Welcome to the iwCAR-T Sessions with the Video Journal of Oncology (VJOncology.com).

A roundtable discussion filmed in Tampa, FL, during the iwCAR-T 2022 workshop with experts Randy Hecht (UCLA), Diane Simeone (NYU Langone), Will Go (A2 Biotherapeutics), and Mark O’Hara (University of Pennsylvania) who discuss emerging CAR approaches in solid tumors as well as associated challenges.

Welcome to the iwCAR-T Sessions brought to you by the Video Journal of Oncology (VJOncology).

Following a fantastic first day at the iwCAR-T 2022 meeting, the experts come together to discuss their highlights. This exclusive roundtable session is chaired by Randy Hecht, who is joined by Diane Simeone, Will Go and Mark O’Hara. The speakers discuss the current state of CAR-T cell therapy for gastrointestinal cancers as well as the key challenges and future directions.

Transcript

Randy Hecht:

My name is Randy Hecht and I’m a GI oncologist at UCLA. I’m here in Tampa at iwCAR-T. I’m fortunate enough to have three people who actually have given wonderful talks here on GI malignancies or solid tumors in general. Diane Simeone is a surgeon and an internationally known pancreatic cancer researcher at NYU. Will Go is someone who’s been in industry and working really on CAR-Ts for over a decade and has helped lead and helped make certain that patients actually get these drugs that have a chance of helping them. Mark O’Hara is really one of the leaders in the use of CAR-Ts from a wonderful group at Penn, that is really probably one of the best in the use of immunotherapies in pancreatic cancer.

Our discussion today started off with me talking about how poorly we’ve done with immuno-oncology in GI malignancies. Unfortunately, unlike other cancers like lung and melanoma, we haven’t done so well. Really, the people here are going to give some ideas of how we can do better. Do you want to go ahead and start because you have a wonderful program that’s a national program that really will help fast track interesting ideas into patients and hopefully lead to moving the bar in pancreatic cancer.

Diane Simeone:

Yeah. Thanks Randy. One of the things we talked about is we’ve actually made a lot of scientific advances in understanding pancreatic cancer. Pancreatic cancer is really a challenge because as a complex tumor micro environment that makes it particularly immunosuppressive. Some of the breakthrough therapies that are out there for other cancers that you’ve heard about like melanoma or now lung cancer, really haven’t worked for pancreatic cancer. What we’ve talked about is how do we make true advances?

One of the things we presented today was a new National Clinical Trials Network that we’ve developed that has organized us as a field where now we have 30 centers all working together with a path to do really innovative clinical trials where we can also deeply interrogate the patient’s tumor as we’re doing them to really kind of crack the code of how we might deliver cell-based therapies more effectively to pancreatic cancer patients. Maybe Mark can tell us a little bit about his experience in this domain. Then, we’ll hear a little about Will, about a new approach that we might think about.

Mark O’Hara:

Sure. Today I had the privilege of presenting some of our data on the evaluation of a CAR-T cell that’s targeting mesothelin, a commonly overexpressed protein in pancreatic cancer and evaluating in patients with metastatic pancreatic cancer. We’ve been basically studying different varieties of this CAR-T cell over the last seven years, two trials looking at an SS1-based CAR which is a murine CAR that targets mesothelin. Then, more recently, a trial that we’re running, looking at an M5-CAR, which is a fully human anti-mesothelin CAR. In showing that, while we’re seeing sort of limited activity, we’re getting some hints at some things that may be actually developing within the CAR-T cells, developing a dysfunctional signature, for example, that the pancreatic cancer is putting up against the CAR-T cells to make them not function well. From that, hopefully learn in terms of what our next step would be in terms of designing novel combinations or novel modifications of CAR-T cells. In terms of novel-T and CAR-T cells, I think that’s a good segue into what you’re working with Will.

Randy Hecht:

Can you talk about what you’re working on now?

William Go:

Absolutely. Again, thank you for inviting me here and also with all the work you’ve done, Mark, has really moved the needle into solid tumors. I think the real challenge about solid tumor CAR-T is that in the FDA approved products in B-cells and also in plasma cells, you can live without a B-cell or plasma cell for a while, but you can’t live without the lining in your heart, your lung, your GI track. The real discrimination is how do we do that? What we can think about is like logic gates or logic switches. One thing that we’ve been developing at A2 Bio is really looking at almost self versus nonself. Then, we can have a CAR activator, our CAR blocker, and then if you lost your tumor loses an antigen, then it’s almost like it’s not self and says, “kill me.” Then, your normal cells have it and it says, “don’t kill me.” I think the real challenge of this truly precision medicine, which then feeds into Dr Simeone is, can we have adaptive trial designs, because it’s truly precision medicine. If we would actually be able to find this to work in a small population, how do we expand that population to broader, other targets, other patients, and across the globe?

Randy Hecht:

Well, the other thing that we’ve been talking about so far is pancreatic cancer, which is unfortunately one of the more dismal outcomes for our patients, with most people being dead with metastatic pancreatic cancer within a year. However, also, I know that you’re looking at this in other GI malignancies and non-GI malignancies. Pancreatic cancer will soon be the second most common cause of cancer death after non-small cell. Colon is still number two for now, but will be number three. I know that you’re looking at really all three of the leading causes of death from cancer, at least in the United States.

William Go:

Yeah, absolutely. The BASECAMP-1, it’s going to be covering non-small cell lung, pancreatic, and colorectal. As many at this conference said with Dr Molina, IO, immuno-oncology has really revolutionized at both in melanoma with Dr Antoni Ribas’ work, as well as many others in non-small cell lung. As you said, Dr Hecht, that MSI-high is great, but that’s a really also small population in GI malignancy.

Randy Hecht:

Colon cancer, even though there is that small group of about three percent of people who have wonderful, perhaps long-term, even off-treatment responses to what we now would call standard immuno-oncology drugs, the chance of finding that in a pancreatic cancer patient we were discussing is still really small. You’ve been fortunate and you have found those patients, but it’s definitely less than one percent. Mark, have you had any patients who are MSI-high? Which is a different way, but very sensitive to so-called checkpoint inhibitors. Really, we’re what we’re talking about how the things that have the chance of helping 99 percent of pancreatic adenocarcinomas and 97 percent of colon cancers.

The other reason that I’m so excited about this is that some of the trials that Diane is doing and some of the improvements that we’ve had, and a lot of my background is in targeted therapies. Targeted therapies, even when they work, only work for so long. The idea of finding immunotherapies that have that promise, a precision promise to that chance of having a long-term benefit, not measured in months, but measured in years. That’s really what our patients care about. They’re not interested in hazard ratios or medians and what they want is they want to say, “Will I be alive five years from now?”

William Go:

And Precision Promise, can you talk about it more? I think how it lowers the gear of activation energy for not just academic centers, but for industry partners?

Diane Simeone:

Yeah. This is a really interesting national effort and I want to give a shout out to the Pancreatic Cancer Action Network, which is serving as a, which is a nonprofit, the largest in the country, focusing on pancreatic cancer and is serving as a sponsor for this trial. Really, this was an effort to say, if we have promising therapeutics, how do we effectively get them to pancreatic cancer patients? Importantly, we’ve talked about it here. We have to move past the era of studying how therapies work in mice, but understand what’s really happening in patient tumors. We can cure pancreatic cancer in mice and we can take those therapies and then they don’t work in people. This is the decade of studying the human patient in pancreatic cancer. That may require biopsies from patients before they start a trial in on therapy. If that’s what we need to do, patients are more than willing for us to be able to deliver effective therapies. What is a really important part of it is to diminish the siloing effect where each institution is doing its own thing in a small number of patients, but more general sharing of knowledge and tackling a complex problem together. If you just look at what has recently happened with development of COVID vaccines worldwide, it’s not hard to see that that’s the model we should be doing. When we have a really tough problem that a single person or a single center can’t solve, we have to work together and tackle the different pieces of it. This is this effort, Precision Promise, where we take the most interesting clinical trial concepts and we figure out how to best test them in patients. We build a lot of science around the clinical trials so that we can learn early on are the hypotheses that we have in place correct. For example, if you take CAR-T based therapy, an initial question is that CAR-T even getting into the pancreatic cancer? We still don’t have the answer to that. I’m hoping Mark is going to be able to share some of that data with us at the next meeting we’re at, but we have to go in a step wise manner where we learn. Why did it work? Why didn’t work in patients? How do we take what we learn and build upon that? This is an effort to do that.

Randy Hecht:

I think two things. One is that we were actually discussing on the way over here, how there really almost is no excuse not to have a trial designed, to learn from the tissue. Even though not every person will be able to have a biopsy, but it should be mandated. The other thing I think is also important from the wonderful work that you’ve done has been the importance of the advocacy group. There are other, this is not a novel. I think it’s a better model, but it’s not a novel model. There are things like in breast cancer with I-SPY, but those have been encumbered to a certain amount by the amount of bureaucracy because of the way that these things were set up. I think obviously this is something that’s near and dear to you and you’ve been the driver behind it, but I also want to say that I think bringing this as a model to other advocacy groups and other malignancies, I think is also really important.

William Go:

Mark, what do you think about these kinds of cooperative groups, especially in self therapy? I think you want, tumor microenvironment is near and dear to your heart. Do you want to make a comment on that?

Mark O’Hara:

In terms of sort of bringing cell therapies to cooperative groups?

William Go:

Yeah.

Mark O’Hara:

I mean, I think overall in terms of looking at sort of clinical trial design in a cooperative group is a good thing. The Precision Promise is a great way of actually studying medicines quickly, relatively quickly, and basically say no go or go decisions at that point. I think that’s a perfect design to evaluate that in pancreatic cancer. When it comes to cell therapy, I think there’s a challenge just because we are so early on in our understanding of CAR-T therapy and pancreatic cancer at this point. I would love to someday have the clinical efficacy, the toxicity, have that all figured out such that we can roll it out at a wider stream into these cooperative groups. That would be an ideal situation, but I think we have a lot to learn before we can do that.

Randy Hecht:

Actually, just to build on that, you come from an institution that of course is really sort of seminal in CAR-Ts and has done a wonderful job in not just where it’s been successful, but also in working in places where we still need to do better. One of the problems with cellular therapies is because it’s so complicated and because actually quality is so important and safety is so important. I was wondering if you could just, because I think you really are a model. The rest of us are trying to put this all together. We have these cell therapy people over here, we have the solid tumor people over here. How do you interact in order to make certain that you’re able to do your studies?

Mark O’Hara:

Yeah. I think every institution does something a little bit differently. How we’ve modeled it at Penn is that while I’m sort of leading the trial, when my patients, for example, are admitted to the hospital receiving their CAR-T therapy, they’re on the bone marrow transplant cellular immunotherapeutics team. On that team, it’s a nurse practitioner PA led team with an attending that’s actually a bone marrow transplant cellular immunotherapeutics doctor. Right now, there are liquid tumor oncologists that are the head of that team. As we get more solid tumor CAR-T therapies, I think we’ll see more solid tumor oncologists in a separate cellular immunotherapeutics.

Randy Hecht:

Do you think that solid tumor oncologists will have to learn then how to take care of these patients? Right now we’re not used to inpatient treatments. Your surgery is always inpatient, but instead we’re used to giving drugs in the clinic, we’re used to writing prescriptions for pills. Not that we don’t have toxicity and all of us are drug development people, but do you think that it will sort of be, each will do what they do best or do you think that you’ll end up having to be a cell therapist as well as a solid tumor doctor?

Mark O’Hara:

Right now I think we’re still on our infancy right now in solid tumors. I’d love for it to get to adopted in several different solid tumors in the near future, such that we have to consider that problem. I think we’ll say in similar to what was said earlier on in the program, that as we have more cellular therapeutics and solid tumors, I think you’re going to have referrals to specialist centers and there’s going to be only specialists within solid tumor referrals.

Randy Hecht:

I was actually going to ask you about that because our colleagues in hematological malignancies, they’ve done a really good job of certifications and things like that. Well, which we really don’t have in solid tumors. Anyone can treat pancreatic cancer, for example.

Diane Simeone:

I realize anyone can treat pancreatic cancer, but I guess I would answer your question that there has to be a team, right? Nobody knows everything.

Randy Hecht:

I didn’t say everyone should treat pancreatic cancer. I said that anyone can treat pancreatic cancer. If you’re an oncologist that you can treat pancreatic cancer, that drugs are FDA approved, they’re paid for by insurance. This may be sort of a hub and spoke, just like you’re doing now with referrals. I think it really is going to be a learning experience. You’ve been there since the beginning with working on this, but for the rest of us, I think it’ll be a real learning experience.

William Go:

I was going to mention from an industry’s perspective, we really want to keep it at fact accredited, which is very similar from how it was regulated internally from bone marrow transplant. Now, with the ASTCT because it’s all cell therapy, not just bone marrow transplant, and fact accreditation, because it takes a team. It’s a multidisciplinary team, as you all know. I think what’s going to happen is that you’re going to have centers of excellence, just similar with previously bone marrow transplant fact accreditation. We want to make sure it’s the same and it’s delivered safely and effectively all across. I know from also, from when we get products approved and eventually reimbursed, that is actually really important as well.

Randy Hecht:

I think the payers, because these are not inexpensive therapies. Not that any of our therapies other than 5-FU if you are inexpensive. That will be something I think that’s really important to the payers.

William Go:

But to what you were saying, I mean…

Randy Hecht:

And patient safety.

William Go:

Right. I think all of our dreams is obviously to treat a lot of solid tumors. One thing that would be really important is a really true Precision Promise type thing where you can say, “Here’s a test. Here’s the right cell therapy for you.” The dream would be to pull something off-the-shelf and into these centers of excellence so we can get that faster to the patients across for all different types of tumor trials.

Randy Hecht:

But I don’t see that ever being done in a place that doesn’t have the whole team that you were talking about.

Diane Simeone:

I think for, obviously, for some cancers where there are standard effective therapies, that’s one paradigm. For other cancers that we have not cracked the code, I really do feel strongly that those patients, when possible, should be seen in a tertiary multidisciplinary setting. If we just keep treating, for example, patients of pancreatic cancer, the same way, we’ll be all looking at each other two to three decades from now and say, “Huh, how come the stuff we’re giving still doesn’t work?” Well, because we have not evolved. I think for recalcitrant problems in the medical field and here we’re talking about certain cancers, we do have to have these patients focused in centers where we try to do research on almost every single one of these patients. I think our patients should expect that we’re not going to move the needleless disease until we look at the problem differently, bring different angles to it, and challenge ourselves to move the needle.

William Go:

I was shocked how low the amount of pancreatic cancer patients or even colorectal, are on clinical trial.

Diane Simeone:

Yeah. I highlighted that in my talk today. It’s only four percent of patients with pancreatic cancer and probably colon cancer, maybe a little bit higher, Randy will comment, on clinical trial. How do you change clinical paradigms if only four percent of patients go on trial? You have to make trials more accessible. You have to make a case to the public of the benefit of being at a center where they can be on a clinical trial.

Randy Hecht:

You also want to make certain that every patient that can go on trial goes on study. That was sort of the discussion we were a little bit having is that the problem is that a large percentage of people will never be trial candidates. They have two different cancers, they have end stage heart disease, they have other reasons why they can’t go on study. In some ways that makes it why it’s even more important that we capture all those patients who are potentially able to go on study. Unfortunately, patients, we’ve been talking a lot about pancreatic cancer. Often, those patients may deteriorate quickly. I’ve always been fascinated. Even in colon cancer, which is a little bit slower. If you actually look at the real world data, the percentage of people that never make it to first line is surprisingly high. The percentage of people, you think everyone gets on first-line goes on second-line. Actually, there’s a big drop off between first-line and second-line. In pancreatic cancer, I think it’s even higher. I haven’t seen those exact numbers. The others were sort of done by industry. That goes back to what you were saying, how important it is to capture those patients and have at least a study for them, a reasonable study.

Diane Simeone:

Yeah. Honestly, the beauty of Precision Promise is someone can come into the trial and if they’re a first-line patient, if whatever they’re given, if it works and then stops working or doesn’t work from the beginning, they can get re-randomized to a second novel therapeutic approach, which I think is really an amazing thing for us to be able to offer patients.

Randy Hecht:

Just to conclude, I want to thank my colleagues here and also the people who invited us at iwCAR-T for allowing us to talk because the last decade, the last several decades in GI cancers have really not been marked by huge advances. I think at least one of the things that we saw here today, if not necessarily things that benefit us now, but at least a pathway that may lead to benefit in the future for these patients. Thank you.

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