Aaron Carroll talks to Dr. Sherif Farag of Indiana University about his work harnessing the power of patients' own immune systems to treat blood cancers like multiple myeloma.
The Healthcare Triage podcast is sponsored by Indiana University School of Medicine whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care.
IU School of Medicine is leading Indiana University's first grand challenge, the Precision Health Initiative, with bold goals to cure multiple myeloma, triple negative breast cancer and childhood sarcoma and prevent type 2 diabetes and Alzheimer's disease.
Dr. Aaron Carroll: Hi, welcome back to the Healthcare Triage podcast. This episode of the Healthcare Triage podcast is sponsored by Indiana University School of Medicine, whose mission is to advance health in the State of Indiana and beyond, by promoting innovation and excellence in education, research and patient care. IU School of Medicine is leading Indiana University's first grand challenge, the Precision Health Initiative, with bold goals to cure multiple myeloma, triple negative breast cancer and childhood sarcoma, and prevent type two diabetes and Alzheimer's disease.
Today, we're going to be talking to Sherif Farag, professor of medicine and medical and molecular genetics, and also Director of the stem cell Program at IU School of Medicine. He in general, is going to talk to us today about stem cell therapy and CAR-T therapy in particular, which you may have heard in the news.
But before we get to that, let's start with some basics. So first of all, welcome to the program.
Dr. Sherif Farag: Thank you.
Dr. Aaron Carroll: Can you tell us some general what it means to be not only a professor of medicine, but a professor of medical and molecular genetics?
Dr. Sherif Farag: So medical molecular genetics, it's a very broad term. It's really looking at the molecular basis of disease, not just inherited disease, but many of the diseases have a molecular basis, even if they're not directly inherited.
Dr. Aaron Carroll: How do you actually get to the molecular basis? What kind of research technologies are you using?
Dr. Sherif Farag: The biggest technology at the moment is sequencing genes, particularly in terms of tumors. In my area, sequencing cancer cells, genome to identify particular mutations that could be targetable, or identifying mutations that in future could be where we could design drugs perhaps to target it. Also, there are ways of personalizing medicine in a way where we can identify, because not all cancer... Even the same kind of cancer is not all homogeneous, there's a lot of heterogeneity.
So if you can identify certain mutations in a person's cancer cell, you may be able to target that specifically for that person's cancer, as opposed to all the people with that kind of cancer.
Dr. Aaron Carroll: So how do you train to do this kind of work? So in your career, what did you do to get to this point?
Dr. Sherif Farag: Well, I guess there are various ways of getting there. The way I got there, I trained actually in Australia. I did all my hematology and oncology training in Australia, and then I did a PhD. It was more related to stem cell transplantation rather than molecular medicine at the time. And then I moved to Ohio State where I stayed there for about six years on faculty. And then the opportunity came to lead the transplant program at Indiana University, so I moved there in 2006.
Dr. Aaron Carroll: So we're talking about treating cancer. Is it all kinds of cancer or specific kinds of cancer that you're interested in?
Dr. Sherif Farag: Well, as a stem cell transplanter, we're really focusing on hematological cancers, blood cancers. So leukemia, multiple myeloma, lymphoma. These are the ones that are amenable really to stem cell transplantation.
Dr. Aaron Carroll: Can you talk about what the differences are between those three?
Dr. Sherif Farag: Sure. So it's really the cell of origin or the origin of the cancer. So in leukemia, we're really talking about cancers of blood stem cells in the bone marrow. In multiple myeloma, we're really talking about cancers of cells called plasma cells, which are really part of the immune system. In lymphoma, we're talking about cancer cells that are also part of the immune system, but they're less differentiated cells than the myeloma.
Dr. Aaron Carroll: So what causes these? What makes someone develop one of those types of cancer?
Dr. Sherif Farag: Well, that's a really good question. And we don't know all the answers to that, but it certainly as with other cancers too, not just blood cancers, there are hits in the genome of the cans of the cells that turns them on to become cancerous essentially.
Dr. Aaron Carroll: And so once they become cancerous, they just start growing and multiplying without control, is that the gist of it or [crosstalk 00:04:21]?
Dr. Sherif Farag: Yeah, that's basically it. They're able to multiply without control, but they're also able to survive better. They have a survival advantage compared to their normal counterparts.
Dr. Aaron Carroll: Can you talk about sort of the history of treatment of those types of cancer? What did we do and what have we gotten into now? And specifically of course, what is stem cell therapy at the end?
Dr. Sherif Farag: Yes. So historically, we have been treating and we still do treat these cancers with conventional cytotoxic agents. These agents are essentially cellular toxins that cause DNA damage to the cells. And as a result, the cells die because cancer cells tend to divide more frequently or more rapidly than normal cells. And these conventional cytotoxics target the proliferating cells more than the dormant cells. So we're able to more selectively kill cancer cells, but they also affect normal cells as well.
As things have evolved, we are now able to... And we learn more about the genetics of the cancers. We're now able to design drugs that particularly target certain pathways, molecular pathways that these cancer cells depend on. So treatment has become less toxic to the patient in general.
Dr. Aaron Carroll: So we're trying to target specifically just killing the cancer while not killing other rapidly or any other kinds of cells in the body?
Dr. Sherif Farag: Yes, yes.
Dr. Aaron Carroll: So what is then stem cell therapy? What's the difference between you're describing there and then going all the way to say, "We're going to do a stem cell transplant?"
Dr. Sherif Farag: So in some cancers, not all cancers, but some cancers are also amenable to stem cell transplant therapy. And they're really broadly speaking, two approaches. One where we use the patient's own stem cells called autologous stem cell transplantation, and where we use donor cells or allergenic stem cell transplantation.
So with autologous transplantation, we're really reverting back to the classic cytotoxic approach, where we give very high doses of chemotherapy to kill as many cancer cells as possible. Now, one of the side effects of this is that it will also cause permanent damage to the bone marrow. So people without stem cell support, they would essentially die of marrow failure.
So to collect stem cells first, their own stem cells, assuming their stem cells are not diseased, then you can give high-dose chemotherapy, give back stem cells and allow the marrow to recover.
Dr. Aaron Carroll: So I have a couple of questions there. First of all, how do you get the stem cells out?
Dr. Sherif Farag: So stem cells live predominantly in the bone marrow, but they do circulate in the blood. So you can either collect them directly from the bone marrow, but more commonly today in the autologous approach, we give growth factors which can move stem cells to circulate more in the blood. And then we collect them by a process called apheresis where basically they are collected like a blood donor machine essentially, that will collect them from the blood.
Dr. Aaron Carroll: How are you sure you're not collecting cancerous cells at the same time?
Dr. Sherif Farag: You do. Some of these stem cell products will be contaminated, to some extent by cancer cells, but it seems that most relapses after autologous transplantation occur not because of contamination, but because the high-dose chemotherapy that you've given has not killed the last cancer cell in the body.
Dr. Aaron Carroll: So how are you also assured that the stem cells are not... Where does the cancer come from if it's not coming from the stem cells as the stem cells or what [crosstalk 00:08:02]?
Dr. Sherif Farag: Well, I'm talking about sort of the hematopoietic stem cells that give rise to the entire hematopoietic system. So for example in multiple myeloma, these hematopoietic stem cells are not cancerous.
Dr. Aaron Carroll: Okay.
Dr. Sherif Farag: And in lymphomas, similarly, they are not cancerous.
Dr. Aaron Carroll: Can you just give us just a brief description of what the hematopoietic system is?
Dr. Sherif Farag: So the hematopoietic system is essentially all the blood forming cells and immune cells. So the very primitive stem cells that give rise to the hematopoietic system, they give rise to white cells, red cells, platelets as well as the components of the immune system, such as B cells, T cells, natural killer cells.
Dr. Aaron Carroll: I'm just trying to figure out in my head where it comes from, because are the white blood cells coming from the bone marrow and the stem cells though in development?
Dr. Sherif Farag: It depends on the cancer.
Dr. Aaron Carroll: Okay.
Dr. Sherif Farag: So essentially, for example, if we take multiple myeloma, so within the immune system, one cancer cell becomes transformed to become malignant and that forms a clone, and that clone eventually expands and has sub-clones of its own. And that's really the cancer, but that's not arising from a... In the actual stem cell of the very primitive stem cell that gives rise to all the blood forming cells in the marrow.
Dr. Aaron Carroll: So let's take lymphoma for instance, or leukemia, I suppose it doesn't matter in my head, that it's not that they're coming out of the bone marrow or out of the stem cells, cancerous it's that you already have lymphocytes which are then becoming cancerous.
Dr. Sherif Farag: Yes, basically.
Dr. Aaron Carroll: And then they just keep dividing and reproducing amongst themselves?
Dr. Sherif Farag: Exactly. Now that's different to a myeloid leukemias for example, where the cancer is really in the stem cell, in the hematopoietic stem cell itself. So autologous transplantation is really not appropriate for most of these patients. And that's where you really need to use a different approach, which is the allogeneic stem cell transplant I alluded to before.
Dr. Aaron Carroll: Okay. So that would be like, again, you try to wipe out everything, but you're bringing... Because the stem cells themselves are somewhat cancers, you have to go to somebody else to get [crosstalk 00:10:29]?
Dr. Sherif Farag: In addition, the allogeneic transplantation is also a form of immune therapy because within the stem cell product that you collect from a donor, there are immune cells, and these immune cells will see the recipients' tissues and actually cancer as foreign and mountain immunological attack.
Dr. Aaron Carroll: Okay. Well, I want to come back to that...
Dr. Sherif Farag: Okay.
Dr. Aaron Carroll: But I have a question for you before... How do you actually put the stem cells back in? You can't inject them back into the bone marrow, do you?
Dr. Sherif Farag: No, we inject them actually into the blood. So it's like a blood transfusion.
Dr. Aaron Carroll: Okay.
Dr. Sherif Farag: And they have receptors where they can locate essentially the bone marrow niche and go there and proliferate.
Dr. Aaron Carroll: Do they go back to sort of all bone marrow or do they preferentially head to different bones?
Dr. Sherif Farag: Well, I think in the bone marrow, not all parts of the bones are marrow producing. So they will go to the marrow producing part.
Dr. Aaron Carroll: Which bones are marrow producing primarily?
Dr. Sherif Farag: Primarily the spine, the pelvis, ribs, the proximal parts of the long bones.
Dr. Aaron Carroll: That's interesting. All that medical school and I didn't know that. Okay, but you mentioned before that allogeneic stem cell transplant can be immune therapy because those blood cells will go and attack... Why don't we do that more often then?
Dr. Sherif Farag: Empirically, when you look at... When we've tested compared autologous and allogeneic, not all cancers are necessarily amenable to allogeneic, or respond to the immune therapy associated with allogeneic transplant as well.
Dr. Aaron Carroll: What are some of the risks?
Dr. Sherif Farag: Probably the main risk is graft versus host disease. Graft versus host disease is really where the immune cells of the donor attack the normal body tissues of the recipient. So that effect is really a double edge sword, so we want it to affect the kill the cancer, but we don't want it to attack the normal body tissues.
Dr. Aaron Carroll: And how does that manifest?
Dr. Sherif Farag: Acute graft versus host disease occurs early on in the first, maybe two or three months after transplant. And that manifests... The target organs are basically skin, gut, and liver. So patients may manifest as a skin rash, but probably the most serious manifestations would be gastrointestinal with diarrhea, vomiting.
Dr. Aaron Carroll: And how do you treat that or how do you prevent it?
Dr. Sherif Farag: So treatment at the moment is really just targeting the immune system in general, trying to dampen down that immune response. So we use immune suppressive drugs. Well, we use immune suppressive drugs to try and prevent it, but then we add more immune suppressive drugs to try and dampen down that response when it occurs.
Dr. Aaron Carroll: So if you get an allogeneic stem cell transplant, is it that you need to treat the immune system or suppressive for a period of time while it takes root, or do you have to wind up being on immunosuppression for life?
Dr. Sherif Farag: Generally, we use immune suppression drugs for about the first 100 days. And typically we would start tapering the immune suppressive drugs over the next three months. So by about 180 days, people should be coming off that. Now, if they develop graft versus host disease during that time, they will require to remain on immune suppression for longer. And that can vary because there's also another form called chronic graft versus host disease which can also occur. And again, depending on the severity, some people can remain on immune suppression for many years and potentially life.
Dr. Aaron Carroll: So how well does stem cell therapy work?
Dr. Sherif Farag: It depends on the cancer. For example, if lymphoma is sensitive to conventional chemotherapy dosing in the relapse setting, then we can probably cure about 50% of patients with autologous stem cell transplantation. In leukemia, we are probably curing about maybe 50% of patients with allogeneic stem cell transplantation, but that depends a little bit on the risk factor of the leukemia itself. Because again, it's not a homogeneous disease.
Dr. Aaron Carroll: So we mentioned immunotherapy before, but certainly that's something we're hearing more and more about in the new. So what technically is immunotherapy and how does it differ from say chemotherapy?
Dr. Sherif Farag: Well, chemotherapy is essentially use of a drug of some sort. Now, immune therapy is trying to use either the patients or the donor's immune cells to attack and kill cancer cells.
Dr. Aaron Carroll: So we mentioned how a donor's cells could be used, but how can you use a patient's own cells to attack cancer?
Dr. Sherif Farag: Early studies really looked at giving what are called cytokines, which are just really proteins that stimulate the immune system, trying to broadly and crudely stimulate the patient's own immune system in the hope that in some way we can... Or the patient's immune system can kill cancer. However, over the years we've learned that cancer cells can actually mask themselves and dampen down any immune attack by the patients on immune system.
So there are now what are called checkpoint inhibitors, which have been approved in a number of different cancers where we can block that masking effect so that the patient's own immune cells can attack the cancer.
Dr. Aaron Carroll: Can I get you to talk a little bit more about... What do you mean by masking effect? What do the cancer cells do?
Dr. Sherif Farag: So they do it in a variety of different ways that we know of. They can express a molecule on their surface, that actually inhibits the immune cell. So the immune cells can't attack.
Dr. Aaron Carroll: They just naturally figure this out? And is that just evolution or why would that happen?
Dr. Sherif Farag: Well, that's a very good question. It's important as part of the normal immune response for example, an immune response against a pathogen. And it's important, so that the immune response, when it starts, it doesn't keep going in an uncontrolled fashion.
Dr. Aaron Carroll: Sure.
Dr. Sherif Farag: So it's actually an important molecule in controlling the severity of the immune response, but cancer cells have worked out a way of expressing that to their advantage and obviously to the disadvantage of the patient.
Dr. Aaron Carroll: And that just sounds almost devious. That's just... Dr. Sherif Farag: It is kind of devious.
Dr. Aaron Carroll: Okay. So when you use a checkpoint inhibitor, is it specifically targeted to help overcome the masking of the cancer cells specifically, or the whole immune system?
Dr. Sherif Farag: Yes. So for example, one of the checkpoint molecules is PD-L1, and that inhibits a molecule on the immune cell called PD-1. So by giving an antibody that masks or blocks that interaction, then you don't have the cancer cells inhibition of the immune cell, and that allows the immune cells to attack.
Dr. Aaron Carroll: How often are we using immune therapy with cytokines right now?
Dr. Sherif Farag: Not very often with cytokines now. That was kind of the early phases. I think there is still a place for them and they are used in some situations, but that's not the common thing today.
Dr. Aaron Carroll: So what do we do today?
Dr. Sherif Farag: So today, we have immune checkpoint inhibitors like PD-1 inhibitors, and there are other molecules too that are important. And other ones where antibodies are still in development, but the PD-1 inhibitors, for example, or PD-L1 inhibitors are approved in a number of cancers today. Then there are other ways of course, that we can turn on the immune system, or we can design the patient's own immune cells to specifically attack the cancer cells by manipulating their surface receptors.
Dr. Aaron Carroll: How do you do that?
Dr. Sherif Farag: Well, that brings us sort of to the CAR-T cell area. You have to identify a certain molecule on the cancer cells which is relatively specific, cause you don't want to have that molecule expressed on vital organs for example, or other vital tissues. So at the moment, it's not amenable to all cancers, but once you've identified that you can design a receptor to that molecule expressed on the surface of the cancer cell. And then you can introduce into the patient's own immune cells, generally using a viral vector.
You can put that DNA and coding for that receptor into the T cells DNA so that as the T cells develop and they eventually come to express that receptor, which then specifically targets the cancer cells.
Dr. Aaron Carroll: I feel like we need to walk through this step by step because it sounds like science fiction. So first, you find a molecule on the cancer that you think this is a molecule we could attack.
Dr. Sherif Farag: Yes.
Dr. Aaron Carroll: Where you think it's on the cancer but not on vital organs.
Dr. Sherif Farag: Right.
Dr. Aaron Carroll: Then how do you actually create whatever the next step is? Physically, how does it actually happen that we create something to attack or attach to that molecule?
Dr. Sherif Farag: Well, again, it's through knowing the sequence, the DNA sequence that encodes for these receptors, then you can construct that DNA. You can also attach to that, several other molecules that are not so much involved in the recognition of the cancer cells, but in the activation and persistence of these immune cells in the body.
And then you introduce that fragment of DNA through a viral vector that allows that DNA to integrate into the immune cells DNA.
Dr. Aaron Carroll: Let's say we even know the sequence, how do you actually build a molecule and then attach it to... I imagine there's not little construction sets that you're physically doing it. So how do you actually build those things and then make them connect in the right order?
Dr. Sherif Farag: Well, I think that's the whole science of medical genetics. There are ways that you can actually construct a DNA with the sequence that you want.
Dr. Aaron Carroll: So you've now got this molecule, how do you attach it to these other molecules that you're talking about? Is it just you know how they're naturally going to attach if you put them together, or do you have to do something else?
Dr. Sherif Farag: You obviously have to choose these different molecules and you know the sequences of these molecules, and you can then attach these different sequences I guess in tandem, so that when the molecule is then produced from the DNA, then it will be sort of like a continuous molecule with certain linkers in between, that is expressed on the surface of the immune cell. And then usually there are signaling molecules that are also attached.
Dr. Aaron Carroll: So at the end, you have some kind of solution that has a lot of this molecule in it?
Dr. Sherif Farag: More or less.
Dr. Aaron Carroll: Okay, and then how do you get it to the virus? How do you then say, "Okay, now let's put these into specific viruses?"
Dr. Sherif Farag: There are certain viruses called retroviruses that can actually integrate into the infected cells genome. So these viruses, you're attaching that piece of DNA, the construct of DNA of interest into the viral DNA, the virus is introduced and then it integrates into the cell's own DNA. And then using the cells own machinery, that DNA then is eventually translated into a protein that is expressed. And certainly, the sequence of these proteins is important because that allows the molecule to be expressed on the surface of the cell, as opposed to, for example, being destroyed within the cell itself.
Dr. Aaron Carroll: So at the end, you wind up with a T cell or immune cell which is specifically created to go attach to the cancer cell, and then signal that this cell should be killed?
Dr. Sherif Farag: Yes. So you have a receptor that specifically targets the immune cell to the cancer cell. And as I said, you also attach other sequences that allow those immune cells to survive, because if they don't live long enough in the recipient, then the effect will not be durable. And also, there are ways to increase the activation of these cells once the immune cell recognizes the target cancer cell.
Dr. Aaron Carroll: How well does this work?
Dr. Sherif Farag: It's actually been quite dramatic because it has... The early studies have obviously been performed in leukemias and lymphomas, and other cancers that are currently being investigated, but really in a setting where the cancer has been resistant to all known therapies.
Dr. Aaron Carroll: Right.
Dr. Sherif Farag: So this is a really hot population to treat. So in acute lymphoblastic leukemia for example, you're getting remission rates of 80%, 90% in lymphoma. You're getting remission rates that are probably in the order of 50%, 60%. in myeloma, you're getting responses, although they are not yet approved for myeloma, but you're getting responses around the 80% mark.
Dr. Aaron Carroll: And those are all numbers that just, again, specifically on patients that were otherwise incredibly hard to treat.
Dr. Sherif Farag: Yes.
Dr. Aaron Carroll: So the fact that they're that high is remarkable.
Dr. Sherif Farag: Yes, yes.
Dr. Aaron Carroll: So why are we not using this more and more?
Dr. Sherif Farag: Well, I think we will. I think we have to really go through the clinical trials, obviously the early trials to demonstrate safety, to demonstrate not just that there's a response, but the durability of these responses. And then really, the next step is to conduct trials earlier in the phases of the cancer.
And for example in multiple myeloma, there are clinical trials ongoing at the moment in earlier phases of the disease, and even comparing it to standard chemotherapy, that one would use to see which is really better.
Dr. Aaron Carroll: Is this hard to do? Is it expensive?
Dr. Sherif Farag: The production of CAR-T cells and manufacturing the actual treatment is quite expensive, yes.
Dr. Aaron Carroll: Why is it expensive? Let me ask you this, is this something that a company is doing, or is it every individual lab that's doing this is doing their own thing?
Dr. Sherif Farag: A lot of these have obviously evolved in academic institutions, but I think to be able to export that technology in a very wide way, you really need a company. I don't think universities were designed for that. And really, the technology is taken up by the companies. And they're able to build manufacturing facilities and do this in a very broad way. And of course, many of them are also doing their own research and development in that area.
Dr. Aaron Carroll: But each time you're making a CAR T therapy treatment, it is literally an individualized therapy, it's only good for one person or is it good for many people?
Dr. Sherif Farag: You're taking the patient's own immune cells and introducing these receptors into their own cells. So it is an individualized treatment, but the technology for a given cancer is [crosstalk 00:26:12]
Dr. Aaron Carroll: When I pay my money and I get my sales back, that's for me.
Dr. Sherif Farag: For you only, yes.
Dr. Aaron Carroll: Oh, okay. So how long does that take?
Dr. Sherif Farag: The manufacturing process takes about two to three weeks.
Dr. Aaron Carroll: Okay. Is it intensive for the two to three weeks, or a lot of it, you do some work and you see it sit for a while, and then you take some steps and you see it sit for a while?
Dr. Sherif Farag: Well, what we do is really collect the patient's own immune cells through the apheresis process, which is similar to the collection of stem cells. And then these cells are then shipped to the company which manufactures it. It takes about two to three weeks to introduce the virus, to expand the cells. And then these cells are shipped back, and when we're ready to treat the patient, we do it.
Dr. Aaron Carroll: And when you say expensive, how expensive is it?
Dr. Sherif Farag: Well at the moment, for example, CAR-T cell products for lymphoma patients are around the $375,000, $400,000 mark.
Dr. Aaron Carroll: Okay.
Dr. Sherif Farag: That doesn't include, of course, the actual other treatments that have to go along with the infusion of CAR T cells. And of course, it doesn't take into account dealing with some of the side effects.
Dr. Aaron Carroll: Of course. Those numbers of course, sound very high to the general public. Is that something that we would expect to come down as we get better at mass producing this, or is it, it really does take incredibly expensive technology in therapy and it's likely to cost that much forever?
Dr. Sherif Farag: Well, I think there's a difference between cost and charge, obviously.
Dr. Aaron Carroll: Sure.
Dr. Sherif Farag: And I think that's how much the charge is at the moment.
Dr. Aaron Carroll: Sure.
Dr. Sherif Farag: I expect as maybe more companies go into doing this, as the technology becomes more broad, then I think probably the price will come down.
Dr. Aaron Carroll: This sounds like it would be a solution for lots of things, not just cancer, that if we can figure out ways to design one's own individual T cells to attack diseases, that could work with all kinds of diseases, infections [crosstalk 00:28:11] Yeah. And so, is that where the future is, do you think?
Dr. Sherif Farag: I think that's where the future is, and I think there are already early research going into that. I think the cancer is just an obvious one.
Dr. Aaron Carroll: Sure.
Dr. Sherif Farag: Cancer is much harder to treat than infections are.
Dr. Aaron Carroll: Are we using this for solid tumors as well as blood tumors?
Dr. Sherif Farag: There's certainly research going into that because there are... But again, you have to identify a target that is specific or relatively specific to the cancer cell that is also not expressed on important tissues. And I think that's really, the difficulty in trying to apply that technology to cancer cells broadly, because the antigens they expressed are also co-shared by important tissues.
Dr. Aaron Carroll: What research are you working on right now? Sort of where are your areas of interest?
Dr. Sherif Farag: So we have a national trial open at Indiana University, looking at the... Comparing chemotherapy versus CAR-T cells for multiple myeloma. There's also a clinical trial that is about to open looking at myeloma in different phases of the disease, including patients who have essentially failed most at least approved therapies. And obviously, there's a big effort to be able to develop our own CAR-T cells perhaps directed against other malignancies.
Dr. Aaron Carroll: For some of the things that we've described that have FDA approval, are these still third, fourth line therapies? Where is it now that we're like, "Okay, let's just go ahead and [crosstalk 00:29:49]?
Dr. Sherif Farag: So it's approved for example, for a subtype of lymphoma called Diffuse large B-cell lymphoma. And it's approved really in the setting where that lymphoma is refractory to conventional chemotherapy. It's approved currently for pediatric leukemia, acute lymphoblastic leukemia, and in young adults up to the age of 25. Again, in the setting where the leukemia is refractory.
Dr. Aaron Carroll: And when you're looking for new research in other areas, is it that most of the focus right now is we need to find the target and then we can just go make CAR T, or is it all the steps need to be sort of worked out?
Dr. Sherif Farag: I think both of those things, because to apply it broadly to other cancers, it's really identifying a safe target. But even with the current targets that we have in lymphoma and leukemia, it's really broadening the application to maybe earlier phases of the disease. In leukemia, extending approval to older patients with acute lymphoblastic leukemia. But there are also ways of modifying the current technology so that perhaps instead of one target, you can design CAR-T cells that have multiple targets.
Dr. Aaron Carroll: Mm-hmm (affirmative). Dr. Sherif Farag: CAR-T cells that can survive longer. CAR-T cells that maybe not generate as much toxicity or side effects.
Dr. Aaron Carroll: That was my next question. So when someone receives CAR T cell therapy, how does that go? They get an infusion or do they get multiple infusions?
Dr. Sherif Farag: First, you have to give chemotherapy that is designed mostly to deplete the patient's own immune cells because if you have a depletion of the patient's own immune cells, you start to develop, or the body starts to produce a lot of cytokines that will allow proliferation of the cells. So once you've depleted the patient cells, then you can infuse the CAR-T cells, and then you leverage that cytokine production to get those CAR-T cells to proliferate inside the body.
So that also is associated with drops in blood counts because that chemotherapy also affects normal hematopoietic cells. So they go through a cytopenic phase where their counts are low, usually for a couple of weeks, sometimes longer, of course. And then as these cells, the CAR T cells proliferate and start to actually attack the cancer cells, there's a lot of cytokine production that produces an inflammatory response in the patient. So we call that cytokine release syndrome, and that can manifest in high fevers, drops in blood pressure, reduced perfusion to important organs such as the kidneys and so forth.
So you need to support the patient through that cytokine storm. And then there are the other main toxicity is really development of neurotoxicity that is less well understood, but probably related to cytokines, where patients can become confused, they may have problems speaking. It's almost like having a stroke, but in most cases it is hematopoietic.
Dr. Aaron Carroll: And do you do this once or do they have to go through multiple cycles of this?
Dr. Sherif Farag: It's done once, unless you can demonstrate that the CAR-T cells maybe have not survived.
Dr. Aaron Carroll: Okay.
Dr. Sherif Farag: So there may be an opportunity if there is enough CAR-T cells that have been produced to be able to give a second dose, but generally speaking, it's a one-off thing at the moment.
Dr. Aaron Carroll: So looking towards the future, what are you working on right now, or where do you see this going that you're most excited about?
Dr. Sherif Farag: I'm most excited about seeing this application more broadly, because it's really restricted just to two very narrow indications at the moment. I think being able to bring those CAR T cells earlier in the disease phase and more broadly in other cancers, this will make a big difference to cancer patients in general.
Dr. Aaron Carroll: And do you see this happening in the near future?
Dr. Sherif Farag: I think so, yes.
Dr. Aaron Carroll: Years, decades?
Dr. Sherif Farag: For example, in multiple myeloma. I think there's a very good chance that we will have FDA approval of CAR-T cells in this disease, maybe in 220. And then as the other clinical trials finish in the next year or two, we may see broader application of the currently existing CAR-T cells in just other subtypes of lymphoma and older age groups with leukemia. And I'm sure within the next five years, we will have CAR-T cells that are targeting other cancers. They already exist in very early phase clinical trials. I'm talking about potential approval for these other cancers.
Dr. Aaron Carroll: Can you tell us what types of cancers?
Dr. Sherif Farag: For example, acute myeloid leukemia. Now that's a difficult one to target because the CAR-T cell has the potential to also destroy normal hematopoietic cells, because the targets are not specific to the cancer cells themselves. There are some targets that are specifically expressed by certain subtypes of myeloid leukemia, where maybe the target is relatively more specific. I think that remains to be seen, but it may be that you have to combine these CAR-T cells with a stem cell transplant because you may use the CAR-T cells to eliminate the leukemia, but in the process, you might eliminate the patient's own normal hematopoiesis. So you then have to come in with a stem cell transplant to restore hematopoiesis.
Dr. Aaron Carroll: How many places in the country can do CAR-T therapy at this point?
Dr. Sherif Farag: Well, I think it's very large and expanding. I think the centers... Mostly these are centers associated with transplant programs and these centers have to be certified by the company. They have to undergo certain training. They have to have the infrastructure to be able to collect the cells, store them when they're received by the company, and also be able to deal with the side effects that I mentioned. They can be more of an intensive care treatment that's required.
Dr. Aaron Carroll: But is it like most big cities at this point?
Dr. Sherif Farag: I think so, yes. Most big cities.
Dr. Aaron Carroll: So this is not a couple of places?
Dr. Sherif Farag: No. Not all, but most big cities. So for example, in Indiana, we were the first at Indiana University. There's the St. Francis Group is starting also their program, they already have a transplant program in existence so there will be two places in Indiana.
Dr. Aaron Carroll: We'd like to thank Indiana University School of Medicine for their sponsorship. Their mission is to advance health in the state of Indiana and beyond, by promoting innovation and excellence in education, research, and patient care.