On November 29th, the Cancer Immunotherapy ETF (Nasdaq: CNCR) visited New York and attended an educational seminar hosted by one of CNCR holdings, Atara Biotherapeutics, to discuss new chimeric antigen receptor cell therapy (CAR-T) technology the company licensed from the Moffitt Cancer Center in Tampa, Florida and Memorial Sloan Kettering Cancer Center in New York. You might already know that CAR-T cellular immunotherapies have revolutionized the treatment of some late stage blood cancers like types of leukemia and lymphoma. As exciting as this is, today’s therapies are just the first CAR-T products to make it to the market. Researchers are hard at work trying to improve on them with next-generation upgrades.
Atara is a company focused on doing exactly that. In addition to having a cell therapy called tab-cel already in late stage development, the company recently licensed next-generation CAR-T assets from these prestigious research hospitals. This “CAR-T Teach-In” event was hosted to explain more about what new features the new CARs will have and why they are needed. Speaking at the event were Atara’s CEO Dr. Isaac Ciechanover, Dr. Marco Davila from the Moffitt Cancer Center, and Dr. Michel Sadelain from Memorial Sloan Kettering Cancer Center. Afterwards, the Cancer Immunotherapy ETF had an exclusive opportunity to speak to all three speakers and ask them about CAR-T’s present and future. Below is a transcript of the interview, which has been minimally edited for clarity.
Interview with Dr. Isaac Ciechanover, Atara Biotherapeutics
First we caught up with Atara CEO Isaac Ciechanover to hear more about the company’s pipeline and what we can expect to see in 2019.
CNCR ETF: Thank you for hosting us today. Maybe at a high level can you tell us about Atara? We know you have a cell therapy product that is in late stage development right now called tab-cel. What exactly is that and why is it needed?
Dr. Ciechanover: First of all, thank you for the opportunity to introduce Atara. So Atara is the leader in the allogeneic T-cell space, be it CAR-T or be it virally directed cells. Simply said, we want to be able to give T-cell immunity to patients in need. Either because their immune system is down or because cancer or some other disease has knocked it out. Our first program is called tab-cel. It is in an indication called post-transplant lymphoproliferative disease (PTLD), which means patients who have had a bone marrow transplant or, for example, a heart or lung transplant for whatever reason, unfortunately they are then susceptible to a lymphoma. Our cells are able to treat that cancer. For patients who have received a bone marrow transplant, for example, they have a median survival of 16–56 days. They have very few options. And you can imagine some of these are even pediatric patients. They have gone through a heart transplant, you waited, you see the light, and then suddenly you have this secondary lymphoma. And so our therapy, which was developed at Memorial Sloan Kettering (MSK), addresses that. It is off-the-shelf and allogeneic, meaning it comes from other people, it is available to patients within days of need, there is no pretreatment that you need to do, and any patient who has had a robust response has never recurred. And on the safety side, it is generally well tolerated.
CNCR ETF: There is one medicine that is currently used in this situation, rituximab. Is your therapy used in combination with rituximab or afterwards?
Dr. Ciechanover: As is normal in the case of development, you usually initially go to the patients who have no options. Our first indication is in patients who have failed rituximab. The potential to use it in the first-line setting is always available but you have to start first in the patient of need.
CNCR ETF: And that is currently in what you call a registration, late-stage study right now. When do you expect to have the result of the study?
Dr. Ciechanover: We will have initial data in the first half of next year (2019) and then our expectation is to file for approval in Europe where we have PRIority MEdicines scheme (PRIME) designation in the second half of 2019. In addition, we have Breakthrough Therapy Designation in the United States and a filing there would follow shortly after Europe.
CNCR ETF: At today’s event we are talking about next generation CAR-T. CAR-T is another type of cellular immunotherapy. Can you talk about the current generation of CAR-T? What are the limitations of it and what are you trying to improve on?
Dr. Ciechanover: At this event we were very lucky to have the leader in the space, Michel Sadelain, who pioneered the current generation CAR-Ts. These are incredibly powerful cells that treat blood cancers. What they do is they require you to take the cells from the patient and then manufacture them and then give them back. For patients who can get all of that done, it can have profound responses. The limitations are, if you have to go to a patient, first of all, it is questionable whether you can even get cells from them, and second, can you manufacture? Can you give it back? The logistics associated with it are very difficult and challenging. So, yes, it is an incredible technology, but if you try to expand it to the masses, it has some significant limitations. We said, ok well, if we can use what we have already shown with our tab-cel program where we can make it off the shelf, make it available within days, wouldn’t it be great to meld the two? So we talked with Michel Sadelain and he now works with us as well as Marco Davila, to basically deal with one of those bigger issues which is can you make it available to everyone? Can you reduce the barrier of entry here? In addition, these first generations are great but they also have other limitations besides just availability. Patients, for example, see their cancer recur. They recur because the cells that are used with first and second generations tend not to persist. We spent a lot of time today talking about some of the new technologies that try to combat this. So what Atara does in the CAR-T space is developing the next-best CAR-Ts that are also off-the-shelf and allogeneic.
CNCR ETF: You have described the need. What are the hurdles of making allogeneic work? Why do allogeneic therapies not already exist today? What do you need to prove in development to show they are comparable to today’s therapies?
Dr. Ciechanover: That is a great question. Because, obviously, if you can make something allogeneic, meaning if you can make it off the shelf, it would be great. If it were just simple in the sense that you could take cells from any one patient and give it to any other, it would be easy. That is the hurdle - you can’t do that. You have what is called human leukocyte antigens (HLA) that define the specific genetic makeup of what the patient is and what the organ is. In this case, we call the T-cells the organ. You have to make sure they overlap. Where Atara is an expert is we have found ways to be able to find them and match those and make the cells ahead of time so that we can hopefully maximize efficacy while reducing any safety issues. Because if you do give cells that don’t match, you will have what is called rejection. That is where you hear terms like graft-versus-host disease and other issues. Those are the hurdles that need to be dealt with.
CNCR ETF: In addition to making CAR-T cells off-the-shelf, can you mention a few of the other upgrades, so to speak. Dr. Davila, for example, earlier mentioned that for acute myeloid leukemia (AML) you are developing a CAR that tries to recognize three antigens. What other things like that are you thinking about?
Dr. Ciechanover: AML is a very common cancer and large market but it is very poorly treated. Myeloid cancer cell targets are often expressed on normal cells and targeted agents have potential toxicities. Dr. Davila’s technology tries to hit what is called an “AND gate”, that is the CAR-T cells will only work if you target A, B, and C to avoid off-tumor, on-target toxicity. That works great in AML. But, for example, in a B-cell disease you don’t want that. So we also have what is called an “OR gate” to address relapse from antigen escape. You either have A, B, or C. As long as you have one of those three, it’s enough. We also brought in what is called the 1XX technology that Michel Sadelain talked about. It allows cells to expand and persist. It is not just important enough that the patient responds when you give the cells, you want to see that the patient can still maintain the response weeks later – that the cells are still being sentinels and are watching out for cancer. We also touched on a PD-1 DNR – the checkpoint inhibition. Rather than having to potentially combine with a PD-1 inhibitor, we will give the cells the ability to block checkpoint inhibition. Those are the type of technologies that we have brought in and what is encompassed when we say “next generation” and “best generation.”
CNCR ETF: It sounds like you have been busy and it sounds like in 2019 you are going to be very busy. You have the late stage tab-cel trial readout and you are getting this CAR-T work rolling. When can we expect to see the next generation CAR-T products in clinical trials?
Dr. Ciechanover: As it relates to the four next generation CAR-T programs we spoke about today, we have said we expect at least one of those programs to go into the clinic around the end of 2019, but honestly it is a horse race about which program from our next-generation CAR T pipeline this will be. The other aspect that we haven’t talked about is we have a multiple sclerosis (MS) program. That program is already in the clinic. It is not a CAR-T, and MS is obviously a very large and important indication. There will be initial results for that in the first half of 2019 as well. 2019 is really an exciting year for us.
CNCR ETF: Lastly, I know you recently built a large manufacturing facility in Thousand Oaks in the Los Angeles area. That is a big investment. Why did you do it and why is it important?
Dr. Ciechanover: I don’t think you can be disconnected between discovery, research, and manufacturing. They go hand-in-hand. It has to be across the hallway. Discoveries or changes in one affect the other. When we looked at this field, say as opposed to just traditional antibodies where you can simply go to contract manufacturers, there is no expertise there to do it in this case. So we had to do it. And, mind you, so did Juno Therapeutics and so did Kite Therapeutics. It is the entry ticket. When you look at many other companies, they do not have dedicated CAR-T and T-cell immunotherapy Good Manufacturing Practices (GMP) facilities, and so they are going to have to rely on a third party. We did not want to have to do that and we anticipated this early on. It is what allows us to be able to do multiple programs simultaneously and control the development from the beginning to the end. This was a large investment, it was about $50 million, but it is here today. I invite you to come and visit. It is a pretty impressive site.
CNCR ETF: Thank you. And thank you for your time today. The Cancer Immunotherapy ETF has been an Atara shareholder for more than three years and we look forward to your continued success.
Dr. Ciechanover: Thank you. We appreciate being a part of it.
Interview with Dr. Marco Davila, Moffitt Cancer Center Research Institute
Later, we spoke with Dr. Marco Davila to learn more about how he is focused on trying to improve the treatment of acute myeloid leukemia (AML) with a next generation CAR-T product that aims to recognize multiple targets on cancer cells.
CNCR ETF: Thank you for speaking with us today. Would you like to introduce yourself?
Dr. Davila: My name is Marco Davila. I am a physician/ scientist who works at the Moffitt Cancer Center Research Institute. I perform laboratory research as well as clinical research involving the adoptive cell therapy of T-cells for patients with cancer.
CNCR ETF: You mentioned during your talk that one type of cancer you treat regularly is a type of leukemia called acute myeloid leukemia (AML). For those who might not know, what exactly is that?
Dr. Davila: AML is an umbrella term for cancer’s transformation of cells of the bone marrow that have a myeloid type of phenotype. There are at least 10 different broad groups of myeloid cells that can transform and become an acute myeloid leukemia. For a long time the only standard therapy available for these patients was a combination of chemotherapy. And when the disease came back, the goal was to get the patients into another remission, and to get them into bone marrow transplantation.
CNCR ETF: There are cell therapies that are approved and on the market today for types of leukemia and lymphoma, but not for AML. Why is that?
Dr. Davila: It is mostly due to the targets. Considering that the CAR-T cell therapies were a first in human type of product, safety was a major concern. One of the great advantages of targeting CD19, a protein that is present of B-cells, is that it is present only on B-cells. So the regulatory agencies were relatively reassured that there were not going to be any major toxicity concerns with targeting CD19 on cells other than the B-cells. But for AML, that is definitely not the case. There is no target that is expressed only on a small component of these cancer cells and not normal cells. These targets are often co-expressed on hematopoietic stem cells, on early stage myeloid progenitor cells, and as well on cells such as neutrophils. Killing of those cells with a CAR product, a toxicity that is known as “off tumor on target toxicity”, would result in the death of many patients. They would die of bone marrow failure or they would die of infections because of a lack of neutrophils.
CNCR ETF: So how are you trying to overcome that and use cell therapy to treat AML?
Dr. Davila: Through developing a multi-antigen CAR-T cell product. What that means is that we are not trying to look for a perfect CD19 target. What we are trying to do is recreate this concept for AML by targeting multiple different targets on a T-cell. We are increasing the stringency of activating the T-cell and having it kill the target by making sure it recognizes two or three targets that have to be expressed on the AML. What we have seen is that if you increase the stringency of targeting, you start to be able to avoid those stem cells, those early stage progenitors, or neutrophils. It reduces the risk for this off tumor on target toxicity.
CNCR ETF: Does that mean that the way you are able to program the T-cells, they will only activate if they recognize all of the targets together?
Dr. Davila: Yes. This is a concept known as “AND gating” meaning that you need to target antigen 1 and antigen 2 for there to be full activation of the T-cell in killing of the tumor target.
CNCR ETF: Where is this in development right now? Is it being tested in clinical trials today?
Dr. Davila: As of today, no. Some of the related gating such as “OR gating” is in clinical trials for acute lymphoblastic leukemia (ALL) because it is known that the patients who relapse after being targeted with a CD19 CAR can oftentimes down regulate CD19 so that the CAR can no longer recognize it and kill it. Therefore, the way they have gone about trying to avoid this is having another CAR target another antigen such as CD20 or CD22. This is useful because it means that some of the infrastructure and biology required to understand how to make a multi-antigen CAR is now present. We have to make small tweaks to the system to make it go from an “OR gate” to an “AND gate”.
CNCR ETF: In laymen’s terms, it sounds like what is going on now is there are multi-CARs and you are trying to consolidate that into one product.
Dr. Davila: Absolutely.
CNCR ETF: Excellent. We look forward to seeing this in the clinic one day and we wish you the best of luck.
Dr. Davila: Thank you.
Interview with Dr. Michel Sadelain, Memorial Sloan Kettering Cancer Center
Lastly, we also had the pleasure to speak with Dr. Michel Sadelain from Memorial Sloan Kettering Cancer Center. Dr. Sadelain has been working in the cell therapy field for decades, and as Dr. Ciechanover mentioned in our interview above, he is an inventor of the first and second generation CAR-Ts. This cell therapy pioneer tells us about how CAR-Ts were first envisioned and where he thinks the field could be headed in the future.
CNCR ETF: You are a cell therapy and CAR-T pioneer. You have been working on this for a long time. Can you please introduce yourself?
Dr. Sadelain: My name is Michel Sadelain and am the Director of the Center for Cell Engineering at Memorial Sloan Kettering here in New York. It might surprise some people to know that this concept of cell therapy using genetically instructed cells, what we call CAR therapy today, goes back almost 30 years. At that time, I was finishing a Ph.D. after a medical degree and thought it might be useful to engineer T-cells to instruct the immune system to perform the tasks that we would like it to perform. Way back then, it sounded like a very odd or even crazy idea to many people and there was no method to do so. So all of this started, at least for me, at the Massachusetts Institute of Technology trying to initially figure out how to introduce a gene into a T-cell. Why would we do that? We would do it because it is a genetic instruction. The way that we train the T-cell to do what we want it to do, to recognize the cancer that we want it to recognize, or to enhance its function, is through a genetic instruction. Therefore, introducing the gene is the first thing you need to do. Everything else I continued at Memorial Sloan Kettering here in New York and over the years we designed receptors and started training T-cells to recognize types of leukemia and lymphoma.
CNCR ETF: Those have finally made it to the market. They are helping patients today. They have been approved in the United States for a type of childhood leukemia and a type of aggressive lymphoma for adults. Toda’s CAR-Ts are what is called autologous – the cells are taken from the patients and re-engineered. But at today’s event we are talking about a newer version of that concept called allogeneic, which is using cells from donors. Can you tell us what the benefits of that might be and also what the hurdles are of getting it to work?
Dr. Sadelain: First, I should explain why it had to develop the way it did. If one uses your own T-cells, they are then brought to a lab and then genetically instructed, and then returned. Because those T-cells come from the very same person, the T-cell will not try to harm that person and the patient will not reject those cells because they are their own cells. It was logical to start in that setting. However, this approach, called autologous, means that we need to manufacture those cells for each and every person. Proceeding this way was critical because it has shown us today that this can work and in fact there are impressive results in refractory diseases as you said. However, going forward it would certainly be much more convenient and more cost effective to be able to make a batch of T-cells and to be able to administer it to not just one person but multiple recipients. So now we start talking about donors and multiple recipients. There are two main barriers to overcome this. First, the donor T-cells should not attack the recipient. And this might surprise some of your readers, but that it what T-cells can do. We know this from bone marrow transplants. When recipients receive the T-cells from someone else those T-cells can attack. Why? Because they say, “Wait, this is not me. I should attack. I should defend.” And of course they are attacking the recipient. One has to find ways to elude this problem. Second, even if the T-cells don’t attack you, your body might say, “Wait a minute, this is not my tissue.” It is like a heart or liver transplant – you begin to reject it. So we need to find a solution for that. The solution lies in the genetic engineering of the cells. This is where we are at today at the dawn of what will hopefully work in the form of allogeneic CAR-T cells.
CNCR ETF: As an expert who has worked in this field for as many years as you have, how optimistic are you that we will be able to overcome those hurdles? And how many years away do you think it will be for allogeneic therapies to show comparable efficacy and safety to the current day autologous therapies?
Dr. Sadelain: It is a little hard to predict how many years. Having said that, I think we are close to the first trials that will test this approach in patients. Of the two prongs I outlined, the T-cells attacking the recipient and the recipient rejecting the T-cells, the first one has a few solutions. At least in theory, they just need to be validated. Indeed this is the platform that Atara is developing by using as the carrier of the CAR a virus specific T-cell that is essentially unable to attack the recipient. This takes care of the first problem. The second problem of the cell being rejected requires a combination of changes and allied treatments to give to the recipient and this will take some clinical evaluation to figure out exactly how to circumvent the problem. So I cannot tell you how many years this will take but what we can say is that there is already enough understood about this that it is worth starting to test very soon.
CNCR ETF: Finally, these cell therapies today are working mostly in blood cancers like leukemia and lymphoma. A lot of people are wondering if they will have utility in other types of cancer, what we call solid tumors – like lung cancer or breast cancer. How do you feel about that?
Dr. Sadelain: I fully agree that this is the other big jump, if you like, that we are all anticipating in the field. Like you said, the first proof of concepts were in these blood cancers and from here on two major directions are exploring these allogeneic cells on the one hand and on the other applying the CAR-T cell approach to these other cancers. To me there is of course no biological reason why it would not work in solid tumors. We already know that T-cells can be highly effective against cancers. In this other big immunotherapy called checkpoint blockade, giving antibodies to PD-1 or CTLA-4, it is actually T-cells that do the work. So we all know that T-cells can reject solid tumors. What we have to do for the CAR-T cell approach is identify the appropriate targets to instruct the T-cells to attack these cancers. Furthermore, there is what is called the tumor microenvironment. In a tumor, there aren’t only cancer cells. A tumor is a mix of, yes, those bad cancer cells but also a whole bunch of other cells that support, sadly, the tumor. They feed the tumor, they protect the tumor, and they can shut off immune responses. And so we know that in solid tumors more so than leukemia we need to address some of these barriers. It is really a two-pronged approach to make this work in solid tumors. Finding the targets and adding to the CAR-T cell the right molecules to enhance their activity in the tumor microenvironment.
CNCR ETF: Thank you for your time and best of luck.
Dr. Sadelain: It is a pleasure, thank you.
Opinions expressed are those of the author, interviewees, or Funds and are subject to change, are not intended to be a forecast of future events, a guarantee of future results, nor investment advice. Fund holdings and allocations are subject to change at any time and should not be considered a recommendation to buy or sell any security. Juno Therapeutics (and its parent Celgene) are not a holding of the Fund or affiliated with the Fund.