in clinic because it’s too difficult so far. So, in standard clinical practice, whereas in lung cancer they stratify by PD-L1, we don’t do any of that melanoma.

We just give combination. And I think, you know, I think all my colleagues would agree, and I don’t say this with like any venom or anything, but I think that that’s a problem. I mean, we have not done the work to really refine out who’s truly going to benefit, and I think that’s kind of too bad.

We’ve been so, you know, so successful developing new drugs that we haven’t taken the time to go back and figure out, you know, what about the old drugs? So, you know, I think this is something that we will all need to focus on, and it will become ever more pressing as we have newer therapeutic modalities, right? So, now that we have TILs, I’m not very enthusiastic about giving TILs to patients who haven’t already had a checkpoint inhibitor because there’s so much toxicity with TILs, right?

But at the same time, if we truly knew who was not going to respond to NEVO plus Ipi and wanted to go straight to Lifelucil, that would be tremendously valuable, right? And I think as a field that does need to be something that we really truly focus on over the next, say, three to five years because we’re getting iteratively more therapies that are coming in, CD8 bispecifics, TCRT cells, et cetera, that this is going to become a pressing question, what treatment for what patient? And we have not done enough yet to really figure that out.

Ravi Karra: Thanks for this insight. Please can you share a bit more details about your translational research lab?

Jason J. Luke: Yeah, absolutely. So, as I was going through my career, one of the seminal moments for me was getting the opportunity to work with Tom Gajewski at University of Chicago. And his lab was seminal in sort of the development of the conceptual model that I think a lot of us take towards the use of checkpoint inhibitors.

So, people have heard of this concept of hot and cold tumors, right? And that was work that, of course, many people contributed to, but Tom’s lab was really one of the major drivers. And so, his lab focused on the concept of using, early on, using gene expression, transcriptional profiling to look at which tumors had high degrees of interferon gamma or CD8 T cell expression as a surrogate for who would likely respond to immunotherapy.

And that model was proposed kind of in the early 2010s and really does, even to this day, is probably the best conceptual model. Of course, it’s not perfect, but it gives you a sense of hot tumors have high levels of gene transcripts associated with interferon and CD8 T cells. Well, so having taken that model, our lab kind of looks at the reverse, and this builds off a paper his lab had published in 20, I think, 14, which is to say if a tumor lacks immune infiltration and manifests as lacking a transcriptional profile that is consistent with an immune response, what are the biological processes that are happening in the cancer that are actually leading to the lack of an immune system infiltrate?

And so, we refer to this as tumor intrinsic mechanisms of immune exclusion. And so, his lab had published initially on Wnt signaling or Wnt beta-catenin, but our laboratory in the past five years has taken a much broader view of cancer in general and tried to ask the question, can we reinterpret cancer signaling pathways that we once thought were only growth advantages for cancer cells and actually interrogate do they have immune implications?

And so, our lab takes sort of a conceptual model of sort of taking cold tumors and then trying to look at what are the signaling pathways that are active in cold tumors, and then trying to mechanistically link them to the lack of T cells targeting the cancer. And then, because I do phase one trials, do we have therapeutics that we could actually apply? So, could we select patients based on the signaling in their tumor that we might apply a targeted therapy, not necessarily because it’s going to kill the cancer, but because it might interrupt the signaling pathway that’s not allowing the immune system to fight the cancer?

And we have one initial observation around this for the signaling pathway, the P38 MAP kinase signaling pathway, where we identified this as strongly active in cold tumors. And we actually have done a clinical trial now of repurposing a P38 inhibitor, and we’ve seen multiple major durable long-term responses in patients who had already had anti-PD1 and it didn’t work. And we treat them with this combination, and now they’ve gone into long-term response.

And so, that’s what our lab really likes to look at is how can we attack tumor cells in a way that makes them more amenable to immunotherapy approaches? And we’re pretty excited about this line of research.

Ravi Karra: Excellent. That’s very promising. Now, moving from our translational research to early-phase clinical trials, you mentioned that there are hundreds of trials running with respect to phase one.
Phase one, solid tumors, where do you think CAR T-cells are fitting in, number one? And what are the challenges you see in running CAR T-cell trials?

Jason J. Luke: Right. So, I think it’s certainly the case over the next couple of years that we’re going to see the entrance and the clinical relevance of adoptive cell transfer. And so, that’s going to be TILs, which are already approved for melanoma, but I mentioned TCR T-cells, and now you’re mentioning CAR T-cells.

And so, I think that there’s no doubt this is going to become an important area of clinical investigation, but I think actually clinical care. We’ve thought about CAR T-cells specifically in hematologic malignancies, where they’ve had just unbelievable success with CD19 and CD20 targeting. But of course, in solid tumors, it’s been a little less clear.
And one of the major reasons for that, I think there are multiple reasons, but one of the major reasons is lack of good targets. And so, with CD19 and CD20, you can completely ablate a human being of those targets, and that kills the cancer, but doesn’t kill the patient.

And so, finding those targets in solid tumors has not been so easy to date, but that is starting to change a little bit, right?
And so, if you look at hepatocellular carcinoma, if you look at colorectal cancer, there are some CAR T-cells that are emerging that are going after antigens that seem to be amendable to this process. Now, it is still fraught. It is still somewhat toxic to do these things, but I think that’s the refinement is coming in.

And that’s where I would note that my personal opinion is that TCR-transduced T-cells are more likely to become a bigger deal in solid tumors before CAR T-cells do. And the reason for that is with TCR T-cells, it’s easier to go after intracellular proteins, albeit that you have to go after them in the context of their binding to MHC. So, you have to HLA-restrict patients, right?

So, that refines the study population to people with the right HLA haplotype and expression of this molecule you’re going to go at. And that’s why, as a first example of this, the IMA-203 program in melanoma, which is a PRAME TCR T-cell, is kind of the perfect alignment, because in melanoma, half the population of Caucasian people are HLA-A201, and melanoma universally expresses PRAME. So, these two stratification, biomarker stratifications, you still have a robust population of patients.

As you extrapolate that to other tumors, that intersection between the HLA profiling and the target expression becomes more difficult. And so, I think we’ll see TCR T-cells come in. But as some of the issues with CAR T around finding good targets and mitigating toxicity, as those become less problematic, I do think we will see them starting to come in.
And there are some good targets that are being explored, things like MUC1, MUC16, mesothelian. These are, I think, probably pretty good CAR targets. But we have to kind of find what is the best way to deliver these, and what are the modifications to the CAR that are going to be necessary to make them active in solid tumors.

And we’ve seen some hints at that. If you look in the TIL literature, adding an inducible IL-15 seems to make a big difference to TILs. That’s probably going to be true of CAR T’s as well.
The idea of inducible dominant negative TGF-beta may be a big deal in CAR T-cells, and there’s a lot of research going on around that. So what I’d say is keep an eye on this space, but we’re still probably, you know, three to five years away from this becoming a really big deal.

Ravi Karra: Okay, thank you. That was quite insightful. Now, moving to a different segment.
You are very active in several medical societies and organizations. I just named ASCO and SATC as just two. Can you elaborate a bit in more detail, for example, your role in SATC, and then probably in ASCO?

Jason J. Luke: Sure. So, you know, one of the things that I found early in my career was that the camaraderie and the commitment to our profession was meaningfully enhanced by contributing to professional societies. And so I think there’s no doubt that my career advancement was enhanced by this.

But I also made a lot of friends by working through different societies and working on projects with people at other institutions. And so before diving into specific ones, I would really emphasize for junior faculty or even fellows that getting involved with these efforts, I think, is really meaningful to your community and also can be very meaningful to you personally. So with CITSE as an example, I mean, obviously, I already talked about immunotherapy being my primary interest level.

I got involved with it because my, you know, colleague and mentor Tom Gajewski was actually the CITSE president early on in my career. And so I kind of just got involved with it because he was so involved with it. But what I found was that the people working on the same scientific questions that I was interested in were really great people.

And they were very generous of their time. They gave me great insight. They allowed me opportunities to do things that I think made a difference both for the field and for, you know, for, you know, me and for the community.
And so I think, you know, it is extra work, right? You’re taking on extra things to do. But, you know, if you really value that part of the field, I think it’s really meaningful.

So I’ve been heavily involved in many, many committees in CITSE from scientific committees to policy committees to regulatory committees. And more recently, I’m on the, I’m an at-large board of directors member for the society. So now I’m on the leadership council for the society.

And I, you know, I, again, I’ve found it to be a very important thing in driving, you know, the science and the clinical care of patients in this realm. Similar thing with ASCO. I was very fortunate early on to be nominated when I was at the Dana-Farber to be the leader of the melanoma science committee, initially as an education member, but eventually on the science committee.
And again, that gave me great insight into, you know, how does ASCO work? And what is, you know, ASCO is a really big organization. It has a really global reach.

And what are all these things? And so really what I said then was, you know, if you call on me, I’m more than happy to give up my time. And I’ve been on many, many ASCO committees as well.

And they range from really interesting things like the program committee for the annual meeting to like really pretty dry things like working on, you know, ASCO university with the, you know, board questions and stuff like that, which is not my favorite, but like, you know, it was probably important. And so, you know, again, that’s been important. And actually, as of today, it’s going to be announced that I’ve attained a fellow of ASCO.

And I think that, again, that’s meaningful, not so much to have the F ASCO thing on your byline, but rather to say that, you know, you’ve made that commitment to all of your colleagues and to the field to have given of yourself and your expertise and your time in a way that probably adds to the, you know, totality of what you do beyond either doing clinical trials or taking care of patients. But this is just another way that you can contribute more broadly. And so, again, I would emphasize that while it is extra time and effort, it is something that’s meaningful.

And I would really advocate for junior faculty to reach out and try to get involved.

Ravi Karra: Oh, excellent. That actually leads, that’s a fantastic segue to probably the last question is, what is your advice to young budding oncologists with respect to patients, with respect to research?

Jason J. Luke: Yeah. So, you know, what I’d say off the top is people have different motivations in their careers and understanding what your motivation and what you want to accomplish is really important. And it sounds tedious and it definitely was tedious to me that when I was early, you know, interviewing for like my first job, people would ask me like, what do you see yourself doing in five years?

And this is like the most generic interview question, but it actually is a very insightful question because what is going to be meaningful for your life will really drive what you decide to do. Right. And so for me, what I wanted to do was be a high volume clinical trialist who was also a translational researcher, but that necessarily meant that was going to be a lot to commit to.
Right. And not everybody really wants to do that. Okay.

And it’s not good or bad one way or the other. That’s the other thing that I think I would really emphasize is that in training, you work at these medical institutions where it’s self-selected for attendings who want to be scientists. Right.

That doesn’t mean everybody has to be a scientist. It doesn’t mean you’re a bad person if you don’t want to be a scientist. Right.
But it is important that you take time for yourself and decide what do you want to do. Right. Because if you want to have a family and be an important person in your community, but not do translational science, that’s okay.

But the flip side of that is if you do want to do this kind of thing, you have to realize it’s a major commitment to do that. Right.
And it can be an all encompassing thing about your life to set up your life in a way that you’re going to be able to make the steps that are necessary. So what I’d say is, is know yourself and spend time and think about what do you want to do. And then after that, what I’d say is mentorship is key.

And I already mentioned in some of the other comments about how I advanced my career, both in the societies, but also in science, mentorship is key. And finding something that you look up to, who has going to take time to both give you opportunity, but also to call you out and make you better is a really, really important part of how your career will develop. And I have a slide in things that I, in a slide deck that I show fellows, and it shows some of my seminal mentors.

And I’ve been very, very fortunate that my mentors that I quote them, Gary Schwartz, Jed Wolchuk, Tom Gajewski, you know, these people have gone on to have very august careers. They’re cancer center directors. They’re some of the most famous scientists.
And I was fortunate to be around these people. Right. But I also note on that same slide that part of it is have a thick spine.

And so I show a picture of Luke Skywalker getting electrocuted by the emperor because these people were straightforward. And they said, here is what you need to do. And if I wasn’t doing it, they were telling me, you need to go do it.
Right. And if you don’t come with a handout, you come ready to do work. Right.

And what are you going to contribute? And this can be a really hard thing for junior faculty, because you maybe don’t, you know, you don’t know everything, but how do you come to someone and say, I can contribute and I’m going to work hard and let me show you that I can help. Right.

If you come with that mindset, you almost certainly will be successful because people respond in a way to offer opportunity. If you take those opportunities, the sky is the limit. You can move as fast as you want to move, but it really goes back to how much of this do you really want to do?

And so that’s what I would set it out. It’s not so granular, but rather know yourself, find good mentorship and then live your life in a way that you find meaningful. And if that’s to really grind and do a bunch of academic stuff, fabulous.
If it’s to have a family, that’s great, too. I like to think I have a good family also, but you see what I’m saying? So that’s what I’d say to people is know yourself first, but then take the track that you find the most meaningful.

Ravi Karra: Thank you very much. I think that was a fantastic message to our budding oncologists and all the questions that you responded and the insights that you’ve given are very, very, very valuable. Thanks a lot.

I am really extremely glad we had this talk and I’m very pleased that you’re wearing so many hats. All the best and hopefully we stay in touch.

Jason J. Luke: All right. Thanks so much for the opportunity. Hope everybody has a happy holiday.