New Developments in Cell Therapy

Podcast Transcript

Dale Shepard, MD, PhD: Cancer advances, a Cleveland clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today I'm happy to be joined by Dr. Paolo Caimi, a member of the Lymphoma Program and Associate BMT Director for Cell Therapy at the Taussig cancer center here at Cleveland Clinic. He's here today to talk to us about cell therapy, so welcome Paolo.

Paolo Caimi, MD: Hi, thank you very much for having me.

Dale Shepard, MD, PhD: Absolutely. So maybe to start, give us a little background, what's your role here at Cleveland Clinic?

Paolo Caimi, MD: So I'm primarily a lymphoma doctor, I see all kinds of patients with lymphoma, lymphoid malignancies, from CLL to Burkitt lymphoma from the most to most aggressive, and we treat them throughout different stages of their disease and it happens as lymphoma doctor, it kind of became, I tend to say a love reluctant transplant and ended up doing stem cell transplant and then, cell therapy been developed and doing cell therapy for my patients. So I, for them the different versions of cell therapy that we have here for our patients.

Dale Shepard, MD, PhD: Okay, well we have a wide range of people who might be listening, so let's take a step back and when we talk about cell therapy, what does that mean? What is cell therapy?

Paolo Caimi, MD: So cell therapy is giving, using cells for treating somebody's disease. In general, you probably could say that the historic version of cell therapy is a halogenate transplant where you're really replacing the whole immune system of a patient to use those cells and the immune response of those cells to combat their cancer. And usually that's been traditionally more effective in Myelo disorders and primarily leukemia and including lymphoid leukemia and it's been used slowly, a shortly less lymphomas where we've kind of had more effective therapies over time.

Our stem cell transplant is really using your patients stem cells to be able to rescue them after you, them high dose therapy. So it's not really a pure cell therapy, it’s just stem cell rescue. And now that we've had a new advanced therapist, I probably would say that cell therapy is using primarily the patient's lymphocytes that are modified XVIVO to have some type of anti-tumor response. We can also select some lymphocytes to be specific to certain cancer like selecting tumor, infiltrating lymphocytes for mostly solid tumors, but in the lymphoma world, we're using CAR-T cells, which is taking T-cell from a patient, modifying them outside of the patient's body. So XVIVO with a viral transfer method that it can introduce a gene that allows them to express a receptor that attacks the lymphoma and have an anti-tumor response.

Dale Shepard, MD, PhD: And those things like CAR-T therapies are now commercially available. They're actually FDA approved, Right?

Paolo Caimi, MD: Yes. There's actually be five different CAR-T products approved. There's two targets now currently approved there's CD 19, which is commonly on BCE and there's BCMA as a target that is in myeloma, there's three products perform lymphoma with multiple indications. There's something called, the names are crazy, but one of them is called axicabtagene ciloleucel. We abbreviated it as Axi-cel and the commercial name of that is just scar. The second one is called vicleucel. I'm just bragging here because I can say, and then we a read as a ide-cel and the third one for lymphoma called lisocabtagene maraleucel, which is called liso-cel.

There's a little variation on the first one, something brexucabtagene autoleucel, which is a modification of the original, but those three cell therapy products target CD 19 under approved, all three are approved for diffuser B some lymphoma, and after at least two lines of therapy, there's one of them that's approved for mantle cell lymphoma and now, one of them is also approved for follicular. So we can treat patients with follicular lymphoma, diffuse start B-cell lymphoma is some variations, including primary mediastinal and mantle cell lymphoma.

Dale Shepard, MD, PhD: As we look forward at those therapies, primarily looking for drugs that have better efficacy, better safety, or just more indications for other types of lymphoma?

Paolo Caimi, MD: Well, I think that you're covering kind of all the aspects that are going to happen with, with CAR-T, right? I think you, at least the way I perceive it, and I think I'm not alone and thinking that we're going to see significant penetrance of different cell therapies, they're going to get to be used earlier. We're seeing now just recently, we had some press releases suggesting that earlier use of CAR-Ts may be more effective than salvage chemotherapy for certain patients with those who have refractory disease. So it is possible that we'll be seeing this in the second line now instead of the third or fourth line, but also you'll see more extended diagnosis, we've seen just through last week or a couple weeks ago, we had a publication on ALL. So we'll see approval pro this in adult ALL.

So we'll see more be a more recent malignancy, including mature one, I'm expecting other lymphomas as well. And then the question is you're going to see new targets. We just have BCMA approved for myeloma, probably that will have another product come using the same target and, probably other hematologic malignancy, I think are the next step. So, that presently penetrating more on lymphomas going to myeloma. I think the next step will be some of the myeloid disorders, possibly Hodgkin and then the final frontier, probably at least in the oncology world of solid tumors, which are a little bit hard, but I think that's the kind of the next step.

Dale Shepard, MD, PhD: So tell us a little bit about that. Why are solid tumors a little more difficult to treat with these therapies?

Paolo Caimi, MD: You know, trying to avoid, to make a joke about solid tumor oncologist. I'm a hematologic malignancy guy, but.

Dale Shepard, MD, PhD: It's okay.

Paolo Caimi, MD: But I would say that, I mean, it's probably mostly because the tumors are more complex. The micro environmental resistance is a factor. So usually you would consider that the capacity of the cells to serve as a single agent and to overcome the resistance that the tumor is presenting is bigger. So that's why I think it's a little bit tougher for cells to work on some of these diseases that have so many other cells surrounding myeloid suppressor cells, as well as some issues with the capacity of the cells to even reach the tumor and the immune escape that happens at the micro environmental level for the tumor itself.

Dale Shepard, MD, PhD: If we think by lymphoma, most people of course are familiar with chemotherapy, maybe a little bit less. These have been around for a while CAR-Ts and things, but maybe less familiar. What are the primary advantages to using a cellular therapy compared to a chemotherapy?

Paolo Caimi, MD: Well, I think you and I probably trained on the time with the cytotoxic, maybe with a few immuno therapeutic agents for us, Rituximab has been available for 20 plus years now. So we've been doing immunotherapy for a long time, and it's begun to be kind of widespread in many of the diseases. Cell therapies have a few important advantages. Probably one that's very relevant is a single course of treatment. So most patients that are getting CAR-T cell with rather high rates of response, 80% rates of response with 40 plus percent patients staying in complete remission beyond the year for third, fourth line diffuse HB. So it's much better than before for a single course of treatment. So that's number one, advantage is just one sitting. The second advantage is that they're, even though they have specific toxicities, they tend to be well tolerated and the majority of the toxicities are not what we're used to with cytotoxic. So the safety profile, and I think it's improving, but the safety profile is different from that of what we use with cytotoxic.

Dale Shepard, MD, PhD: I must say one therapy with a 80% response rate as a solid tumor guy. I'm a little jealous.

Paolo Caimi, MD: I know, right? And I think that it's been a change in how we look at our curves, right? You go, and even assenting, you go and present 40, 50% response rate for certain, certain new drugs, single agents under lockdown upon. And those are drugs probably five, 10 years ago would be considered effect valuable assets. I think they still are. I think the question is how are all these new drug that are coming up that have value of single agent can be that maybe reach 40% on their own? How do we strategically use them to achieve the 84 or 90% response rate that we can do and sustain that response in the long term?

Dale Shepard, MD, PhD: Makes sense. So good efficacy, well tolerated. What are the drawbacks?

Paolo Caimi, MD: Well, I say for poorly safety is still an issue. We are learning how to use them with every new drug and new drug category, you are learning the safety profile of them, that these adoptive immunotherapy strategies, right, where you're modifying yourselves to attack the tumor, have a couple things. One of them is because of the activation of the cells. You get a cytokine storm, or we call a Cytokine release syndrome, which happens usually the first couple weeks, primarily the first week, which in the first few patients, there's a learning curve. It can be pretty scary when you're first doing it. Now I say probably most of the people who are doing CAR-T are used to them, they used to detecting it earlier, usually manifest with a fever for the first time and we're very proactive about treating them, but people can get sick.

People get hypertensive, can go to ICU, can require mechanical ventilation. Now there're antidotes with the Tocilizumab that we've been using, but it can get, can be scary. And then people can have a neurologic symptom that I think is a little bit less well explained that also happens earlier. Let's say probably in the first, usually four to eight weeks in the first couple weeks the medias around seven days, depending on the product. And those patients will usually start with a dysgraphia with trouble writing, but they can have anywhere from a mild confusion to coma. It's reversible with steroids in the majority of patients.

There's some long term side effects in the neurologic side you occasionally see them, but not very frequent. And then you see some, one target effects, right. If you're using anti CD 19 targeting cells, these patients are going to have long term hemolytic anemia, I challenge mostly people to say that as fast as I do, but also people can have infrequent or rare infections that happen or uncommon infections like PCP, occasionally that happen several months down the road, because you occasionally see patients that have low antibody levels for beyond six months and some people are staying on, on a V I G for long term.

Dale Shepard, MD, PhD: And I'm guessing they like most adverse events that we get from our therapies, our ability to predict who's going to have cytokine release syndrome, neurotoxicity is relatively poor.

Paolo Caimi, MD: Yeah. Well, particularly with these drugs being best 10 years and, and less than five years in the market, I think we're learning that there's certain inflammatory markers that the patients bring with themselves that predisposed them to do this reaction. So, it's not just the cells getting activated is also the inflammatory MILU of the patient that leads them to have a more aggressive inflammatory response. Also, patients who have much more tumor bulk will have more so, we tend to choose patients with, or develop them before if we can. But I think it's part of the learning curve with a new drug, how to use them and I didn't get to see Rituximab first use, but, people were having severe reactions and now Rituximab is given anywhere in the world. Nobody's really be scared of it and all these antibodies as well. So, I think it's a matter of a learning curve that will reach with better results.

Dale Shepard, MD, PhD: So it sounds like with everything going on with these drugs and sort of the, the observation and the potential, it sounds like these aren't easy to give. It sounds like there's probably a team approach, and what does that look like when we treat patients who all gets involved.

Paolo Caimi, MD: I think the same way you ask two oncologist, you get three opinions in general, you go to different centers, they're being given different and it, or by a different team. I would probably say that the majority of the cell therapy is being given around the bone marrow transplant and stem cell therapy groups, in part because of the experience that the groups have had with cell therapy, the side effects are, tend to have a little bit in common with what we do. And that's how I say probably and they started with hematologic malignancies. So I think it's been all around.

It usually requires a inpatient unit. You required to incorporate the ICU as a team, as a backup, many places including us have ICU protocols, they have engaged the team to know what to do with this patients going to rapidly. So you can, I intervene upon them pretty quickly, but also once the patient goes home, and if I have a side effect, you also need to engage the emergency room, give them a card and give them some documentation that if they're coming through, there're certain things you need to do pretty quickly.

So, it really takes, does take a village of doctors, nurses, ER, physicians, ICU, just a lot of coordination going. Plus if you also think of it, there's a lot of additional components. So this patient, these are cells that are defreezed. So the collective from patient, their shipped takes several weeks to come back and they reinfused to the patients. So, there's also a lot of timing in between, so it's a lot of coordination.

Dale Shepard, MD, PhD: You mentioned before that, rituximab certainly had its issues and that now it's commonplace. Do you foresee that this will, at some points become more common place or will you think it'll stay rooted in academic centers that have the resources to do it?

Paolo Caimi, MD: I think that probably if you think of stem cell therapy, I think to stay at quaternary centers like ours, or I think there's, I don't think there's anything above quaternary center, but the clinic is probably something above quaternary plus, right. And I would expect that they're going to stay at academic centers or large hospitals where you have the complexity of the services in case something happens. But I think that there's going to be a transition towards doing a brief stint in the hospital, or even do it as an outpatient with frequent return visits.

So transition towards an outpatient management and as the products get better, which we are already seeing it with a second alteration of drugs approved. They're slightly easier to give, you can't have outpatient management. The toxicities are better recognized that you're going to be able to manage them with less complexity, actively and have data as a backup. So I think that probably the lifespan of the currently products is not going to be as long as we've been used to for our drugs that are, approved for 20 years on the standard for 20 years. My suspicion is that new versions are going to come real quick everything is accelerating. I think new, better versions are going to come sooner that are going to replace the standard, that's going to be a little bit safer, maybe more active. So, approaching that silver bullet that we all try to get in an oncology.

Dale Shepard, MD, PhD: Tell me a little bit about the agents that are what we call off the shelf, so instead of using patient’s cells and generating those is what do you see in terms of things coming along the line for that?

Paolo Caimi, MD: There's two strategies there. At least the ones that I can mention, one of them is, doing allogeneic or doing donor or derived cells. And I think that using T-cells from donors, then you can create a bank and expand and using them as a target.

They require a little bit more extensive engineering because you need to remove like the MHC that recognizes tissue and only recognize that. So you only want them to target the tumor as a or in target, but there's been several studies going through, and they're, I'd say probably they're not that far away from getting into the market or getting a little bit larger studies. And those will overcome a couple of barriers. One of them is that you need to take the cells out of the patient and they manufacture them. So, there's a little waiting time, so will make it much quicker, faster to give to, particularly to our patients with lymphoma that sometimes are rapidly progressive or leukemia. And also we'll overcome some of the logistics with the collection process itself that is also ATS costs. So may reduce the prices as well.

Dale Shepard, MD, PhD: Tell me about other types of cell therapies that you find exciting that are being developed.

Paolo Caimi, MD: We think for sure, beyond T-cells the other cell that can be used as an off the shelf product that may have actually a better safety profile and may actually have an enhancement and tumor effect is NK cells. And I think they're lagging a little bit behind because they just don't grow us easily. They're a little bit harder to transect, but NK CARS are probably very close. We're about to have a study here at the clinic with an NK CAR product, but also combining NK cells with other agents like one is something that, that very likely can enhance is going to be a combination between immunotherapy and cell therapy. The nice thing about NK CARS is that they tend to be less inflammatory in their response, and they tend to be kind of more purely antitumoral and, at the same time their persistence is less, which it may allow us to avoid long term side effects.

Dale Shepard, MD, PhD: You mentioned combinations with immunotherapies. Are there also combination trials or considerations of things like chemotherapy in combination with cellular therapies?

Paolo Caimi, MD: For sure. And the one thing I didn't mention is that you actually need to give a little bit of chemo before, not just because this is done by oncologist, but it's because even though these are cells, you need to leave for deplete the patient. Before we do that with cyclophosphamide mostly lymph for toxic chemotherapy, some products can be begin with before. So decreasing the patient before permits these cells that you refuse to persist for a longer period of time. But you can combine these either CAR-T cells with antibodies that can ideally promote their activity. There have been studies with PD ones that haven't yet been successful, but I wouldn't be price that this is something that should be looked at once we enter the solid tumor world and maybe other checkpoint inhibitors, right. This not just BD one, but there's, three and Tim as well. And there's several other markers that you can interfere upon where you facilitate the work of the T-cell or you decrease the inhibitor effects that the tumor does against those T-cells.

Dale Shepard, MD, PhD: What do you think are the biggest gaps? What do we need to overcome to make that next big step?

Paolo Caimi, MD: Well, price is one, right? Many of these products are extremely expensive. I think we need to figure out how to make this in a large scale and make it faster, right? So time and money always important, even though it's not my personal specialty. I still think that harnessing the capacity to target solid tumors will be important for everything else. I think once we learn how to target lung cancer sarcoma, for example pancreatic cancer with immunotherapies and cell therapies will allow us to get the knowledge, to be able to avoid resistance in lymphoma, for example. I think that the mechanisms are more complex and once you're recover for solid tumor, you can probably use that for lymphoma as well. So certainly solid tumor is the biggest target and I think we're going to get there.

Dale Shepard, MD, PhD: Very good. Well, Paolo, I appreciate you being with us and all of your insights. Thank you for all you're doing and advancing this field.

Paolo Caimi, MD: Thank you very much, my pleasure.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional cast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget you can access real time updates from Cleveland Clinic’s Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening, please join us again soon.