Novel Therapeutics Clinic

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma programs. Today, I'm happy to be joined by Dr. Alex Adjei, Chair of the Cleveland Clinic Cancer Center. He was here previously to talk to us about his vision for cancer care at Cleveland Clinic, and today he's here to talk about the Novel Therapeutics Clinic.

So welcome back, Alex.

Alex A. Adjei, MD, PhD: Thanks, Dale.

Dale Shepard, MD, PhD: So, remind us a little bit about what you do here at Cleveland Clinic.

Alex A. Adjei, MD, PhD: Well, so I'm Chair of the Taussig Cancer Center, which means I oversee cancer care in our institute, which has radiation oncology, hematology, medical oncology, palliative care, both in the Main Campus and in the region, and I also help coordinate cancer care across the other institutes who are not in Taussig. So, we have a cancer executive committee with leadership from the various surgical departments and so on, and we meet to make sure that the quality of care, access to care and everything is seamless across the institution.

Dale Shepard, MD, PhD: Which is fantastic because when you think about the group that gets together on a regular basis to ensure that care across the institutions, it's pretty impressive.

Alex A. Adjei, MD, PhD: Yeah, it is.

Dale Shepard, MD, PhD: So, we're going to talk about the Novel Therapeutics Clinic. So, there are a variety of people that might be listening in. Let's just start basic. What are we considering novel therapeutics?

Alex A. Adjei, MD, PhD: So, the idea of novel therapeutics is really any new therapy that we are bringing to the clinic to treat cancer.

In the old days, we always used to say Phase I clinical trials because all these drugs were drugs. So, either chemotherapy, targeted therapy, and then you are trying to test it for the first time in patients. But now, that has expanded, and we have cellular therapies where it is not just antibodies or chemicals or targeted agents, but sometimes you're taking the patient's own cells, arming them, and then giving them back to the patient. We have new radiation techniques and so on, and we have some sort of antibody drug conjugates, what we call theranostics, where you have a radiation source attached to an antibody that hones in on the cancer.

So, we need to step back and think about all the new ways we are treating cancer. And so, we feel like it encompasses all these approaches, including one big one that I forgot to mention as well. Now we are using viruses that have been engineered to attack cancer. So, if you think about all the new approaches we are using, in addition to the old and true ones of just testing new drugs in patients, it seems to make sense to broaden the term and make it novel therapeutics.

Dale Shepard, MD, PhD: It makes sense. So really, these are the drugs that help us move forward to the therapies in the future.

Alex A. Adjei, MD, PhD: In the future, yeah.

Dale Shepard, MD, PhD: What do you think are the biggest misconceptions that patients and providers have about these types of trials?

Alex A. Adjei, MD, PhD: Yeah, so I think the biggest misconception is that these early phase trials, we are just looking to find the right dose of the drug. And so, you get into these studies if you have no other options left and that these studies usually don't work. I think that that was the case probably 15, 20 years ago where we have chemotherapy drugs and then we are finding new chemotherapy drugs. So, every new drug we found, to a large extent, was similar to what we had already in the clinic.

So, then it makes sense that if you have a drug that attacks a specific protein and you've already had that drug and now there's a second drug that comes along, but guess what? The second drug also attacks that same protein, then of course the second drug is not going to work. So, in that case, you are only going to treat patients who have no other options left. So, as it was, a Hail Mary, if you are lucky, it may work. If it doesn't work, well, you have no options. But now, we've moved to where we have a lot of drugs that are targeting specific proteins in specific tumors and so on.

So, these days, sometimes the novel therapy is actually better than the standard of care because sometimes that standard of care is chemo, which is all drugs that we use, doesn't target your tumor specifically. So, if your option is regular chemo versus this new drug that's attacking the protein that's expressed in your tumor, common sense will actually say you want to try that targeted one first. So, this area has changed tremendously.

There's still some of our drugs that are so broadly targeted. So there, you want to treat patients who have gone through all the standard therapies, but it's not always like that. So, this has now become as important as even our Phase II and Phase III trials. And as you know Dale, we have a number of drugs we could name that get approved from the Phase I study. So that phase in human, you test it, and it works very well, and then you just increase the number of patients. And we have a number of these drugs, they've worked so well from that first in-human, that got expanded to, let's say, 100 patients. You've gotten the drug approved before you go on and do the later studies to really confirm the effectiveness.

Dale Shepard, MD, PhD: Yeah. But it's an important point because oftentimes, the thought historically was low efficacy, but because of the design of the trials, it's probably much more effective.

Alex A. Adjei, MD, PhD: Exactly, yeah. And it's fair to say that we know what we are doing a lot better now than we did 10, 15 years ago. 

Dale Shepard, MD, PhD: So, the Novel Therapeutics Clinic, we've sort of restructured what we're doing in terms of how we're seeing patients in a clinic. Tell us a little bit about how we've restructured things to make that work.

Alex A. Adjei, MD, PhD: So, the idea then is that I think if our listeners think about somebody who has breast cancer, in a big academic center like ours, you have some physicians who only see breast cancer. They are experts in their area, so you want to send them there. If they have lung cancer, you send them to the lung cancer doctors. And when it comes to novel therapeutics and drug development, we have a number of our colleagues who have an interest and an expertise in that area.

The second thing is that a lot of the drugs that we are testing is not for just one disease, it's for multiple diseases. So, then it makes sense to have a group of physicians who have the expertise and the interest in drug development to run a clinic which runs just like a breast clinic where you send all the breast cancers. So, in this case, all the patients who are coming from novel therapies come to one clinic where you have a nurse, you have the physicians who have the expertise in developing that drug to see the patient.

So, it's much more efficient, it's much more effective. You don't have these physicians who now have to see the patients in their different clinics and have the nurses and coordinators running from clinic to clinic with patients to see them. And so, what we've built is a clinic where you have all these aspects, and apart from the physicians and nurses and coordinators, we are having pharmacists who will be specifically involved in that.

And so that's the clinic where all these patients for these new treatments come. And then we have a unit where after they've seen the caregivers, they go and get their treatment. And this is important because now you have this whole team that meets every two weeks to go over all the new studies that are coming in, if there's a new drug.

Remember, a lot of times with our novel agents, you have a drug that is safe from the lab standpoint, we've tested it in animals, we know it can melt human tumors and so on, but this is the first time we are giving it to patients. You don't know all the side effects yet, so we have to learn from each other. So, it's important to have just one group of physicians working with these drugs, regular meetings so that we all discuss what we are finding and so on. So, we learn a lot about what to expect from the drugs and so on. So, it's safe for patients because if we have a new drug and we find that or guess that this drug is causing skin rash, when we are seeing every patient, we warn them about that, we might give them medications to start using if they develop a rash and things like them.

Dale Shepard, MD, PhD: How are we working to incorporate not only patients on our Main Campus that are seeing our colleagues in, say, a specialty clinic, but also our regional practices and things?

Alex A. Adjei, MD, PhD: So, these days, most of these novel treatments tend to be in two parts. Because we typically know how the drug works and we know the protein that's attacking and the diseases, what these proteins may be expressed in, typically these days what happens is that we get the drug, and we have that first in-human that we don't know anything about it. We are giving it to people for the first time. So, you need a complex system with a number of experts and so on to make sure that it is safe.

And then once you determine that it's safe and now you have the right dose, typically these days then, if we have a new drug and we know that the drug affects proteins in breast cancer, sarcoma, lung cancer, melanoma, once we do the initial part where we take multiple blood samples to figure out how the drug works and fine tune the right dose to give, in that same study, we are now going to go ahead but treat only patients with these tumors where the drug targets. So, at that point, we know about the drug, how to use it, the right dose, and so on.

So, when it gets to that point, we should be able to have some of our colleagues who also have interest in clinical trials in the region treat some of these patients because now we've worked out the dose, we know all the side effects so we can warn them about it. And now all they are looking for is somebody with colon cancer, breast cancer, lung cancer, sarcoma, and so on.

So, what we are building is where the initial stages of the study are folks in the region who will refer their patients to Main Campus for us to treat them. But once we work out all the kinks and the right dose and we know about the side effects and so on, we can continue some of the studies out in the regions.

So hopefully, what we are building is where you have a hybrid system where the complex parts of the study are done on Main Campus, and then when you get to the parts, that it's almost autopilot because you know the right dose and so on. We could have some sites in the region treat some of these patients. And this is important because it makes the study more available to everybody because as you know, these early studies, sometimes there are multiple visits and so on. And so, if somebody is on the West Side, they may find it a lot easier to go to Fairview for their treatment rather than come to Main Campus once a week, for instance.

Dale Shepard, MD, PhD: And we would've already gotten them through the phase with all that.

Alex A. Adjei, MD, PhD: The phase, yeah.

Dale Shepard, MD, PhD: With all the complex sampling and all that sort of thing as well.

Alex A. Adjei, MD, PhD: Exactly, yeah.

Dale Shepard, MD, PhD: Tell us a little bit about, I mean, one thing that sometimes patients are worried about are the financial parts of participating in trials in general, but early phase trials.

Alex A. Adjei, MD, PhD: Actually, in terms of financial issues and early phase trial is probably the most affordable thing we do, and that's because everybody who has had a loved one with cancer or whatever knows the biggest cost of all our treatments are the drugs that we use, the chemo drugs or the pills. Those are the ones that might run into 10,000 dollars a month, 15,000 dollars a month. And if you have insurance with a 10 percent copay for instance, you could easily be hit with a bill of 500 dollars, 1,000 dollars and so on. So that's a problem, right?

And the good thing is that with the early phase trials in novel therapeutics, because the drug is new and is being tested, you are not billed for that. So, the biggest chunk of expense from cancer treatment is paid for, which is the medications you are using or the radiation you are using if it's all new.

And every study that you have to do, every blood draw, every CAT scan, every MRI, every PET scan, which you would normally not do and as part of the study, you don't get charged for it. So, it's actually probably one of the treatment types in cancers in this country which is the cheapest for the patient.

But apart from that, we have patient assistance services and so on. So, if you have a patient who, in spite of all of this, needs assistance, we have programs and we have philanthropic funds that can support our patients for transportation and a number of these other expenses that come with clinical trials. And sometimes that's much more challenging for standard of care.

Dale Shepard, MD, PhD: Yeah. I mean, these are important things too. We wouldn't want people to avoid considering it because of financial concerns and not being covered because it's not standard. And oftentimes, companies are paying for travel and things like that as well.

Alex A. Adjei, MD, PhD: Yeah. In fact, in a lot of our studies, if patients are from a long distance and have to stay overnight and so on, a lot of times they have sponsors who pay for the hotel stay and so on.

Dale Shepard, MD, PhD: You mentioned before how a lot of these trials are very specialized, there's a particular gene mutation or a particular receptor or abnormality thing. And so oftentimes, we'll end up with trials that are three or four different histologies, maybe very specific components, but that unfortunately leaves really common cancers that are not really covered in a lot of these trials. So prostate cancer, colon cancer, pancreatic cancer, really serious diseases, but oftentimes aren't included in these trials.

How do you think we're going to make a leap to get more involvement of diseases that are just kind of underrepresented in early phase trials? Is this just going to be grunt work on the translational science side in finding effective targets, or how do we make that better?

Alex A. Adjei, MD, PhD: Yeah. So, all of that is in the research, I think. So, some of this is good, some of this is bad. Obviously, the good is that because we know a lot about the drugs and their targets, if those targets are not present in the cancer, then we don't treat the patients because we know the drug is not going to work. So, in a sense, that's good for the patient because they're not going to spend all the time on the drug that doesn't work.

But having said that, the bad part then is that for a lot of reasons we can't go into now, a lot of the common mutations and proteins that our drugs are targeting tend to cluster in some diseases. So, then you get other diseases like you mentioned, which are not represented. But I think that this is slowly changing in that more and more, we are getting drugs that may be targeting proteins that are broadly available so that we have a class of drugs called antibody drug conjugates, where you essentially are attaching a really, really potent chemotherapy to an antibody that might go for a protein that is present in cancers, and some of these proteins are present in a lot of cancers. So, we have somewhere you might have representation from prostate and pancreas and so on.

And then the other thing is that because the scientists and pharmaceutical companies are aware of these big areas of unmet need, with the antibody drug conjugate technique, they can now hone in on some of the proteins that are expressing prostate cancer or pancreatic cancer and so on and design drugs against them. So, we are finding more and more studies now where it might actually be relevant to prostate cancer. And we talked about the theranostics where you attach some radiation source to a protein, and there's one, for instance, approved for prostate cancer that's going after PSMA, which is a protein that's only expressed in prostate cancer.

So, I think we've had some orphan diseases that we're not having drugs for, but more and more, we are getting more drugs coming. So, I'm just hopeful that, for instance, as we build our program, we'll get to a point where we have multiple treatment options for every cancer.

Dale Shepard, MD, PhD: We have a good mechanism we're getting in place to do the studies themselves. You always sort of have this consideration of where we are now, but we need to be where people are going to be in the future.

So, what kind of therapies? You mentioned a wide range of types of drugs. What excites you most? What do you think is going to be that next immunotherapy for instance? There was a big leap in our ability to treat. What's going to be the next big thing? What's exciting you most?

Alex A. Adjei, MD, PhD: Well, so there are a lot of them.

One of the things that's exciting, just like immunotherapy, has been a big leap. I think that there are going to be sort of different forms of immunotherapy that are going to come along. And the immunotherapy thing has been something that we always felt was important because for instance, I'll digress a little bit and say, let's say, bone marrow transplant that we use for leukemias and so on. We have the autologous transplant where you take the patient's own cells, and you give them mega doses of chemo to destroy their bone marrow. You give their cells back to them.

And what we found was that particularly in the early days, a lot of times, the cancer came back because even though you took their cells and you thought they were clean, there were a few cancer cells in them. And when you did the allogeneic where you took somebody else who matches the patient a little bit in a number of proteins, if you took their bone marrow and now you treated the patient and gave them their allogeneic cells, almost always the cancer never came back. The problem was that the new cells from the other person attacked the patient's normal organ, so you had a lot of graft versus host disease, which also killed people.

But I think way back then, we knew then that the difference probably is that that new patient's immune system recognizes the few cancer cells that may be left in you and kills them. So, immunotherapy has been something that we know, as humans, one of the things that protects us is our immune system. So, I think that now that we've made the breakthrough, we are going to make more breakthroughs.

And so now that we have these checkpoint inhibitors, the other area where we had never been successful in the past is cancer vaccines. And I think we are going to be more successful because the checkpoint inhibitors really, that's why we call them checkpoint, it's the checkpoint that the cancer cells use to thwart your immune system and now we can block that. So, if we come in with a vaccine, it should be able to work.

And so, I think one of the areas I'm most excited about from the COVID vaccine story, these therapeutic messenger RNAs that you can design against various proteins in the cancer and so on are now in development. And so, we are going to see situations where the same technology that was used to develop these COVID vaccines are now going to be used for cancer vaccines. So, you can have their RNA and what the COVID stuff taught us is that you can package them in nanoparticles that you can then give, and then you add your immunotherapy. So, I think that's going to be great.

And then along the same line, we have always had this notion that you could engineer viruses to attack cancer. And in the past, they've only worked to a limited extent because you engineer the virus, it gets into the tumor, the immune system recognizes the foreign virus is trying to attack it, and then the tumor has this checkpoint that prevented the virus from working. Now with the immune checkpoint inhibitors, we may be able to block the protective devices of the tumor and have these viruses work. So that's also pretty exciting.

And then everybody has at least heard something about CAR T-cells where you are arming the T-cells to attack cancer. And so far, they've worked very well with hematologic malignancies, lymphoma and so on. But there's a lot of research in that arena for solid tumors. And that's also going to, I think, be a game changer.

Dale Shepard, MD, PhD: Well, certainly lots of promising things in the future. We have a great system getting in place here to test those, and you've provided us with some great insight today, so thanks for being with us.

Alex A. Adjei, MD, PhD: You're welcome. Thank you.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You'll receive confirmation once the appointment is scheduled.

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