CAR T-cells in Non-Hodgkin Lymphoma, A Hopeful Option

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CAR T-cells in Non-Hodgkin Lymphoma, A Hopeful Option

Thursday, January 13, 2022

Presenter: Gary L. Simmons DO, Assistant Professor, Virginia Commonwealth University; Medical Director of Ambulatory Cellular Immunotherapies and Transplant, VCU Massey Cancer Center, Richmond VA.

Presentation is 47 minutes long with 14 minutes of Q & A.

Many thanks to Kite, a Gilead Company, for their support of this webinar.

Summary: CAR T cell therapy is a promising form of immunotherapy for Non-Hodgkin Lymphoma. It has distinct advantages over prior therapies as well as its own limitations. This presentation discusses when CAR T therapy is indicated, how it works, and why it is beneficial for relapsed or refractory lymphoma.

Highlights:

• Non-Hodgkin Lymphoma is very common. There were 77,000 cases and 20,000 deaths in 2020. Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma.
• CAR T-cell therapy is approved for treatment of patients with non-Hodgkin lymphoma whose disease is refractory (does not respond to treatment) or relapsed (comes back after treatment).
• CAR T cells are genetically altered versions of the patient’s own cells. They combine the best features of B-cells and T-cells for treating lymphoma. Unlike transplants, patients do not need to be in remission to receive CAR T-cell therapy.

Key Points:

(00:05:14) There are different types of non-Hodgkin lymphoma. The initial treatment will vary, depending on the type of non-Hodgkin lymphoma a patent has.

(00:09:53) Patients who relapse after initial treatment (the disease comes back) or do not get into remission with initial treatment generally do poorly with additional chemotherapy.

(00:15:35)  B-cells and T-cells are part of the immune system and have different functions.  B-cells fight threats outside the cell, while T-cells fight infections within the cell.

(00:17:31) CAR T-cells are genetically modified versions of the patient’s own immune cells that utilize the strengths of both the T-cells and B-cells to fight cancer.

(00:20:48) CAR T cell therapy is much more effective in achieving remission in patients with relapsed or refractory non-Hodgkin lymphoma than chemotherapy.

(00:23:37) PET scans show CAR T cell therapy can work very quickly, with great responses in as little as one to three months.

(00:28:02) Whether a patient should have a stem cell transplant or CAR T-cell therapy is dictated by the disease and scientific evidence at the time.

(00:28:36) Transplants are most effective when patients are in remission.

(00:29:50) Transplant toxicity in autologous transplants (transplants using the patient's own cells) is mainly due to pretransplant chemotherapy. Toxicity in an allogeneic transplants (transplants using donor cells) is mainly due to graft-versus-host disease (GVHD).

(00:38:20) The primary toxicities associated with CAR T-cell therapy are cytokine release syndrome and neurotoxicity which can usually be well managed.

(00:45:09) The future is moving toward immunotherapy and wider use of CAR T cell therapy.

Transcript of Presentation:

(00:00:01) [Susan Stewart]       Introduction. Welcome to the webinar CAR T-cells in non-Hodgkin lymphoma, a Hopeful Option. This is brought to you by Blood and Marrow Transplant Information Network, or BMT. My name's Susan Stewart and I will be your host for the evening. Tonight's speaker is Dr. Gary Simmons. Dr. Simmons is a hematologist-oncologist specializing in stem cell transplantation and cellular immunotherapies for the treatment of blood cancers such as leukemia, lymphoma, and multiple myeloma. He serves as the Medical Director of the Ambulatory Clinics and he leads the research working group in the Cellular Immunotherapies and Transplant Program at Virginia Commonwealth University Massey Cancer Center in Richmond, Virginia.

(00:00:52) Dr. Simmons is also an assistant professor at the Division of Hematology-Oncology and Palliative Care in the VCU] Department of Internal Medicine, and in his free time I'd like to let you know Dr. Simmons runs. And he runs a lot. Dr. Simmons is fond of taking part in 100 plus mile ultra-marathons and twice ran non-stop for 36 hours, which I cannot imagine, but he tells me it's true. So without further ado, please join me in welcoming Dr. Gary Simmons.

(00:01:24) [Dr. Gary Simmons]   Overview of Talk. Good evening. Thank you, Sue, for that kind introduction, and thank you for asking me to give a lecture on CAR T-cells in non-Hodgkin lymphoma. Definitely a hopeful option. I welcome all the audience and thank you for your time beforehand, and please, I'll do my very best to answer as many questions as I can in the time allotted, and do our very best to make sure that we answer all of your questions for you on this evening.

(00:02:04) First, disclosures. I've been on speaker's bureau for Kite, served on the advisory board for Kite at the American Society of Hematology and I've been consulted for Jazz Pharmaceuticals.

(00:02:20) Learning Objectives:  Learning objectives for the evening. First, we're going to review what non-Hodgkin lymphoma briefly is. It's a big category so we're going to try to make things as simple as we can. We're going to review the history of immune-oncology and the need for CAR T-cells. We'll talk briefly about the FDA indications for non-Hodgkin lymphoma, differentiate between stem cells and CAR T-cells, review the treatment of CAR T-cells, both the success and the toxicities, and comment on my experience at VCU, and look at the future in immunotherapies.

(00:02:58) Description of non-Hodgkin lymphoma. First, what is non-Hodgkin lymphoma? Non-Hodgkin lymphoma is a blood cancer. If we look at the body here in this diagram, you see this green network of vessels and what look like little beads. And inside those beads, if you were to open those up, those are lymph nodes. And our body has a lot of lymph nodes scattered throughout and they play a very important purpose to kind of clean the lymphatic system and make sure that we stay healthy.

(00:03:25) So opening up the lymph node, if you looked inside, you would see a great deal of lymphocytes. Lymphocytes are white blood cells. So you would see B-cells, which have a unique job description of binding things, B for binding, and then you have T-cells, which have another different job, which are designed to get rid of and kill infected cells with tumor antigens or proteins, as well as viruses. When you open up the lymph nodes you see all this network of B-cells and T-cells and other things in there.

(00:04:01) Cancer, in general, is abnormal. Our body has a system of checks and balances and when we go to the Tanning Hut and we get too much UV light and we damage our skin, we don't walk away with melanoma, because our body is able to recognize the damaged errors and get rid of those broken, damaged cells. We develop cancer when those errors stick around and our body doesn't get rid of the abnormal cells, and if this happens in a lymph node, in a B-cell or a T-cell, then we start to develop error B-cells and T-cells and they start to live and live and have baby cells that live and live and live, and therefore, you start ending up with large lymph nodes.

(00:04:46) Regardless of the tumor type, B-cell or T-cell, you can get big lymph nodes throughout the body, in the neck, in the groin, and in some other areas wherever the lymph nodes are. Non-Hodgkin' lymphoma is defined as a blood cancer, typically of the lymph nodes, because that's where the B-cells and T-cells live, and non-Hodgkin lymphoma is broken down in a large bunch of subcategories.

(00:05:14) Different types of non-Hodgkin lymphoma (NHL). The pie graph here shows that the largest amount of non-Hodgkin lymphoma is what's called diffuse large B-cell lymphoma., But you can also have the gray area of the chart Follicular. Yellow is Marginal zone. The light blue is Mantle Cell. And least common, if it's not a B-cell lymphoma, which these others are made up of, it can be a T-cell lymphoma., So all these different sorts of lymphomas makeup that big umbrella term of non-Hodgkin lymphoma, and that is a whole other class of lymphoma, different than what you might hear Hodgkin lymphoma. We're not talking about Hodgkin lymphoma, and for the bulk of this talk, we're talking about non-Hodgkin lymphoma, not T-cell lymphomas, B-cell lymphomas. Non-Hodgkin Lymphoma is very common. 77,000 cases per year, and 20,000 deaths in 2020. Diffuse large B-cell lymphoma, as I stated, is the most common of the non-Hodgkin Lymphomas.

(00:06:23) Different types of NHL will receive different initial treatment. Large B-cell lymphoma is typically treated with chemotherapy. How do we treat? This is outside of our context of our talk here, but I'm not going to dive deeply into the different paradigms for different diseases, but it's important to understand where we're going with CAR T-cells, is that diffuse large B-cell is treated first line with chemotherapy. A lot of times, people are given what's called R-CHOP chemotherapy.

(00:06:45) Follicular lymphoma is treated differently. It depends on the type of lymphoma. Should it be a watch and wait? Sometimes people are given radiation or bendamustine with Rituximab or obinutuzumab, so there's lots of different options based on where the lymphoma is and what's going on with the follicular, and mantle cell lymphoma is treated both with chemotherapy, traditionally followed with autologous stem cell transplant and maybe maintenance therapy. As we go through the slides and we have an understanding of frontline therapies are very different and your doctors out there in the community and in academic centers do a really great job of initiating all these therapies appropriately, but cancer cells are smart and they want to survive, and so they have an ability to evade the immune system.

(00:07:48) Relapse after initial treatment can occur for several reasons. Relapse and mechanisms of tumor evasion. Even though you get really good upfront chemotherapies and radiations and transplants, even, sometimes the cancer cells figure a way out of the immune escape and they survive, and there's different reasons for that. First, in the first box, we see that sometimes T-cells are just unable to recognize the cancer cells as foreign so they kind of all roam around in the bloodstream and they don't see each other because the cancer cells have hidden the proteins away from the T-cells and the T-cells can't see it.

(00:08:27) Sometimes in the middle there, specific T-cells are just deficient in number, and we saw this back in the late '80s, early '90s with HIV patients. We know that HIV and AIDS patients have more cancer, and that's because their T-cell numbers are much lower.

(00:08:45) And then lastly, sometimes the T-cells are unable to function properly and they are just exhausted, and so the T-cells have exhausted signals on them and they just have no oomph in them, if you will, and therefore the tumors  live. There's really good frontline therapies and they're very effective, but there's still a group of people who have relapsed or refractory lymphoma.

(00:09:11) Relapsed lymphoma is different than refractory lymphoma. The mechanisms as I just described are the reasons for that. What does relapsed lymphoma mean? It mean that the lymphoma returns. That's the definition of relapse, so it went away, and now it's back. That's different than refractory. Refractory lymphoma is a lymphoma that really never goes away, so a patient gets chemotherapy, lymphoma is still there, gets chemotherapy, lymphoma is still there. Relapsed lymphoma patients get chemotherapy, the lymphoma goes away, and maybe four months later it returns or maybe two years later it returns. That's how we define relapsed and refractory lymphoma.

(00:09:53) Patients with relapsed and refractory lymphoma don’t do well with conventional therapy. What we're showing here in this graph based on this very quoted Scholar trial is what it's called, is that outcomes for patients that are in this relapsed/refractory non-Hodgkin lymphoma group, typically do not do well with conventional therapy. So 636 patients were in this study. They had relapsed and refractory lymphoma, diffuse large B-cell mainly, and the complete response that the tumors went away was only 7%, and the survival rate was only about a median of six months, so clearly that, and this diffuse large B-cell lymphoma group, if they were in relapsed or refractory lymphoma, they didn't fare very well with traditional therapies.

 (00:10:41) That's also been found and shown in other B-cell non-Hodgkin lymphomas such as mantle cell lymphoma and follicular lymphoma. So mantle cell lymphoma, if the cancer is progressing after ibrutinib, a BTK inhibitor, they traditionally have very poor prognoses. The overall response rate is only 25% and the survival, again, is measured in 5.8 months. Follicular lymphoma, after more than two lines of therapy, the complete response rates have dropped to less than 14% and remissions start to shrink to less than 12 months or about a year. The long and short of these last few slides is that non-Hodgkin lymphoma has very good effective upfront treatments.

(00:11:26): However, there is relapse refractory lymphoma that still exist in a subgroup of patients, and for those patients that tend to continue to relapse or just cannot get into remission, whether it be diffuse large B-cell lymphoma or mantle cell or follicular, the outcomes are very poor with traditional therapies. So we need to do something else. There needs to be another therapy and that's where we kind of start to shift our gears into immunotherapy.

(00:11:59) Immunotherapy can offer better outcomes than traditional chemotherapy alone. The immunotherapy fits with this paradigm shift that we've seen in oncology treatment over the last years. Chemotherapy was the beginning of it all, 1950s, 1960s. Very cell cycle-specific. What does that mean? It means that when cancer cells are, chemotherapy works on cells that are trying to grow, so cancer cells grow through a cycle to grow, just like your hair cells go through a cycle to grow. You cut your hair, a month later you cut your hair. Why? Because those hair cells are growing? That happens in the blood system, as well, so chemotherapy in the traditional sense is not smart therapy. It just hits things that are trying to grow through the cycle, so it's not specific, and that's where autologous stem cell transplant fit, and that's what I'll talk about in a little bit.

(00:12:53) Targeted therapies also offer promise. After that, oncologists and science moved forward to targeted therapies. They started looking at monoclonal antibodies. What do certain cancers possess that we can target, and that's where rituximab was used for CD20-positive lymphomas, or HER2 positive breast cancers got something called Herceptin, and then lastly this new revolutionary field of oncology has been immunotherapy. And allogeneic stem cell transplant replacing immune systems from different donors is the epitome of immunotherapy and that's been around kicking since, well, it started out in the '60s but really been taking off in the late '90s and early 2000s.

(00:13:42) Checkpoint inhibitors and CART-cell therapies are the new immunotherapies. Checkpoint inhibitors and CAR T-cells are now the new immunotherapies that we'll talk about here in the next few slides. This is just a slide to honor some of the pioneers that I think are important to recognize. Here on the left is Dr. Rosenberg from the NIH who treated metastatic, which is traditionally incurable disease, kidney cancer, and he gave IL-2, which is a growth factor for T-cells, and it really stimulated T-cells to grow and proliferate, and he was able to cure about 5% of what was incurable renal cell cancer.

(00:14:20): Fast forward to 2018 two guys, Allison and Honjo, win the Nobel Prize for their checkpoint inhibitor use in metastatic melanoma. So patients that had metastatic melanoma, they were taking exhausted T-cells and really recharging those T-cells that stimulated them against cancer and were curing metastatic melanoma.

(00:14:42): And on the far right you have Dr. Carl June who is one of the pioneers along with Rosenberg and others in the field of CAR T-cells who has an amazing story about T-cell immunology and how he was  driven by his wife and her disease of cervical cancer or ovarian cancer, if I remember correctly, and devoted his life into using T-cells to cure cancer, and here we are now with CAR T-cells.

(00:15:16): Now let's switch gears and talk about CAR T-cells and what they are. First, to understand CAR T-cells, we've got to really take a little bit of an immunology course and I'll consolidate all my graduate immunology into 30 seconds for you.

(00:15:35) B-cells and T-cells have different functions in the immune system. Immune system, it's made up of a lot of cells but mainly the B-cells and T-cells. And if we look at our little diagram here, B-cells, they are good at attacking invaders outside the cell, and T-cells are really good at attacking infected cells, things that are internally to the cell. So B-cells have receptors that are specific to bind things and they're really excellent at binding things. They have a lock and key, if you will. If you take your house key that fits your lock and you plug it in there, it goes well, but if you take your car key and try to insert it into your house lock, it doesn't go well, so that's kind of like the B-cell receptor.

(00:16:20) It's really, once it knows what it wants and can bind to it, it's really excellent at fitting it in, and those B-cells will present the protein it binds to T-cells, but B-cells are not great at killing things. They're just not great killers.

(00:16:35) T-cells, on the other hand, have receptors that are very finicky. They don't want to play around with other cells unless they're perfectly matched, and that's what we strive for when we're doing allogeneic stem cell transplants, is perfectly matched immune systems, and that's because of the T-cell biology. The T-cells' limitation is they're finicky on what they're going to engage with, but once they engage, not only are they good at killing but they need a lot of signals to get them excited, so they're finicky on who they're going to engage with, then they need a lot to get them started. But once they're going, they're great at killing tumor cells when they're activated. The take home point is, Bs and T-cells have  unique systems built into them. B-cells are great at binding. T-cells are very finicky on who they're going to engage with and bind to, but once they're activated, they're great killers.

(00:17:31) CAR T cells are genetically altered versions of the patient’s own cells. CAR T-cells, in general, and how we make CAR T-cells, and I'll explain this in a second on the next slide, but what we want to do is collect the patient's blood cells over one to two hours. So we hook patients up to a machine, we use their blood volume, it's cycled through a machine, and a bunch of white cells are taken out and isolated. Once those white blood cells, which have B-cells, T-cells and other cells, once all those are isolated, we ship those off to a manufacturer, a company. Those companies, then, what they're doing is they're isolating and activating specifically the T-cells, so they're isolating out the T-cells.

(00:18:18) They're getting rid of all the other cells that were collected. Once they have the isolated T-cells, they use a virus that has a genetic code in it for the CAR T-cell gene. They put that virus with the CAR gene in the patient's T-cells, they grow and expand the number of T-cells, and then they ship those products back to the site, which is usually, depending on time, two to three to four weeks. We admit the patient and I'll go through that later on, and we infuse the cells.

(00:18:51) CAR T cells blend the best features of B-cells and T-cells. What is the CAR really made of? Again, it's using the patient's own T-cells. So it's patient's own T-cells, and the genetic information that was on that virus that goes into the T-cells gives us the best of both worlds between a B-cell and a T-cell. So the SCFV region, this blue and green part of our receptor, is now very, very specific for our yellow antigen on the tumor cell, and for non-Hodgkin lymphoma, that's CD19, so, again, that's the B-cell part.

(00:19:32) That's great at binding CD19, the antigen, and once it binds, it's already linked to the T-cell receptor. So now, once we come in contact with something that we're really good at binding, the T-cell is activated.

(00:19:49) You can see here that in our previous slides back here, our B-cell is really good at binding, but not a good killer. The T-cells don't like to bind things but are great killers. And when I go forward, the CAR T-cell in general takes the best of both worlds, allowing the receptor now to bind to the antigen, whatever antigen, genetically we've manufactured it for, and once it does that it activates the T-cell, and now the T-cell can go forward and get rid of the tumor.

(00:20:24) Here's a picture of the CAR T-cell here. It has the CAR T-cell receptor, and once that comes in contact with the cancer cell, you can see it releases all of its yellow protein spicules here which goes on to kill the cancer cell. That's the biology, if you will, of the CAR T-cells.

(00:20:48) FDA approval for CAR T cell therapy usually requires patients to have had prior therapies that did not work. When are these FDA indicated? When can we use these CAR T-cells in the relapse/refractory setting? This is just a summary of some important trials that were done. In science, as doctors, we want to do safe clinical trials to show that the therapies we're giving are safe and regulated and effective. I recognize that I don't want to go through all these study details, but the long and short of it is that in the first columns, you can see all the patients, the first row, if you look at the indications, all these patients that had lymphoma, they had diffuse large B-cell lymphoma or follicular lymphoma or they had relapse lymphomas or, in the last column, they had mantle cell lymphoma, and they all got different CARs. They all got different CARs. In the first trial, ZUMA1, they got axicabtagene. In ZUMA5, they got axicabtagene for follicular and marginal zone. In the third column, they got tisagenlecleucel, which is Kymriah, for diffuse large B-cell lymphoma, and then in the fourth column they got brexucabtagene for mantle cell lymphoma.

(00:22:08) In such cases, CAR T cell therapy was much more effective in achieving remission than chemotherapy. These were all patients that had number of prior lines of therapy. A lot of therapies, mainly two to three, sometimes up to seven, so none of them had a prior allogeneic transplant. And if you look at that complete response, meaning how many of them went into remission after the CAR T-cells were infused, you can see these numbers are very high, 55, 60, 40 and 59% respectively, versus what that Scholar-1 data showed where only 7% of patients responded to chemotherapy. So this was a huge home run in non-Hodgkin lymphoma, where we had patients that were traditionally refractory and not able to get into remission or continued to relapse and were unable to get into remission, and when we could give them different chemotherapies, only 7% responded. Now, when we gave them CAR T-cells with different settings, our complete response rates were 40 to 60%. so this is a marked improvement in response rates and curability for this group of patients.

(00:23:16) This is just a slide showing that now you know all these complicated names have some brand names, Tecartus, Kymriah, Breyanzi and Yescarta are now all FDA-approved for different types of lymphoma in different settings.

(00:23:37) PET scans show CAR T cell therapy can work very quickly. CAR T-cells, this is what we're looking for. Here's a patient that had a PET scan, a patient here in the black and white, if you will. You can see the brain area at the top is all lit up and that's normal, that's normal. But on the left hand picture here, the bones and the body, you see lots of black spots throughout the entire body, and then within one month after CAR T-cell infusion, you see all that clearing out, and that's what we're looking for with the CARs. They tend to work very quickly depending on the type of cancer you have, but they tend to work very quickly with expansion and getting rid of cancer, and when we do PET scans at one month or three months, we often see great responses like this in 40 to 60% of the cases.

(00:24:24) Again, the other picture here is a PET scan. The far right picture shows a PET scan that is very active. You have on the left hand, the big, big, big liver that's going all the way down and a spleen. You see all that yellow stuff throughout the entire cavity of the belly, and then a month later the PET scan is completely not yellow except a little bit in the center of the chest which is the heart muscle which is normal. This is, again, someone who had a complete response within one month of CAR T-cells. This is what we're trying to achieve.

(00:25:04) When lymphoma recurs, patients often notice it before imaging tests. There are several questions patients should ask their doctor about detection, referrals, clinical trials, and type and timing of treatment. CAR T-cells, so, questions to ask your physician. A lot of the patients that I see are referred to me, but 80%, 90% of the patients come from the community, so questions to consider as a patient if you're in the community or if you're with your loved one as a caregiver.

(00:25:29) When lymphoma comes back, or when there's a question that lymphoma comes back, in about 80% of lymphoma recurrences, patients pick up on it, okay? Either clinically or in the blood work, there' some signal. It's not necessarily done by a CT scan or a PET scan, but one of the questions we should ask is should we get a biopsy to prove that it has come back? That's always a good question to ask, and it's always encouraged to have biopsy-proven relapse, especially sometimes when patients have PET scans that are somewhat questionable.

(00:26:04) PET scans are really good at showing things, but sometimes everything lights up on a PET scan. It's like, some areas are a little bright on a PET scan. That doesn't mean cancer is back. It could mean that there's just some inflammation going on there, and so biopsies are always good to prove that the cancer has come back.

(00:26:25) Other questions you can ask is, is it time that I be referred to a transplant or a CAR T-cell center. I think it's always good to get different opinions. There's a lot of novel agents out there and new agents that oncologists in the communities and others can give to patients that have lymphoma or follicular lymphoma or mantle cell lymphoma, but the question is, is that the right time for it? Should you have transplant first or CAR T-cells, and really it's best to get an expert opinion on that, so I think it's always good to kind of ask if you should be referred for transplant or CARs.

(00:27:03) Do we need to start treatment now or can we wait until we meet with the transplant center? Sometimes, the patients are very quick. They're concerned that they're relapsing and they want to start their therapy right away and oncologists want to start therapy right away because they want to make sure that they're not missing something, and all that is appropriate. But certain cancers, a lot of cancers, are slower growers than we think, and so sometimes the discussion that needs to be had is, can we wait or does it need to start right now.

(00:27:37): Why wait? Well, sometimes we miss our opportunity to put people on good clinical trials to answer these questions of what therapy is best. For yourselves, patients can go online and search for authorized treatment centers for CAR Ts, and here's the link here, so you can kind of be very proactive. That's the benefit of the internet today.

(00:28:02) How does a stem cell transplant differ from CAR T-cell therapy?  A big topic I wanted to talk about here is the difference between stem cell transplant and CAR T-cells. I get questions asked a lot about this, about how do I make a decision and what's the difference, and so I wouldn't mind spending a few minutes on this slide. Here at VCU, myself and my team here, we specialize in both transplant and CAR T-cells, and so, I'll first say, the disease and science should dictate really what the right therapy is.

(00:28:36) Transplants are most effective when patients are in remission. It's not Dr. Simmons' opinion or what he's feeling today, should it be an auto transplant or a CAR T-cell or an allo transplant? It's really driven by science, and the disease dictates really what we should be offering. But in general, autologous stem cell transplant, the principle is based on using high dose chemotherapy, so it is most effective when people are in remission. So if people have a lymphoma, the lymphoma comes back, and now they put them back on therapy and they go into remission and traditionally, autologous stem cell transplants would be used when they're in remission at that time. That paradigm is shifting a little bit with new information coming out about when to do CAR T-cells there, but in general, most people that have a lymphoma, they go in remission, then it comes back, their doctors put them on more chemo, it goes in remission, and we know it'll continue to come back unless we use high dose chemotherapy, so we use high dose chemotherapy and autologous stem cell transplants. It's best achieved results are if the patient is in remission.

(00:29:50) Toxicity in autologous transplants is mainly due to pretransplant chemotherapy. The toxicity is driven mainly from the chemotherapy. The chemotherapy is toxic, and as I mentioned in slides earlier, chemotherapy traditionally is not smart therapy. It doesn't know the difference between a cancer cell and a non-cancer cell. All it knows is that the cells are trying to grow, so toxicities from autologous transplants is really driven by the chemo. So patients have hair loss, they have nausea, some diarrhea. They have poor appetite. All that is because the hair cells, the GI cells and the blood cells are all beaten up from chemo.

(00:30:32) Autologous and allogeneic transplants differ in several ways. In autologous stem cell transplant, we collect their stem cells over one week. The collection and infusion of stem cells has nothing to do with the cancer. It is a regeneration of blood forming. If we do high dose chemotherapy and we don't have stem cells to rescue you with, then you won't be able to grow white cells, red cells or platelets. So the collection of stem cells and the reinfusion of stem cells is really driven to restore blood-forming elements. Patients are generally in the hospital for about three weeks. Outpatient, it's a pretty short recovery, maybe a couple weeks, two to four weeks, and the risk of death from the procedure is very low, less than 1%, okay?

(00:31:19) Toxicity from an allogeneic transplant is more due to graft-vs.-host disease. The difference been an autologous stem cell transplant and an allogeneic stem cell transplant is many, but the first is the principle. In allogeneic stem cell transplant, we're trying to do an oil change on the immune system. We're taking out the old and putting in the new, so it's not so much driven by high dose therapy chemo, but it's replacing immune systems, hoping that these new B-cells and T-cells will work together to get rid of any residual cancer. It's best achieved, again, if you're in remission. The toxicity from an allo transplant is largely graft versus host disease when the donor cells attack the host, and/or infection. The donor gives the cells, so the patient doesn't have to have a collection.

(00:32:07) Patients are generally in the hospital for four to six weeks. The outpatient recovery is months, and risk of death from procedure is about 10 to 15% in the first year, much higher risk.

(00:32:21) CAR T cell therapy combines the benefits of allogeneic and autologous transplants and patients don’t have to be in remission to receive the procedure. CAR T-cells, on the last column here, these are, I always like to look at them almost as a cross between the auto and the allo. They have a lot of commonality between both, so the principle is to use the T-cell biology, just like in allo. It's using engineered T-cells but they're the patient's T-cells, so they don't come with the risk of graft versus host disease. But we're using engineered T-cells to kill cancer cells. The patients do not have to be in remission, and in fact, the data is they shouldn't be in remission thus far. To be FDA-approved, you cannot be in a complete remission, so these are good options for patients who still have active disease. In fact, I would argue they're the best option and only option for those with active disease.

(00:33:13) We collect the T-cells not over a week but in hours. Patients are generally in the hospital about two weeks in my experience. The toxicity is not necessarily from chemo at all. It's from the expansion of the T-cells. As the T-cells grow and come in contact with cancer and grow and expand, they release lots of proteins that I'll talk about in a few slides, and those toxicities are what we see from CAR T-cells.

(00:33:38) It's a short recovery. Between inpatient and outpatient, in my experience, patients are typically back home within 28 to 30 days, and risk of death from the procedure is low, 1 to 2%. I've had one death in over 70 CARs in the last two years.

(00:33:55) The disease should determine the choice of an appropriate treatment. Again, I kind of emphasize this. It is important. The disease determines the treatment, so mainly, in the US, autologous stem cell transplants are for the diseases myeloma, most common, relapsed amyloidosis, which is a plasma cell problem like myeloma. Relapsed non-Hodgkin Lymphoma and relapsed Hodgkin lymphoma are still times where we do autologous stem cell transplants, but relapsed non-Hodgkin lymphoma, we're doing less of them due to the CAR.

(00:34:28) For leukemias and myelodysplasia and MDS, allogeneic transplants are the preferred modality. Aplastic anemia when you're trying to regrow blood, allogeneic transplant is preferred, and CAR T-cells, the FDA-approved CAR T-cells currently are for non-Hodgkin lymphoma and not talked about tonight but myeloma, relapse/refractory myeloma, I should say.

(00:34:58) VCU, so what do we do here? We've developed our own, based on science and guidelines and data, we've  developed our own VCU algorithm. So for patients that have, and this is just an overview, this is not specific to anyone individual, because every case is different, but generally speaking, relapsed diffuse large B-cell lymphoma, we look at to see if they've relapsed within a year or not.

(00:35:27) Patients with refractory disease or who relapse within 12 months may move quickly to CAR T therapy. If they've relapsed within 12 months or they're never in remission, we really try to move quickly to CAR T-cells. That's because of new data that has come out of the American Society of Hematology supporting both the transform and ZUMA data showing that cars are better, and if they're refractory then we really need to move to therapy with CAR. Now, sometimes patients are started on chemotherapy very quickly in the oncology office out in the community, and they've gotten two or three cycles, and by the time they come to us, they're in a complete remission. As I mentioned earlier, if they're in a complete remission, then CARs are not preferred, so we move usually to auto transplant, ASCT as in autologous stem cell transplant.

(00:36:10) If patients relapse after CAR T-cells up there, we try to get them back in remission and move to allogeneic transplant.

(00:36:18) If relapse occurs after one year, patients may receive second line therapy and then transplant. If you start from the beginning with relapsed diffuse large B-cell lymphoma and go down and the patient relapses later than a year after being in remission, often we move to second line therapy and try transplant. If they relapse after that, we move to CAR. That's just a little algorithm to show you how we kind of think about it here at VCU. The general process for CAR T-cells is generally you're referred from your doctor to the patient or CAR T-cell center.

(00:36:48) The team reviews your options, myself and then we review the options for you and the patients, and depending on the disease and current literature and clinical trials available, we kind of make the determination. Then, we do organ testing. We work very closely with your doctors in the community, and we communicate effectively with them. We do organ testing to determine candidacy.

(00:37:14) Treatment choices are no longer age dependent; fitness is more important. This is an important point that I'll make, is that it's not age dependent. I still get a lot of bias about age. We don't delineate candidacy based on age. I've done CARs at 79 years old and I've done transplants in 74, 73 year olds, so it's not an age thing. It's based on performance status and organ function, so we have to prove that your organs are safe enough to undergo the testing. Once we do that, we typically sign your consent forms and collect the cells, typically one day for CAR and one week for stem cells.

(00:37:56) Switching gears, there's a lot of good there. Obviously, the slides preceding this demonstrate that CARs or super novel, super effective in a relapse/refractory setting and even moving up there in non-Hodgkin lymphoma, easy to kind of go through a little bit with the processes, so now lets' switch gears and talk a little bit about the toxicities of CARs.

(00:38:20) The toxicity of CAR T cell therapy comes from the rapid expansion of T-cells and cytokine release syndrome. The toxicity of CARs, as I described a little bit earlier, is really driven by the T-cells expanding. When those T-cells go in, your T-cells or the patient's T-cells go in with the receptor, they come in contact with the cancer cells very quickly and they engage, and these, they release a lot of cytokines, such as IL-6 and others, and as demonstrated here on the graph, over time, day 0 to day to day 14, you see the CAR T-cells really expanding, and then you start to see toxicity such as cytokine release syndrome.

(00:38:55) Cytokine release syndrome is basically what we see at the bedside which manifests itself with patients having fevers, high heart rates, low blood pressure. Their kidneys or liver can be injured. Sometimes there's clotting. Sometimes patients have heart problems. Sometimes patients have trouble breathing, and all of this is really driven by the blood vessels getting really leaky with fluids and shifting and things because of all the cytokines and proteins that are being released by the T-cells that are expanding and killing tumors.

(00:39:31) Cytokine release syndrome can be graded and treated based on its severity. We know how to grade this and treat this. We have four grades of it. It's driven by high temperature, how low the blood pressure goes, and how much oxygen the patient needs. I'm not going to go through all the treatment issues that we go through here, but we know how to treat it, we treat it very effectively. We give lots of fluids and antibiotics. We give a drug called tocilizumab which is a great drug at shutting down the inflammation and cytokines that are driving this process.

(00:40:03) Neurotoxicity often follows the onset of cytokine release syndrome. Over the last couple years, we've really learned a lot about how to safely take care of the CAR T-cell patients using these different algorithms. Outside of the body kind of getting sick, the brain can get a little toxic, as well. That's called neurotoxicity, and here's an example of a patient with impaired handwriting. We do a handwriting sample every four hours or six hours after the CAR infusion, because, as we start to see handwriting samples deteriorate, we recognize that neurotoxicity is starting to develop. Neurotoxicity generally develops a few days after cytokine release syndrome. Traditionally, cytokine release syndrome occurs two to three days after the cells are infused, and then neurotoxicity two to three days thereafter.

(00:40:51) Within that first week after the infusion of cells, you can see a lot of what's going to happen. Neurotoxicity manifests itself by patients having confusion, tremors, sometimes seizures, trouble speaking, headaches, and hallucinations. We manage it here at VCU. We put patients in the ICU when they're neurotoxic, just for better monitoring. We check for seizures. We check for infections. We give anti-seizure meds, and we give steroids, which is the standard therapy here, and tocilizumab is the standard therapy for the cytokine release syndrome and steroids are the standard therapy for neurotoxicity. How common is toxicity?

(00:41:38) CAR T cell toxicity is quite common but can often be effectively treated. It's pretty common. I tell patients to expect cytokine release syndrome. 80 to 90% of the patients have cytokine release syndrome. The bar graphs here are difficult to go through all at once, and the concept of time, I'll say that blue is Yescarta, orange is Kymriah, and gray is Tecartus, and you can see they all have a fair degree of toxicity. Grade 1 and 2 cytokine release syndromes are typically treated very easily at the bedside, fevers and low blood pressures, et cetera, but grades three and four are much more sicker patients population, and we see that about 15% of the time in general.

(00:42:22)  ICANS is that neurotoxicity, and overall that happens at about 35% of the time, grade 1 and 2, which is fairly easy to treat, and then sometimes grade 3 and 4, which happens sometimes up to about 20 to 30% of the time, still does occur, which is where we have to put them in the ICU and give steroids. What happens when the patients leave the hospital? Well, they're traditionally in the hospital for about two weeks. When they leave the hospital, we have to monitor them very closely for any delayed toxicities and make sure they're doing well before we send them home.

(00:42:58): At VCU, we require to stay within 30 minutes for 30 days after cell infusion. We monitor their blood counts because they might need transfusions. We monitor their IGG levels which is a marker of B-cells, if you will, to help prevent recurrent infections. We keep them on infection prophylaxis antibiotics as long as their white cells are low enough, and we watch for delayed neurotoxicity. As the FDA requires they not drive or operate heavy machinery for eight weeks after CAR T-cells due to neurotoxicity.

(00:43:35) CAR T cell therapy can only identify proteins on the outside of cancer cells; if they are internal it will not work. Limitations to the CAR, so, the limitation to CAR T-cells is, number one, proteins need to be expressed on the outside of the cell. The reason why CAR T-cells are very effective for non-Hodgkin lymphoma, is that B-cells, which are non-Hodgkin lymphomas, have a lot of CD19 on them., So if we generate a CAR and manufacture a CAR against CD19, it's very effective at killing lots of forms of non-Hodgkin lymphoma that might have different B-cells at different phases. Proteins need to be expressed on the outside of the cell. The CAR T-cell receptor cannot see what's on the inside of the cell, so that is a limitation of CAR T-cells. 75% of cancer proteins in all cancers are internally, in the inside of the cell, so the limitation to CAR is it can really only see what's on the outside of the cell.

(00:44:27) Another limitation is that CAR T cannot be used to attack T cells which patients need to live. The other thing that we have to be mindful of as a limitation is that you must be able to live without that cell, so CD19 CAR T-cells attack all CD19, whether it's a good CD19 or a bad CD19. And CD19 good is your B-cells, but we know that patients can live without B-cells. They cannot live without stem cells or T-cells, so we couldn't safely to have a CAR against T-cells or stem cells, although that's being challenged in science right now. But generally speaking, a good take home point is we must be able to live without the cell that is being attacked. Those are two limitations to CAR.

(00:45:09) The future is moving toward  immunotherapy and wider use of CAR T cell therapy. Where is the future going? The future is heavy in immunotherapy. Here at VCU we have approved CAR T-cells in the relapsed setting for myeloma, mantle cell, large cell lymphoma, follicular, in children, adolescents, in adult ALL, and we're using lots of clinical trials for T-cell receptors for even solid tumors like metastatic sarcoma. We have gene therapy moving in for sickle cell disease and thalassemias, and we have TILs, which are tumor-infiltrating lymphocyte therapies for lung cancer and solid tumors.

(00:45:46) In summary, the paradigm shift of immunotherapy has really reached myeloma and myeloma with CAR T-cells. CAR T-cell therapy is novel and has shown to have a great response in patients that have highly treated hematological B-cell malignancies with curative intent. Immune therapy is a powerful therapy with toxicities requiring complex monitoring and care of patients and ongoing trials will challenge stem cell transplant versus CAR T-cells in the future.

(00:46:15) Lastly, or two of the last slides, one, I want to acknowledge my working group, the cellular immunotherapy working group at VCU. I'm the lead of that, and Dr. McCarty and Toor, Clark, Chunk, and the rest of the group here that has really been instrumental in the growth and success of our cell immunotherapy and CAR T-cell program.

(00:46:34) In closing, I just want to say that without y'all, this would not be possible, so we're very grateful at VCU and the CIT program, to all the patients and families for their trust in us and their support, and at this time I'm happy to answer any questions that any of you have.

Question and Answer Session

(00:46:51) [Susan Stewart]  Thank you, Dr. Simmons. That was a very interesting and thorough presentation. And so we will try to get to as many as we can. First question is, what causes CAR T-cells not to work or stop being effective?

(00:47:11) [Dr. Gary Simmons] What causes CAR ... Good question. CAR T-cells are really, again,  it goes back to that limitation, so sometimes cancer cells are really smart and they recognize that the CD19 CAR T-cell is coming, and so what it does is that it takes its CD19 on itself and hides it and puts up something different, like CD22., And so what the cancer cells are, it's a game, they're trying to live and win, and they're trying to evade whatever therapy or immune system stuff we throw at them. A lot of what happens is relapses is that the cancer cells figure ways around survival, and one of the mechanisms is taking off their CD19 target and putting on CD22.

(00:48:10) [Susan Stewart]  All right. The next question is, once the therapy is complete, what happens to the CAR T-cells that were introduced into the patient? Do they continue to look for and find any recurring cancer cells? Do these genetically altered cells continue to coexist with the patient’s natural cells, or do they have a shelf life?

(00:48:29) [Dr. Gary Simmons]  Yeah. That's a good question. There's been a lot of studies out there about CAR T-cells and things like that, and looking at that persistence of the CAR, and there's some variation things, but generally speaking, the CARs, a lot of them die off. The T-cells expand and in different trials, you know, you can find persistence of the CAR, meaning it's still ongoing, sometimes a few months later, but there's a lot of studies that show that maybe a year or two years later, the CAR T-cells, you can't find the CAR T-cells., And that doesn't mean that the patient's going to relapse. It just means that T-cells are always in competition in the body, as well, so your own native T-cells are competing with the CAR T-cells, and only the strong survive over time., But generally speaking, the CAR, once it goes in, it expands very quickly as I showed in that one slide with cytokines, it expands quickly and then it kind of peters off and dies off.

(00:49:35) [Susan Stewart]  All right. The next question is from somebody who had an allogeneic transplant, that is a transplant with donor cells. They developed mild graft-versus-host disease, and they want to know what the implications of that are for having a CAR T-cell therapy, if it's recommended for them in the future.

(00:49:52)[ Dr. Gary Simmons]  Yeah. Another great question. CAR T-cells have been given to patients after allogeneic stem cell transplants, so we know that its' safe to do. It's been done. I still think you'll see more and more data come out about it being safe to use. It will bring up the question of how much graft versus host disease is going on, so that's a complicated question. I can definitely say that having an allo transplant does not exclude you from getting a CAR, but having graft versus host disease, mild graft versus host disease with some steroid cream is very different than more GVHD with tacrolimus and prednisone. Those patients, I think it'd be a little bit more risky to do CAR T-cells on.

(00:50:44) [Susan Stewart]   The next question is someone wants to know what the difference is between transplant and CAR T-cell therapy in terms of the fatigue the patient feels after the treatment.

(00:50:59) [Dr. Gary Simmons] Yeah. I think the hardest, well, that's a hard question to answer. I guess, as I've never had it, but I can tell you from my experience is that for non-Hodgkin lymphoma, the large component of this talk, when you do an auto transplant, you give what's called BEAM, B-E-A-M chemotherapy, and that's much more intense than what we give for CAR T-cells which is fludarabine and cyclophosphamide. So I think that in CAR T-cells, as I showed in that one slide, the toxicity is mainly from the T-cells expanding, and I find patients have very little side effects from the chemotherapy they get.

(00:51:45) [Dr. Gary Simmons] In autologous stem cell transplants, the toxicity is driven largely by the chemotherapy, and it is pretty yucky to go through the BEAM chemotherapy, I think.

(00:51:56) [Susan Stewart]   believe you addressed it in your presentation, but just to repeat, is there an age limit for anybody going through CAR T-cell therapy?

(00:52:06) [Dr. Gary Simmons]  No. Not with us. I mean, I had a patient that was 84 years old that I was going to do CAR T-cells on, but didn't work out, but he got close to coming in, so I don't think it's so much of an age thing. I think there's very healthy 70 something years old people out there that run marathons and I think they have curable disease with CAR T-cells, and I would go more on organ function than I would age, and I think that's been the consistency throughout the nation with my colleagues,

(00:52:38) [Susan Stewart]  Next question, wants some clarification. Can you have CAR T after an allogeneic transplant?

(00:52:46) [Dr. Gary Simmons]  Yes. The answer to that question is yes.

(00:52:49) [Susan Stewart]   Next person wanted to know, why do CAR T-cells utilize CD19 versus other targets like CD20 that are used by Rituxin and monoclonal antibodies.

(00:53:07) [Dr. Gary Simmons]  Good question. I don't know if that answer is that well studied, but I can tell you it's probably due to density of antigen. The CD19 is an antigen, and we know that B-cells carry about 10,000 plus CD19 molecules on them. And so the more antigen that the T-cells engage with, the more engagement and cytokine release and expansion of T-cells. So CD19's a great target, number one, because it's ubiquitously expressed on all phases of B-cells from the bone marrow out, all the way out, so if you have an ALL, CD19 is on it. If you have mantle cell, CD19 is on it. If you have follicular, CD19 is on it. And not only is it present, but it's also present at super high densities, 10,000, versus things like CD20 and CD22 which have 2,000 units or density on the B-cells., So I think there's a couple different answers there, but I think it's due to where it is in the phase of development is the CD19 is through all phases of B-cell development where lymphomas arise, and also there's a lot of tumor there for T-cells to engage with.

(00:54:27) [Susan Stewart] The next person had an allogeneic transplant for follicular non-Hodgkin lymphoma, and the way she read your slide suggested that that really is not what is indicated. Did she read that correctly or incorrectly?

(00:54:42) [Dr. Gary Simmons]No. Follicular is ... I mean, no. No. We've done allogeneic transplants for follicular lymphoma, for sure. Follicular has always been, it's a tougher disease to put in its own box. I think, I say it all the time. There's CLL and follicular are hard. When I see those consults, those are really hard because there's a lot of different options, chemotherapies versus autologous stem cell transplant versus allogeneic stem cell transplant, or now CAR T-cells. So I think we at VCU have done a lot of follicular allogeneic transplants and cured a lot of people in the past with allogenic transplants. I think, going forward, CARS will be moved up over allo due to the less risk. It's less involved. It has similar, less involved, and then less risk of GVHD.

(00:55:42) [Susan Stewart]  The next person wants you to comment on the effects of this, the CAR T-cell therapy, on mantle cell lymphoma that has invaded the central nervous system.

(00:55:53) [Dr. Gary Simmons]  I don't know if I can speak so definitely about that. There's not a lot of information out there. I believe, what led to the FDA approval of Tecartus which is what we use for mantle cell, the ZUMA2 trial is where it came from and I don't believe there was CNS disease in there but I may be wrong on that. I'd have to review the trial. Anyway, most of the time, CNS disease has been excluded, but I don't want to misspeak. Generally, though, we've done, with mantle cell, in the ZUMA2 trial, the complete response rates are near 60% and super effective. In my experience, and even reported, CNS lymphomas, people that have lymphoma in the body as well as in the brain, the complete response rates are usually pretty high.

(00:57:01) [Susan Stewart]m What's more difficult for a patient to undergo? CAR T-cell therapy or an auto stem cell transplant?

(00:57:08) [Dr. Gary Simmons] That's a hard question. There's too many variables there. Well, I guess what I would say, to answer that question, there's too many variables. So, not age but organ function is important there. How much chemotherapy have they undergone? How much tumor is around? You know, people that have higher tumor volumes seem to have higher toxicities from CAR T-cells, so it's just a different beast altogether in terms of what's going to be harder. Everybody's different. Some people are genetically predisposed to having more toxicity to chemotherapy and they have more GI toxicity and more arrhythmias with chemotherapy versus someone who may not, but again, it's more driven by the disease. The disease dictates what you should have in science, and then its candidacy based on organ function. Sorry. I don't know if I answered that well.

(00:58:21) [Susan Stewart]  The next person says that they have undergone autologous transplant but their non-Hodgkin T-cell lymphoma came back. They want to know what risks they should be aware of if they go for CAR T-cell therapy.

(00:58:37) [Dr. Gary Simmons] Well, right now CAR T-cell therapies are not approved for non-Hodgkin T-cell lymphomas, if I understand that question correctly. So T-cell lymphomas, if they're getting a CAR, it would be done under a clinical trial, and so I think a lot of the same toxicities that we talked about in the CAR lecture here with cytokine release syndrome and neurotoxicity are to be stated for, but again, ultimately, when you're undergoing a clinical trial it's investigative to  figure out what the toxicities are and how common they are.

(00:59:15) [Susan Stewart] There's some confusion here. A patient wants to know whether a CAR T-cell patient will be without B-cells forever?

(00:59:24) [Dr. Gary Simmons] Yeah. Good question. No, not usually, or no. I mean, the answer is no. The B-cells tend to regrow back. B-cells are formed in the bone marrow, and then studies are starting to show six, nine months after the CAR T-cells, we start to see B-cell recovery, and IGG levels coming up.

(00:59:46) [Susan Stewart]  Next question, the person wants to know whether insurance including Medicare covers CAR T-cell therapy.

(00:59:54) [Dr. Gary Simmons]  Yes. I mean, yeah. These are FDA products and they have science behind them, and again, I've done over 70 here at VCU, and I'm very proud to say that at VCU, I've never had an issue getting anybody a CAR T-cell whether they have commercial insurance, Medicaid, Medicare or the like, so, yes. They are approved. They're just like autos and allos, and haven't had any trouble getting the correct therapy to the patients.

(01:00:26) [Susan Stewart] All right, and this is going to have to be our last question. Patients want to know how long people stay in remission after they've had CAR T-cell therapy. Is this a cure or is this temporary remission?

(01:00:39) [Dr. Gary Simmons] No. We believe this is a cure. Data from the American Society of Hematology, the ZUMA1 trial, which is the Yescarta CAR, four year cure rate or four year overall survival and disease-free survival is 44%, so let's say 45%,. So that's that group of people that usually lived about six months, so now we're showing four years later, 45% are still good and in remission,. And most of these blood cancers, lymphomas, leukemias, they tend to relapse very quickly, within two years, so you're starting to see people four years out, five years out in remission, they're cured in my mind,.

(01:01:18) [Susan Stewart ] That's good to hear.

(01:01:19) [Dr. Gary Simmons]   Yep.

(01:01:20) [Susan Stewart]  Closing. Well, that's great, and at this point we will need to close the webinar. I want to thank Dr. Simmons for helping us all better understand the role of CAR T-cell therapy and stem cell transplantation in treatment of patients with non-Hodgkin lymphoma, And I'd also like to thank you, the audience, for your excellent questions. That was really very helpful.