Treatment Options for Lymphoma Patients: When to Consider Transplant or CAR-T

Presenter:  John McCarty MD, Professor of Medicine, VCU Massey Cancer Institute

Summary: A stem cell transplant is a treatment option for some lymphoma patients who are at risk of relapsing after standard chemotherapy. CAR-T therapy is a new type of immunotherapy that is available to patients with B-cell lymphoma who relapsed or did not obtain a remission after standard chemotherapy. 

Highlights:

• there are two types of stem cell transplants: autologous (using the patient's own stem cells) and allogeneic (using donor cells)
• allogeneic transplants rely on the stem cell donor's immune system to kill cancer cells
• CAR-T therapy uses the patient's own immune cells (T-cells) to kill cancer cells
• both transplant and CAR-T therapy are effective strategies to treat B-cell lymphomas.

Key Points:

00:04:53  Lymphoma patients who relapse after treatment or do not get into remission do poorly with standard chemotherapy and may be a candidate for a stem cell transplant or CAR-T therapy

00:08:36  Autologous stem cell transplants (using your own stem cells) rely on high-dose chemotherapy given before a transplant to kill cancer cells

 00:09:34  Allogeneic transplants rely on the donor's immune cells to kill cancer cells, rather on high dose chemotherapy alone

00:29:13  Graft-versus-Host Disease (GVHD) can occur after an allogeneic transplant as a result of the donor’s immune system attacking the patient’s organs and tissues

00:31:48  Chemotherapy and radiation given to patients before transplant can cause long-term health complications

00:32:59  CAR-T therapy uses modified cells from the patient’s own immune system to fight cancer

00:38:05  Main complications after CAR-T therapy are cytokine release syndrome (CRS) and neurotoxicity

00:39:50  Studies of two FDA approved CAR-T therapies – Yescarta® and Kymriah®– show overall response rates of 70-8% and complete remission in 50% in patients who failed three to eleven lines of prior therapy.

00:45:51  50% of people who get a partial remission from CAR-T therapy convert to a complete remission by day 100

00:49:35  Both transplant and CAR-therapy are effective strategies to treat B-cell lymphomas

Transcript of Presentation:

00:00:01  Good evening and welcome to the BMT Infonet Webinar, Treatment Options for Lymphoma Patients, When to Consider Transplant or CAR-T therapy. My name is Sue Stewart and I'll be your host tonight. I'm glad you're able to join us this evening and hope you find this presentation valuable as you consider your treatment option with.

00:00:22  Introduction of speaker John McCarty: Now, it's my pleasure to introduce to you Dr. John McCarty. Dr. McCarty is Professor of Hematology and the Medical Director of the Cellular Immunotherapy and Transplantation Program at VCU Massey Cancer Center in Richmond, Virginia, which is the largest stem cell program in Virginia. Dr. McCarty has more than 30 years of experience as a transplant physician, treating patients with a variety of disorders including leukemia, lymphoma, multiple myeloma, bone marrow failure diseases, myelodysplasia, myelodysplastic syndromes and other blood disorders.

He's a member of the American Society for Transplant and Cellular Therapy and a member of the BMT CTN Steering Committee, which is a group that oversees clinical trials for transplant and CAR-T patients. Dr. McCarty has authored more than 100 publications on the topic of stem cell transplantation and has won numerous awards for his community service, including top doctor from the Richmond Magazine and my personal favorite, You Knock My Socks Off Award from the Leukemia and Lymphoma Society. He's an excellent speaker, a warm generous person and I know you will enjoy his presentation. Welcome Dr. McCarty.

Thank you very much. Very thank you all for your time and attention this evening. I hope to give you information - this is a rather broad topic - but I hope I can give you good information and we can generate some good discussion as we move forward.

00:01:55  Overview of presentation: We're going to talk about a topic, one that's been around for a while, transplantation, both autologous and allergenic, which I’ll define those in a moment and also CAR-T therapies, specifically for lymphoma.

What we're going to talk about mostly is data supported recommendations: autologous transplant, where the patient is their own donor for the source of stem cells; allogeneic transplant, where someone else is the donor.

We're going to talk about what these chimeric antigen receptor T cells or CAR-T cells, what are they and how are they different from these kinds of transplant. For both of these procedures and approaches, how do we determine who's a candidate and perhaps even, how do we choose one therapy over another. We'll talk a little bit about what it's like getting these therapies and where do we hope things are moving for the future.

00:02:54  There are many different types of lymphoma: If you look at this rather nasty slide here, this is how the pathologists and experts divide up the types of lymphoma that we are often diagnosed with. It's purposely not readable. In a very practical sense, we usually break it up into what we call working diagnoses, so indolent or low-grade non-Hodgkin’s lymphoma. You may be familiar, some of you with terms like follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma.

Another category, intermediate grade, such as diffuse large cell or follicular lymphoma grade 3 or transformed lymphoma. There are high-grade lymphomas such as Burkitt's lymphoma or lymphoblastic lymphoma and leukemia. There are also primary CNS lymphomas. These may look like diffuse large cell lymphoma under the microscope, but they present only in the brain and structures of the central nervous system and nowhere else. There's Hodgkin's lymphoma. There are T-cell lymphomas that may be mostly what we call a periphery or in the lymph nodes or in the skin. There are those that are primarily in the skin and don't exist elsewhere. Then, finally a group of things called lymphoproliferative disorders, which are sort of halfway between a response and reaction to an inflammation or an actual lymphoma.

One of the things that we know is that, for example, in lymphoma - I'll use diffuse large cell lymphoma - is that when we want to make sure that we do the best therapy upfront. And in the majority of cases, patients will actually be in remission at that point. But the people or the patients we're talking about when we're discussing transplant or discussing CAR-T cells, by and large, are people who had their lymphoma come back after what should have been very good chemotherapy.

00:04:53  Lymphoma patients who relapse after treatment or do not get into remission do poorly with standard chemotherapy: In patients - what this Scholar-1 study discusses - is patients who have had relapsed or even refractory, didn't respond to the initial therapy, they don't do quite as well as we would like to see. Their survival is very poor. In fact, an overall objective response rate of only 26% to chemotherapy alone, only 7% get into a complete remission. This upper graph shows that transplant, depending on response, does add a certain amount and adds a fair amount to these patients compared to just relying on getting a remission with chemotherapy alone. Overall median survival with chemo alone is only six and a half months and only 20% are alive at two years. This wants us to be able to do better and that's where the addition of transplantation and the CAR-T therapy, the need was identified.

For transplant purposes, whether we're talking about a person serving as their own donor or someone, who is getting a transplant from someone else, we are at the endpoint, replacing stem cells. We're also replacing some elements of the immune system to a certain extent.

00:06:10  What are stem cells? Let's talk about what are stem cells. Well, these are cells that replace what we lose during age or injury. The largest reservoir is in the marrow. For example, what does that mean? Let's say this weekend, I'm going to go work on my yard and I overdo it and I pull a muscle. Well, there's kind of a stem cell that's committed to help the muscle to repair, but once it does that repair, it's missing the stem cell. The bone marrow serves as this trust fund for cells to go to injury to help do the repair. Different tissues have better ability to do that. This relocation is something that happens all the time.

00:06:50  Sources of stem cells for transplant: When we want to do a transplant, we will either harvest it directly from the bone marrow or we will actually use a process to mobilize stem cells into the blood and capture them through IV. We've actually seen stem cells that have been isolated in other tissues such as the skin, the brain, the prostate and the muscle.

Another source of stem cells, excuse me, are from umbilical cord stem cells. After a baby is born, the mother donates the placenta and the cord blood is very rich blood, very rich in stem cells is clamped and then that blood is donated before the placenta and umbilical cord are discarded. This has been used in stem cell transplant since the 1980s. Because there are a limited number of stem cells, it's often used in children and small adults, but what has been lately perfected is the use of combining two of these umbilical cords to proceed to transplant. Again, this would be considered an allogeneic transplant because it's coming from someone else.

00:07:54  The difference between autologous and allogeneic stem cell transplants: I've used these two terms, autologous and allogenic. Autologous, this is where someone serves as their own donor. Here, the cells, we take them out and put them back in. They're coming back home. There's no difference. I mean these are yours, so it's no different. The main reason that this particular approach works is that we're actually doing … The transplant is not the therapy. The true name for this is high-dose chemotherapy with autologous peripheral blood stem cell transplant support. That won't fit on too many slides and we'll never get through this talk if I keep using it, but it tells you what we do.

00:08:36  High-dose chemotherapy is given before an autologous transplant to kill diseased cells: We give chemotherapy at sometimes 10, 15 or even 20 times more biologically effective or potent then standard chemotherapies you might receive in your physician's office. That is very effective at killing more of the cancer cells or lymphoma cells we're trying to eliminate. However, it is above the tolerance of the stem cells in the bone marrow and thus, the bone marrow function to replace white cells to fight infection to replace red cells to carry oxygen and platelets to keep you from bleeding is overcome. It becomes, yes, it's a lymphoma lethal dose, but it's also a marrow lethal dose. The cells that we collect from the patient before we ever start to chemotherapy are stored and frozen. The treatment dose chemotherapy is given and then, the stem cells, the transplant is given back, not as a therapy, but instead as a way of recovering from that effective dose of chemotherapy.

00:09:34  Allogeneic transplants rely on the donor's immune cells to kill cancer cells: In contrast, allogeneic transplants, we may use any kind of varying intensities and doses of chemotherapy, but whether the donor is someone who is related to us or unrelated to us or cord blood, this is a form of cellular immunotherapy because, in part, what we're asking is for the donor’s immune system to move into the patient to, on one hand, become comfortable living in this new body and become the person's new immune system, but for it to reject the lymphoma or the cancer we're trying to treat. It becomes very much a … We want that degree of immune response. In fact, one of the most powerful immune therapies that we have, but we want to keep it focused on the cancer at hand and to ignore the patient. If we are too careful at trying to eliminate that response to help prevent that auto patient response, then we increase the risk of relapse. If we're too lax about doing so, then the patient may suffer a complication called graft-versus-host disease, which can lead to problems. However, at the right balance in the Goldilocks zone, we get this rejection of the cancer and we get this new immune system to adopt the patient as their own immune system for the future and for the rest of their lives.

00:11:00  How do doctors choose whom to transplant and when? How do we choose when to do transplant, how do we choose patients and candidates and so on? Well, what we're really doing is doing a calculation of an assessment of what happens to the patient, this is what will happen, this is the course of things. If over time, we don't do the transplant, disease progresses. Okay that's not very good. We know if we do transplant, we can actually do very well in the long term at affecting the cure, but not for all. What we're really trying to do is limit this area, the risk to the patient, where the transplant might represent higher risk than the disease in the early point, knowing that in the long term, we can do better than no therapy or chemotherapy alone.

00:11:42  Age is a factor considered when recommending transplant: What are the different factors associated with that? This is also the same kind of assessment we use for CAR-T, which I'll explain more fully. What about age? Well, age is not your birth certificate. Age is what your physical fitness and frailty is about. It is how old you are physically. Autologous transplants are covered up to fit patients, up to age 78. Allogeneic, using donor cells can also be done up to age 78. In fact, patients aged 65 to 80 represent the highest growing population of patients on a percentage basis of all transplants being done in worldwide than any other age group. That's not just because we transplanters are getting older, we want to keep our options open. I promise, this is from good data.

00:12:33  Quality of stem cell donor is factor in recommending a stem cell transplant: We also want to make sure we have a good donor. Now, we can have a family member that can usually be a sibling, it could be a child, it could be a parent, it could be a mismatched related donor or even an unrelated donor, but we do have to worry about a little bit more reactivity from a donor that we're not related to. We are seeing similar outcomes from mismatch related donors and match related donor transplants. There's evidence that unrelated donors who are younger, when a younger donor is perhaps better than even the outcomes for, if we have a sibling who is older. These are some of the considerations. It's the fitness of the match, the risk towards graft-versus-host disease or that rejection of the patient rather than rejection of the cancer that we're really trying to moderate and find that these characteristics, the degree of match that we're trying to have can often impact that.

00:13:38  Other health problems are a factor in considering whether to have a stem cell transplant: Now, for someone obviously, especially as we're talking to people as we gain age and experience, we also develop and have other medical conditions, which could increase the risk or perhaps impact how we carry out the transplant or the cellular therapy. We can often adapt and we have very specific validated scoring systems, which help us understand the risk that different things like having a prior cancer or having heart disease or having kidney disease or liver disease or prior or current autoimmune diseases and so on. Even lab tests that show us what the heart function, how lung function, what the kidney function may be that determine what contribution to long term risk. Now, if we just had one size transplant fits all, then basically this would be a yes or no or are we going to do this or are we not. We have the ability to alter the intensity of the regimen and I'll show you a little bit about that in a moment. There is such a thing as a reduced intensity treatment and in a situation, often used in allogeneic transplants, where someone else's immune system is doing the work. We're relying in this situation less on the strength of the chemotherapy to take care of the cancer problem. Instead, we're relying more on the strength of the immunotherapy that the transplant represents in order to take care of it.

00:15:10  Other treatment options are evaluated before recommending a stem cell transplant: Elements of the of the stem cell transplant, again mostly talking about allogeneic transplants here. It's first, we evaluate the patient, does the disease warrant the transplant or are there better additional therapies, is this the right time to introduce transplant, does the risk of the transplant or does the risk of disease warrant the risk the transplant might represent? Again, the risk/benefit is based on what alternative therapies there are and the patient's own sense of testing for fitness and frailty.

00:15:43  Stem cell donor is selected first, based on tissue type (HLA type): The donor, it's based on tissue typing. This is a slightly more stringent typing. It is much more, it's actually stringent typing than is used for solid organ transplants. Here, think about what this HLA antigen, this is essentially the password that the immune system uses to determine what is you and what is something else that needs to be attacked as an infection. Now, doing tissue typing is very much like those cheesy old spy movies or novels that we have watched in the past, where the spy just has to know enough of the password to get by and the rest, we need to have the differences to make this work. The rest, we could get by with. That's important here. We match for the most important things, so that we don't automatically have rejection of the cells we're giving or this immune system reject the patient, but we have enough differences that there is still a graft versus lymphoma effect that we need.

Autologous transplants, where the patients are using their own cells. Since you're giving it to yourself, there's no reason or no need to do any tissue typing.

00:16:55  Stem cells can be collected from the bone marrow or from the bloodstream: Next, we harvest the stem cells from the donor. I'll show you some examples of that. This either can be a bone marrow harvest or something called pheresis of peripheral blood, where we do a process of shifting the stem cells into the blood stream. Right before the transplants, once we know we have cells, we give patients either combination of chemotherapy and/or chemotherapy plus radiation. The purpose here is to eliminate the cancer, to suppress the immune system and also to make room within the bone marrow for the recipient cells or the returning cells to grow and repopulate the marrow and start the process of blood reconstitution and immune system reconstitution. That happens with the stem cell infusion. These are given intravenously. I am not a surgeon. I do a bone marrow harvest in the operating room, but all of this is done essentially through a specialized form of these transfusions from either peripheral blood or bone marrow derived stem cells.

00:18:02  A patient's immune system is weak after transplant: Post-transplant supportive care, patients are considered immune compromised or immune deficient for up to 100 days after an autologous transplant and for allogeneic, it's not really a date on the calendar, it's actually at least a 180 for the donor cells and the recipient to come to a common agreement to work together and may take as much as a year to a year and a half or longer, depending on the process and depending on any complications that may occur.

00:18:39  Types of lymphoma that warrant an autologous stem cell transplant: What is it that warrants the need for autologous transplant in lymphoma? Well, diffuse large cell lymphoma that is recurred after achieving an initial remission. We do in all these situations prefer to see that chemo responsiveness happen. If it recurs, we talk to the referring physician. You'll get some additional chemotherapy, usually half the number of cycles that you had to begin with and as long as we see that this is responding ideally to a complete response, but at least a 50% or better response, then patients can move forward. Same thing for what we call transformed or follicular lymphoma at grade 3. Primary T-cell lymphoma, if you have it after you received your chemotherapy with your referring oncologist, you should receive a transplant, an autologous transplant at first remission.

Mantle cell, except for very indolent forms, which can be described most patients with mantle cell should receive autologous transplant on first remission. Obviously, any low-grade lymphoma that isn't responding to what should be good enough chemotherapy, should be considered for an autologous transplant to achieve the remission that they weren't able to accomplish with the chemotherapy alone. I mentioned a myeloproliferative or a lymphoproliferative disorder I should say in the past and AILD or angioimmunoblastic lymphoma is a representative of that kind of process. That is something we also do autologous transplant for as well. Patients whose Hodgkin's disease recurs after good remission after chemotherapy also benefits and does very well with autologous transplant. Primary central nervous system lymphoma responds very, very well. One of the high-grade lymphomas, recurrent Burkitt's lymphoma does also respond very well to autologous transplant after, again we have shown from standard second-line chemotherapies that we have had a good response.

00:20:53  Types of lymphoma that warrant an allogeneic stem cell transplant: In allogeneic transplant, what warrants that? Well, if you have the recurrence and you've had an autologous transplant and it comes back after that, any of the previous diseases would warrant that. I mentioned the primary T-cell lymphoma, if you didn't get the autologous transplant in first remission and it recurs, then the responses are far better for patients in the long term to receive an allogeneic transplant. Patients with Hodgkin's disease that may have recurred after a prior autologous transplant are those that have had more than one recurrence. I mentioned things like follicular lymphoma, marginal zone lymphoma, the indolent non-Hodgkin’s lymphoma, if they've had what is considered good standard of care chemotherapy and I think we've just all seen the reports of a new novel agent that you’ve seen, which has been approved by the FDA, but if they relapse within 18 months, then those patients really should receive allogeneic transplant.

Patients with what we call a double or triple hit diffuse large cell lymphoma, this is looking at some of the molecular changes that are driving this lymphoma to behave as a lymphoma, in that setting, these are patients who should receive an allogeneic transplant because an autologous transplant results in response, but a rather a much shorter kind of remission. Mantle cell, just as I said with the primary T-cell lymphomas, who have not received a transplant at first remission. AILD that is recurred and any T or B-cell lymphoma, leukemia hybrid indicating a faster response and faster, what we call kinetics of the disease.

00:22:43  Photo of bone marrow harvest: I gave you some ideas. Here's bone marrow harvesting. It's done the operating room. Basically, anyone who's had a bone … For all of us, you are sitting on your largest source of bone marrow, the pelvis. Doing multiple aspirations to fill a bag, there's a certain number of stem cells we expect and we test for. We have a target amount. We know that we can draw up to 5 CCs from each of the bone marrow aspirates to get stem cells and not dilute that with what would be peripheral blood.

00:23:17  Photo of stem cell collection from the bloodstream: The alternative is something called apheresis and peripheral blood collection. As I mentioned, stem cells are constantly circulating from the bone marrow to other places for injury repair as a normal process. We can give certain medications that amplify that process and drive these stem cells, these seed cells out into the bloodstream. Then, using a process of apheresis, which is sort of the complement to dialysis. Dialysis is working on the liquid part or the electrolyte portion of the blood. Here, we're actually spinning the blood, so the cellular components are pulled out that we're looking for that where these peripheral blood stem cells exist on that centrifuged column. They're stored into these bags, frozen until they're needed or in the case of an allogeneic transplant, even sent fresh for use by the recipient.

This gentleman, who I know is very clear here is someone who received a transplant with us. He's a lifelong teacher and he gave us permission to use this anytime we try to teach about transplant because he said, “Even after I am no longer a transplant patient and even after I retired, I want to continue to be engaged in education.” Here he is doing his thing.

00:24:43  How the type and intensity of chemotherapy given before transplant is determined: I mentioned something about the intensity of preparative regimens, when do we choose, how do we choose what chemo you get prior to the transplant to again make room and so on and so forth? We have a whole bunch of different kinds of different regimens. They fit on this graph based on the agressivity of the malignancy. For example, some lymphomas and CLL moves very, very, very slowly. The control with a large dose of chemotherapy is less essential because this will move slower than the graft-versus-cancer effect of the immunotherapy that the transplant represents.

On the other hand, acute myeloid leukemia may move very fast and so we need to, since we know that the graft-versus-cancer effect may not kick in for almost two months after the transplant actually occurs. We want to make sure that this disease is going to hold still for that to kick in. The amount of immunosuppression we need to incorporate into the transplant regiment also is based on how well matched, so you can actually right down here would be an identical twin transplant. A little less well matched is from a sibling. Next from a match unrelated donor and then, a haplotype transplant is essentially if you've got a mother, brother, sister or child, you've got a donor. They're typically a half matched. This gives us some, based on both the disease as well as the type of donor, we can actually choose between various types of chemotherapy that balances risk and benefit.

In addition, I mentioned some people may have other medical conditions, where certain of these chemotherapies or certain intensities may not be wise or may not be tenable for them, in which case, we can tailor the transplant preparative regimen chemotherapy to not just a disease and not just the donor, but to the patient, who is going to be undergoing this particular procedure. That's very important.

00:26:59  Photo of man receiving stem cells: Here's our gentlemen. He had an autologous transplant. As you can see, the preparative regimen has now taken his hair. His chemotherapy has taken his hair. In preparation, he shaved himself and he is receiving his stem cells that are going IV through a central line.

00:27:20  Graft-versus-leukemia effect in allogeneic transplant: When we talk about an allogeneic transplant, we can actually try to drive the therapy in the direction we want. Let's say, for example, we have a patient, who has this cancer, this lymphoma, shown up in the black dots. We have tests that we can do to determine what part of his blood, his bone marrow, his immune system, his T-cells, his white cells and so on are made from the recipient and how many from the donor. We do the transplant after the chemotherapy and/or radiation. Often, we're in what we call sort of a mixed chimerism state. We still have a residual lymphoma. There's still some of the recipient cells left behind. They haven't quite disappeared. They haven't responded to the chemotherapy yet. The immune response from the donor is still not quite fully operational, but clearly, the donor is in there. They live as essentially immunologically and from their bone marrow standpoint as a dual citizen, if you will.

00:28:19  Donor lymphocyte infusion: We can do things like manipulating the immune suppression medicine by lowering it or by recruiting additional cells from immune system cells, T-cells, for example, in what we call a donor lymphocyte infusion to drive the hematopoietic, the blood system and immune system, to fully donor in such a way that we eliminate the cancer, we eliminate any recipient blood cell or immune system, so that we can get this patient more readily and more reliably into a remission.

This becomes in a way a treatment that we can continue to manipulate even if patients start to show evidence of early recurrence, we can re-manipulate, we can get the toothpaste back in the tube and we can often get patients back into remission with this type of an approach.

00:29:13  Graft-versus-Host Disease: I mentioned the thing called graft-versus-host disease. This is when that graft-versus-cancer gets a little bit too exuberant or it gets a bit off target and starts attacking or affecting part of the patient, who we love and has nothing to do with the cancer. Chronic graft-versus-host disease can have an impact on quality of life post-transplant. This number, occurs 30% after matched related donor transplant or 60 to 70% after mismatch or unrelated transplant is essentially all grades.

That can be as mild as, “My eyes are a little dry, I have to put some drops in my eyes. I have skin changes and so when I wear shorts or wear a T-shirt or wear my swimsuit, I have some changes.” It also could be severe enough to impair and interfere with some organ function.

.We've seen by better HLA typing and matching, by understanding other factors that play a role in promoting graft-versus-host disease versus graft-versus-lymphoma by using better immunosuppression such as something called ATG, which depletes the cells that can lead to graft-versus-host disease. We've actually seen a reduction and a moderation of the incidence and severity of this graft-versus-host disease.

00:30:33  What graft-versus-host disease looks like: It could present as many different kinds of autoimmune disease. It can look like scleroderma like changes with skin thickening or loss of flexibility, hair loss, nail changes. It can cause dry eyes, dry mouth and actually can even affect the vaginal mucosal membrane, can increase the risk of dental problems.

GI, can cause dry swallowing. It can cause something called cholestasis, where the liver is essentially constipated in terms of the bile process and may affect how food is absorbed. Can lead to changes in the lung that may represent like emphysema. It can lead to defects in the immunity and it might require more time on immunosuppressants than someone that didn't develop this.

The whole focus on an allogeneic transplant is less on the time in the hospital where the transplant actually takes place and is much more on the post-transplant care for that 180 to 365 or longer days, making sure that we avoid things that may promote graft-versus-host disease that we make the appropriate interventions to diagnose graft-versus-host disease and to also mitigate and moderate and lessen graft-versus-host disease when it's detected.

00:31:48  Late effects of chemotherapy and radiation before transplant: Just having chemotherapy and transplant can also lead to other long-term complications. It depends on the type of the chemotherapy, may have different target, off target effect. Radiation can do the same thing. Immune system may be moderately or mildly impaired.

It can affect fertility. It can have impacts on the heart or the lung function. Ironically, in some situations, secondary cancers can be affected. There can be impacts on social and work functioning and of course, relapse can still occur.

Not all of these are certainties. Part of what we do in transplant is we do a lot of pre-planning and a lot of monitoring afterwards for making early intervention. We also work on making sure that patients have a very good support system and in terms of some of the functional ability that patients are very strongly engaged, not just in rehabilitation, but an ongoing pre-habilitation to make sure that their physical functioning and they're not regarded as having someone with frailty, but as someone having fitness.

00:32:59  The role of T-cells in regulating cancer: Let's talk more about how and as an entree into talking about CAR-T cells, let's talk about these T cells and how they have a role in how cancers occur. Now, I'm not going to give you biology of what gene goes wrong to cause this kind of cancer. I'm going to look instead at this immune system because really at the basis of what we're talking about here is how we're adjusting, manipulating or schmoozing the immune system to basically be able to cause a very powerful immune therapy against cancer.

00:33:32  How tumors evade the immune system: Why doesn't the immune system keep us from getting a cancer? It can happen for, there are many reasons, but the main ones are maybe the T-cells are there, but they don't recognize this cancer as something that's foreign. They just don't see the cancer is something different from normal. A second thing could be that there are T cells that recognize, but they're not in enough numbers and they just can't get the job done. Then, there's another situation, where T-cells get exhausted, where there are actually [inaudible 00:34:04] mechanisms or hormones or chemicals that the tumor itself excretes that puts the immune system to sleep. I use the analogy of in The Wizard of Oz when Dorothy and the crew are going through that field of poppies, everyone falls asleep. That's the same thing that can happen, tumors have the ability to have that effect on the immune system.

Now, we have some other things. We've talked about the allogeneic transplant. Well, heck if this immune system isn't working, let's use a new one that's going to be a little more stimulated, a little bit more vigilant and more prone to getting rid of the cancer. We also have medications called PD-1 inhibitors or checkpoint inhibitors that act like ,again, going back to Wizard of Oz, it's like the snow that kills the poppies that wakes up the immune system and stops that sleepy mode. The other and more elegant thing that we're going to talk about now is the modified directed T-cell therapy, where we're actually modifying someone's own homegrown, native autologous T-cells into becoming cancers that can recognize the cancer, are present in large numbers, are stimulated and can in part overcome this poppy go to sleep effect.

00:35:28  How patients are evaluated for CAR-T therapy: In this situation, what happens is a patient who is a candidate for CAR-T and again, they've gone through the same kind of evaluation and testing to determine whether a candidate for transplant or candidate for CAR-T. We'll talk about right now where that situation is, but the same concepts of having adequate functioning, adequate fitness, adequate organ function and the ability to collect cells is very much the same.

00:35:54  How CAR-T cells are collected: In this situation that same apheresis process that I showed you the picture of the gentleman, sitting next to that machine that looked like a [inaudible 00:36:02] machine, we again collect a similar set of cells. The difference here, we're not having to push any stem cells into the bloodstream. We're just collecting the mature cells, the T cells of the immune system that live in your blood all the time. In fact, they represent a very high percentage of the cells that still carry a nucleus in the blood.

00:36:24  T-cells are engineered in the laboratory to recognize cancer cells: These are then shipped to a central manufacturing lab, where the T cells are isolated. Then, using a … We essentially reverse engineer these T cells, not to recognize what they may have grown up. You may have these cells we're working on, maybe they grow up in your body to recognize the mumps or the measles vaccine or the cold or a colon cancer or this kind of bacteria or the stuff that happens when the proteins that are on a piece of wood when you get a splinter. We can actually say for lymphoma, something we call CD19, this is a protein that exists on lymphoma cells that is something we can use as a direct target. We can literally reprogram T cells to now focus on anything that is carrying this CD19 protein.

It's very similar to you got a new phone. I need to basically do a tool … I need to do something differently with it, so I go to the AppStore, I go to the Google Store, I go to the whichever store and I download the app I want. Now, I have a new functionality. That's what we're doing using special viruses that go in and reprogram the cells. These cells are then expanded and stimulated. They're sent back to us. Patients receive a very mild form of chemotherapy that makes room in their immune system for these cells to work. They are infused IV and then, they go to work and they identify the cancer cells and go to work, eliminating them fairly rapidly.

00:38:05  Potential complications after CAR-T therapy: Anytime the immune system gets overactive that's a good thing. We have to watch for, as we did as I mentioned graft-versus-host disease off target or over exuberant responses. We have to do the same thing for CAR-T. There's two things, cytokine release syndrome. This is actually the cells are releasing many of the same hormones and chemicals that your body does before you actually get the symptoms of a flu or an infection. It can actually represent fever, tachycardia, fast heart rates, low blood pressure, hypoxia, almost like you're having sepsis or a severe bacterial infection. In addition, you can also have neurologic events. This is that if the not so much, it can be the CAR-T cells cross the blood-brain barrier and get into the central nervous system. It can be as simple as confusion or tremor or other changes.

When this can occur with this kind of therapy coincides when the CAR-T cells are expanded most in response to the tumor and actually, patients develop a little bit of this cytokine release syndrome are ones who will tend to do better. Now, obviously, we don't like people to get sick and have problems. These are reversible issues. We have a very strong and very rigorous staging system to look at identifying when this is starting to occur and a grading system and that we can turn it off by … Since IL-6 is the main driver of this, we can actually stop up the IL-6 like a sponge and turn this over active immune system down without compromising the response.

00:39:50  How well does CAR-T therapy work for patients? How well does this work? Early responses were fantastic. There's a non FDA-approved drug that we're currently studying called JCAR from JUNO. KITE is using Yescarta and Novartis is using Kymriah. Based on these studies, for patients that may have had anywhere from three to 11 different prior therapies, we're seeing overall response rates in the 70-80% and complete remission rates in the 50%. Remember, this is a lot better than that 26% overall response rate and 7% complete response rate that we saw in similar patients or even these patients are more heavily treated from chemotherapy alone. This is something very exciting and why we've got very excited from the early responses. Sorry, try and move along here.

This is an example from a single patient, how well this can respond. Anyone who has seen a PET scan knows that this scan lights up any areas, where there is active tumor. You can see it shouldn't belong here in the liver or in the spleen or in the lymph nodes. After nine months of therapy for this patient, gone. Here's a patient with a lymphoma in his liver. After his first stem cell or CAR-T infusion, he still had some residual disease. After the second, it continues to respond. This is a very, very powerful response, a very powerful tool.

Studies are fine. What happens when it really gets FDA-approved as, for example, the Kymriah, I'm not even try to pronounce that name because it just doesn't roll off the tongue. There is definitely no poetry in that name. In the real-world experience, patients do just as well. Patients, so response is within 30 days, but they continue to respond even out for the first 100 days.

Interestingly, it seems that while patients seem to may continue to relapse with lymphoma, once you get to 6 months, there's a tendency not to have any further relapse. Thus far with the data we have, this is very new. Internationally, if you have a remission in six months, there's a very strong possibility that remission will continue for two years and longer. We need longer follow-up.

00:42:28  Factors associated with best outcome with CAR-T Therapy: Interesting, this is one of the situations in these studies, where women rule, women do better than men, not to a point where I would say, “Men don't look at this,” but it is nice to have an advantage. Better performance status, so this is where the idea of even though you have going through therapy, trying to maintain as much of your physical fitness as possible, doing low level, low-impact exercise is very, very important.

Someone who has disease that comes back, tends to do little bit better than patients whose disease just isn't responding to begin with. If the lymphoma cells are bulky or not is very important. Again, it doesn't change whether we do it or not. These are factors that have been associated. Also, this is really just a slide to say that this is the same CAR-T cells are also been … Kymriah has been also approved for refractory ALL in adolescents and young adults and kids. These also bear the same target of CD19 as we are treating for diffuse large cell lymphoma.

00:43:43  Patients may need to have chemotherapy while CAR-T cells are being made: In the interest of time, I'm going to move along, this is really just an idea that no cellular therapy, whether it's transplant or CAR-T is going to be as effective chasing a lymphoma that is moving very, very quickly. Patients who must have bridging therapy and they have a very rapid progressive disease tend to do not as well as patients who actually didn't have, the disease is not moving fast enough, we need to do chemotherapy while we're waiting for the CAR-T cells to be made. They have a later delay in their progressive disease.

00:44:21  Long-term effects of CAR-T therapy: What about long-term effects? This is looked at specifically for CAR-T cells in patients with lymphoma and CLL, looking only at the group who they survived at one year and continue to be evaluated. The biggest thing is low IgG levels. Now, why is that? It's because unfortunately that CD19 target that makes this effective for lymphoma also has a problem. It's also present on normal cells. Therefore, we're knocking out normal B cell function. Now, you would think that’s a problem. Yeah, it can be for people how may develop infections if they do. However, just having low IgG level does not guarantee you will have a risk of infection. Plus, we can always supplement by giving patients IVIG or basically a bag of antibodies to replace and borrow that immune function. It's given all the time.

Interestingly, you might worry in a patient who gets allogeneic transplant, are we potentially stirring up graft-versus-host disease by stimulating these cells? Of nine patients who got CAR-T, after having had a prior allo transplant, only one developed graft-versus-host disease. This is a very powerful tool that could be used for a variety of patients.

00:45:51  Follow up after CAR-T therapy: Where is this headed? How do we put this together with our current thinking? I think if someone gets CAR-T cells and they get a complete remission from the CAR-T cells, we're just going to watch them. If we get up to six months and two years and they haven't relapsed, we're going to just continue to follow and you know only 11% seem to relapse overall from day 100 through the two-year time point. If they do, then these are patients that we can actually retreat and reconsider for an allogeneic transplant at that point.

50% of people who get a partial remission from CAR-T cells will actually translate into a complete remission by day 100. We don't want to make any decisions about success or failure in the absence of any true progression until after the first three months after CAR-T therapy. As I said, six month therapy is essentially a CR. For those with a partial remission that doesn't go to a complete remission, then we will consider them for an allo transplant, but in the current setting, these were patients who weren't eligible for either an autologous or an allogeneic transplant because we need to see a response. Transplant is again not made as effective for patients that are not responding to at least some therapy.

00:47:16  Why not use CAR-T therapy for diseases other than lymphoma: I know there are some questions that are coming about not going outside of lymphoma, why doesn't CAR-T work for there?

The problem is we have to come up with a whole new strategy, if we make CAR-T against T cells, then the CAR-T are going to eat themselves. Even if we have a way of protecting the CAR-T, these are patients that are going to have no T cell immune system. They're going to still require an allo transplant to replace a functioning immune system. Myeloid malignancies, myelofibrosis, AML, myelodysplasia and so on, these are cancers and processes that are based in the stem cell. If we use CAR-T to eliminate the stem cells, then we're going to have to do an allogeneic transplant, a donor from someone else in order to [inaudible 00:48:00] that blood function.

Now, there are things like cancer testes antigens, we're hoping to do for some of the solid tumors, like synovial cell cancer, which is a cancer that develops in what we usually tear in our knees and our shoulders and other kinds of sarcomas. The question is what happens to the gonadal tissue? What about the testes. We have to do sperm and OVA banking and that's a possibility. These are questions that need to be resolved.

00:48:30  Efforts to improve CAR-T outcomes: We are trying to improve indications, trying to expand it, how can we do that, looking at how to optimize CAR-T in CLL.

00:48:38  CAR-T therapy for Hodgkin Disease: Someone asked a question about what about CD30? CD30 is the marker on Hodgkin's disease, it's also a marker on T-cells as well and so, studies are ongoing to determine the best way to use CD30 CAR-T for Hodgkin's disease as well as T-cell lymphomas.

00:48:56  Is CAR-T better than an autologous transplant: They are using combination, CD19, CD20 targets, these are again proteins that are uniquely on central nervous cells lymphomas and can we use that potentially? There's a study ongoing comparing CAR-T versus autologous transplant, so go back to my slide where we talked about the list of where we would do autologous transplant. Now, we're looking to see can CAR-T do as well with less impact and better outcome and less risk than doing an autologous transplant? Studies are also being looked at multiple myeloma and another epithelial solid tumor cancers.

00:49:35  Transplant and CAR-therapy are both effective strategies to treat B-cell lymphomas: What I hope I've shown is that we have both transplant and CAR-T cells as effective therapy choices for relapse and refractory B-cell lymphomas. Their powerful therapies would represent the need for very complex care and monitoring of patients, so that we can [inaudible 00:49:50] maintain benefit and minimize risk. We have numerous trials that will expand the targets, the kinds of cancers and as well as compare CAR-T against classical transplant earlier in the disease course. This is something that requires a lot of collaboration with the referring physicians, since the complications of a cytokine release, graft-versus-host disease and so on, we have long term follow-up, following patients for 10 to 15 years thereafter, in which we collaborate as a group with the patient, with the patient's caregiver and family, the referring physician and the transplant center.

I'm going to stop there and see if you have … For any questions?

Thank you Dr. McCarty. It was an excellent presentation, lots of information there for us to digest. We'll now do the question and answer session. Again, if you have a question, please type it into the chat box. I see a number of questions. I think some of them have been answered in the course of the presentation, but let's take them from the top. Sylvia wants to know, she's been diagnosed with myelofibrosis. She wants to know are there transplant or CAR-T options available for myelofibrosis.

00:51:06  CAR-T options for patients with myelofibrosis: Absolutely, myelofibrosis is one of the areas that I have both the research and a clinical and basic science interest in. We do transplants for that here. We do a fair number of them here actually. Having the diagnosis doesn't warrant having a transplant. It's about certain characteristics of myelofibrosis that determines that. It is by necessity an allogeneic transplant that is very effective and beneficial at treating myelofibrosis.

All right, Marina is asking what type of infusion centers usually provide stem cell infusions? Are they mainly just NCI tertiary cancer centers that operate them?

00:51:53  What kinds of hospitals do transplants: That's a very good question. It's going to National Marrow Donor Program or going to Be The Match is a way that you can determine whether you have a transplant or a cell immune therapy program within your region. Not always, but typically these are academic centers. However, there are some very high-quality academically associated private practices that also do this as well. The three websites I would look at … Susan, you probably may have some pointers on BMT Infonet as well, but CIBMTR and Be The Match are probably the two websites where you might be able to look at your state and look at your region and see where transplant centers might be.

That's correct, also on the BMT Infonet website. At the top, there's a button that says, “Transplant centers,” you can get that information there as well. All right, McCormick wants to know what your thoughts are on the efficacy of CAR-T therapy versus transplant for a physically fit 75 year old patient with MDS? Are there clinical trial options available for MDS patient?

00:53:14  Clinical trials for MDS patients: Well, right now, we don't have CAR-T because that's the same problem we have. The basic problem is is that if we treat … MDS is a stem cell based disease, just like AML, just like myelofibrosis. You can do CAR-T, but you're going to end up needing to do a transplant. Right now, the standard of care is an allogeneic transplant. The candidacy is again based on your fitness, based on the other medical conditions you may have that could represent a process that complicates the transplant and also, what kind of donor and the suitability of the donor that you may have.

00:53:52  Question about TTI-622: All right, Kevin is saying that he is receiving TTI-622 treatment, he relapsed within 10 months after an auto transplant. His transplant center is telling him that if the TTI-622 puts him in remission, he'll immediately go to an allogeneic bone marrow transplant. If it is a partial remission, he'll have CAR-T. Do you have any insight into this process?

I don't because I am not familiar with that particular agent and what the scope and mechanism of action of that particular agent is about. In general, if I replace that with, given the fact that it has that mellifluous name, usually means that this is an early phase trial. We don't have a whole lot of information about durability of the response to that chemotherapy. Therefore, I'm looking at that particular intervention that therapy would represent, I guess another good way of getting your disease under control for either, if it gets a complete response, then we know that disease is going to be in remission presumably for the allogeneic transplant for the graft versus cancer effect to kick in. If a partial response, then there's a concern that because the timing for that immune response is longer than allogeneic transplant that it might recur before the allo transplant donor is able to do something. A CAR-T has much more immediacy at getting a better response. I think I absolutely agree with that particular thought process based on response to your current treatment with the investigational drug.

All right, Patricia says, “These are exciting therapies, what are the potential financial impacts to patients and their caregivers that we should consider?”

00:55:51  Financial impact of CAR-T therapy: Well that's a very good question. Typically, for transplant, the things that I put down on your list are what are usually considered the approved indications medically and by and large by third-party commercial payers. Medicare is a little bit more restricted. Medicaid follows Medicare guidelines and is a state-by-state kind of thing. Bottom line, before going into any CAR-T or any … I'm saying outside of a clinical trial, going into any CAR-T or any transplant, this is not something you just walk in, you get your therapy and then, we get the bill and we figure out if you can cover it. Patients for these kinds of therapies are always informed beforehand. These are pre-authorized typically by the transplant center and there is a financial coordinator that sits down and talks about what's going into all of this. I think it's a matter of working with each person individually and their insurer to make sure that your coverage pays for what they need to pay and you're not blindsided by any out-of-pocket or co-payments that may be involved in the care.

Chris would like to know approximately how long it takes for clinical trials to complete and the therapy to be available on the market and would the criteria for getting into a clinical trial be different from the criteria for receiving the therapy once it's out in the market? He's particularly interested in the JUNO trial.

00:57:28  How long it takes drugs to become available after a clinical trial and how to get into a clinical trials: Yeah, so that really varies. I'm going to talk about … The problem is you can't predict how long it takes because what happens is truly someone comes up with a great idea in biology and they test it in cells. They test it in animals. They test it in models. Then, we move to what we call phase one studies. The phase one is in early phases, where we're really just trying to determine what is the right dose of this therapy to give and what is the maximum tolerated dose to determine the safety profile.

The second, phase two and that's usually a small handful of patients, depends on how many dose escalations or how many dose steps there might be. Phase two, which typically depends on how rare the disease might be or how quickly the disease might … How many patients are eligible is really to determine is there a signal that this responds and it's not really to compare it yet to the standard of care. That's where the phase three and I'm assuming JUNO, you're talking about the phase three trials are typically what they call registration trials, where by showing a comparison against the standard of care or if they are the first on market for this particular problem, then they're approved by the FDA.

A clinical trial typically accrues patients for anywhere from two to three, sometimes even five years in the case of less common cancers. You then need to see at least one year or more from the last patient to enter the trial to see outcomes. The first patient in may actually end up waiting five years to get the response of the trial. I know this seems like a long time, especially when people want to have access to it, but we have enough evidence from other trials, where rushing to judgment can actually sometimes lead to long time, “I wish I hadn't done that.” This is really built in for patient safety.

The answer to whether the entry criteria for clinical trials is what it would be when is commercially available, I would say for the most part, yes, initially yes because the FDA that pivotal study, they basically look at the data. They say, “Therefore, it is indicated based on the kinds of patients have went into the trial.” In reality, over time, as more experience and real-world experience accumulates and as we have more experience in using new agents, very often the indications expand. For example, I would … Additional clinical trials go on place. I expect by the end of the year, for example that we will start to see indications expanding and opening for CLL. We will see you expanding for mantle cell. We might even see trials in some of the higher risk follicular or indolent lymphomas as well. Then, after the first of the year, we will get our first reports for the Bluebird Bio CAR-T product for multiple myeloma. I know it's long-winded, but essentially it's a very complex thing and I hope I was able to answer it to some degree for you.

Thank you. Mariana wants to know if all bone-marrow transplant centers also do CAR-T or do you have to go to a specific center for CAR-T therapy?

01:01:05  Do all transplant centers do CAR-T therapy: Everybody does it little bit differently. There are centers, larger centers, sometimes they have a separate immunotherapy program. It's a separate set of docs that collaborate with their transplant doctors. What I decided, based on my own just how I feel philosophically and how my team philosophically feels is that I'm not sure that a patient coming to me … Well, I guess the analogy is if I'm a hammer, then everything is a nail, right? I don't want to be a transplant center and basically, inadvertently be biased to offering transplant when CAR-T might be available. Secondly, I think that patients who might be on my transplant list, I won’t say maybe, I just say this happens, who are on my transplant list suddenly, they're not getting the remission or they're not getting the response to their upfront chemotherapy with the referring doctor. They need to get CAR-T. We have a combined program, cellular immune therapy and transplantation program, which a number of centers are doing.

I think you have to look at your local place and see how that happens. You have to ask the question. If you go to a center that has separate programs, asking to advocate for yourself, so why CAR-T, why not transplant? Why transplant, why not CAR-T and how is that decision made at your institution? How do you all collaborate? I think that's a very valid and very important question to ask. Right now, it's a little bit clearer because quite frankly patients eligible for transplant have shown response. The current indications for autologous and allogeneic transplant are that you have to have chemo responsiveness. CAR-T are people who have not shown that response. We kind of are looking at two different populations and it's a little bit clearer. When we have data comparing them head-to-head, then we'll have a better answer about do you go to transplant or CAR-T as we have a better understanding.

All right, [inaudible 01:03:10] would like to know if you're aware of any clinical trials having success with cutaneous t-cell lymphoma, CD30?

01:03:20  CAR-T for cutaneous T-cell lymphoma: I know that University of North Carolina has been doing a CD30 CAR-T cell. What I would encourage you to do, there are some others, I would go to clinicaltrials.gov. It's a website that the government maintains and it does a search engine that allows you to type in your disease and you can type in … I think it allows you to type in your disease and type in a treatment modality. You put in cutaneous T-cell lymphoma and put in CAR-T and it will generate a list of clinical trials really throughout the world that are registered with the NIH and will tell you whether they're completed, whether they're accruing, whether they're active and will tell you the various places around the country, where those clinical trials might be occurring.

[moderator] I might add that Be The Match has a program called the Jason Carter Clinical Trials Program, where there's actually a human being that helps you go through those trials on clinicaltrials.gov and identify which might be important for you. It's a nurse that helps you with it and that’s very helpful if you have any questions contact Be The Match or BMT Infonet, we can help you with that.

Often your referring physician will do that, your oncology will do that. That's a service that we provide also to our patients, if they have a disease, is progressing and we do not have access to that particular clinical trial, we work that search with them and get them referred to the most convenient or local place.

All right, Genevieve wants to know if you can collect CAR-T cells from donors or only from the patient?

01:05:03  Can CAR-T cells be collected only from patients or from donors as well? Yeah, so right now, it's all about the patient. When you start doing it from donors, so there are two answers to that. If I want to do a transplant version of a CAR-T, I'm going to have to deal with not just graft-versus-host disease and rejection. Now, I've got cells that have basically drunk about a case of Red Bull and the concern for graft versus host disease and response is going to be very overwhelming. However, there is a way of what … Maybe what you're talking about is what we call off the shelf or allogeneic CAR-T, where essentially it's a way of emasculating the T cells to the point, where it doesn't require the tissue typing that we have to do when the immune system cells come from another person. Those are still not quite ready for prime time and are still being looked at for clinical trials.

Mariana would like to know if CAR-T therapy is an option for Richter's syndrome?

01:06:15  CAR-T for Richter's syndome: It can be. It depends on how it's defined and that's actually likely right now, it's on the clinical trial. If it's a Richter's transformation, the strict definition of transformation from CLL to a diffuse large cell type lymphoma that is something that can be considered. If it is a true transformation from a low-grade to an intermediate grade lymphoma, then CAR-T is currently indicated for that.

All right, Marina has a general transplant question, are postmenopausal women still good bone marrow donor candidates?

01:06:52  Can post-menopausal women be bone marrow donors? Post menopause doesn't make a difference. What it is strictly is it's about our age. If you're a related donor and you're under age 60 and you have a family member that you match, go for it. Even if you're over age 60 and you're the best match in a family member, go for it, be that donor. Obviously, we ensure that being a donor is safe for you and safe for the patient.

Secondly, when I talked about an unrelated donor, the preference for people under age 30 is not an absolute. If an older donor is the best match, we will go with it. It's just that all things being equal when we look at they're at least six or seven or eight different kinds of factors that we look at when we're picking among the different range of choice of donors that we would choose someone younger.

Why is that important? It's because the immune cells are still a little bit more malleable. When we turn 35, we lose a function called the thymus or an organ called the thymus, which you think about it is, for me, it would be John McCarty University for my immune system to learn what is me and what isn’t me.

After that time, we can still generate new T cells, but it's a different process, is a little bit more bulky and a little bit more bulky, which is why older donors, it's all about literally age and time after having your thymus involute and disappear as it normally does.

All right, then, we have one more question and I think you did touch on this a bit, but maybe you could expand on it. Martin wants to know what the current evidence is for the use of CAR-T therapy in recurrent mantle cell lymphoma and other rarer types of lymphoma?

01:08:41  Current evidence for CAR-T to treat mantle cell lymphoma: That's being looked at right now. I have a feeling that we will see … I haven't seen large data on that published, but I believe expecting to see it from JUNO and potentially from Yescarta I believe from the Kite product the data from studies in mantle cell. As I said, I would not be surprised if within the year, either within this year or within a year from now, we would see mantle cell being an appropriate target and appropriate CAR-T treatment for it. I just don't have that date.

Thank you so much Dr. McCarty and thank you everybody who participated on the call and offered those excellent questions.