The Present and Future of CAR T-cell Therapy

Transcription:

00:03 (Marla): Welcome to the workshop, The Present and Future of CAR T-Cell Therapy. My name is Marla, and I will be your moderator for this workshop.  

Before we begin, I'd like to thank Bristol-Myers Squibb and Kite for their support in making this workshop possible.

00:20: It's my pleasure to introduce today's speaker, Dr. Connor Johnson. Dr. Johnson is an Assistant Professor of Medicine at Harvard Medical School and an attending oncologist at Mass General Brigham Cancer Institute. He specializes in cellular therapies, including CAR T-cell therapy, and treating patients with lymphoma.

Dr. Johnson's research focuses on addressing the supportive care needs and mitigating treatment-related toxicity in patients with lymphoma, patients receiving cellular therapy, and lymphoma survivors. Please join me in welcoming Dr. Johnson.

00:58 (Dr. Johnson): Thank you so much, Marla, and what a privilege it is to be here with all of you today talking about a really important topic, which is how CAR T-cell therapy has changed the landscape of options for patients now, and what the future holds for this important treatment modality.

01:16 We're going to begin with an overview of how CAR T-cell therapy works, discuss the side effects of CAR T-cell therapy, the different outcomes we can see with the treatment, and then we're going to focus on the future - what diseases are emerging for treatment with CAR T-cells, and how we can improve outcomes and the quality of life of those receiving this treatment.  

So, to begin with, CAR T-cell therapy stands for chimeric antigen receptor T-cell therapy. And what it is is a type of immune therapy that uses the body's own immune system to treat cancer.  

The first CAR T-cell therapy was approved in 2017. And in a short time, we now have seven fully FDA-approved products available for the treatment of various blood cancers. We have more than 100 clinical trials ongoing for various cancers, and I'm going to share with you some non-cancer conditions where CAR T-cells are being investigated. 

So, what is a CAR T-cell? A CAR T-cell is a normal T-cell, a type of white blood cell that fights invaders like microorganisms, bacteria, and viruses that affect the body, and also helps clear abnormal cells. We take a normal T-cell and genetically engineer an antigen-binding domain, which is a latch that can recognize and bind to cancer cells.

Essentially, we're teaching a normal T-cell how to better recognize a cancer cell, which is an altered version of the patient's own cells.  

Cancer cells are very good at hiding from the normal healthy immune system. And this is a technique for genetically engineering the immune system to recognize and, hopefully, kill these cancer cells.

03:18: Steps involved in CAR T-cell therapy. CAR T-cells are very different from standard drugs. It’s altering the patient's own immune system to treat cancer, so it has some unique logistics.  

The first step in CAR T-cell therapy is called leukapheresis. We have to collect a portion of the patient's own T-cells to create CAR T-cells.

The next step usually occurs in a laboratory. The patient's T-cells are altered by introducing this latch into the T-cell.

Then those T-cells have to be expanded, meaning they have to grow into a specific number of active CAR T-cells, and they're tested to ensure they meet the appropriate criteria, are alive, and have the features we expect to see in these active T-cells.

Then the T-cells are sent back to me or whatever treating clinician is going to take care of the patient, and we administer typically two or three days of chemotherapy. We do this because if you don't give at least some chemotherapy to lower the patient's intrinsic blood counts, the CAR T-cells could be rejected, because remember, they are altered from the patient’s typical T-cell.

And then a one-time infusion of CAR T-cells is typically administered, and we monitor for side effects and let the CAR T-cells take root, with the goal of eradicating the cancer and putting the patient into remission.

04:54: So, what diseases do we currently use CAR T-cell therapy for?

They include aggressive B-cell lymphomas and indolent B-cell lymphomas, like large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and mantle cell lymphoma, as well as two types of leukemia, chronic lymphocytic leukemia and acute lymphoblastic leukemia. Finally, CAR T-cells are also available to treat patients with multiple myeloma. The common theme is that these are all blood cancers.

So that's where the FDA-approved CAR T-cell products are currently used as of May 2026.

05:30: When do we usually use CAR T-cell therapy for these different blood cancers?

For aggressive lymphomas, we actually use them after just one or sometimes two prior cancer treatments. That's the space where CAR T-cells are routinely used today.

For low-grade lymphomas (indolent lymphomas), the leukemias I mentioned, and multiple myeloma, CAR T-cells are typically administered after the patient has already received multiple prior therapies, but there are some exceptions in which they can be used as early as the second line of therapy.

06:03: I want to give you a deeper dive into the typical patient journey for receiving CAR T-cells.

As I mentioned, the first step is to collect the patient's T-cells because we're essentially creating a personalized immune therapy. The collection of T-cells typically takes about 3 to 5 hours and looks like donating blood. There's a special pheresis line placed, and then a machine filters out the T-cells while returning the rest of the blood to the patient.

It takes about three to four weeks to make the CAR T-cells, so some patients require treatment, such as chemotherapy or other therapies, to control the cancer while we wait for the CAR T-cells to be returned.

Once the CAR T-cells are administered, most patients receive three days of lymphodepleting chemotherapy to lower the intrinsic blood counts and allow the CAR T-cells to grow.

06:59: CAR T-cells can be administered either in the hospital, where patients are hospitalized for 1-2 weeks, or in the outpatient setting.

That decision is typically made by the treating oncologist in consultation with the treating center and the patient.

Then we monitor for CAR T-cell toxicities, particularly in the first 30 days after infusion. Usually, we assess the cancer's response to the CAR T-cells 30 days after the infusion.

Then we transition to long-term monitoring, ensuring patients return home and are appropriately monitored for potential long-term side effects.

07:38: What are the key toxicities of CAR T-cell therapy?

A very important side effect is called cytokine release syndrome (CRS). Cytokines are chemicals of inflammation. Remember, this is an immune therapy. These CAR T-cells, these altered versions of the normal immune system, are supposed to bind to cancer cells and then work to eradicate the cancer. As part of this, chemicals that promote inflammation, called cytokines, are released.

08:06: The common symptoms of cytokine release syndrome are fever, chills, muscle aches, fatigue, and loss of appetite. Some patients experience a lowering of their oxygen or blood pressure and may have other symptoms. In rare cases, cytokine release syndrome can cause injury to various organs.

Cytokine release syndrome feels a lot like having the flu or another systemic inflammatory syndrome. That's why all patients of this get a fever, and these other symptoms can co-occur.

08:36: Another critical side effect to be aware of with CAR T-cells is what we call neurological toxicity.

Neurologic refers to the brain and central nervous system. We think this occurs because inflammation develops from CAR T-cells trying to eradicate the cancer. This inflammation can affect the blood vessels in the brain, leading to confusion, trouble with speech or language, or writing, and sometimes tremors.

In rare circumstances, more severe symptoms such as somnolence (feeling very sleepy), seizures, or brain swelling may occur. This is a very important and unique side effect of these immune treatments.

09:20: Another critical CAR T-cell toxicity to be aware of for any patient  are a lowering of blood counts. This occurs because of the CAR T-cells and the chemotherapy patients receive.

A lowering of immunoglobulins. Immunoglobulins are proteins that help fight infections. So this contributes to the risk of infections after CAR T-cell treatment

Very rarely, patients can have something called an immune effector cell-associated hemophagocytic syndrome, or IEC-HS. This is a distinct inflammatory syndrome that can cause liver inflammation and reduce cells that protect against bleeding.

And very rarely, patients can have cancer after CAR T-cell therapy, which we'll talk a little bit more about specifically.

Specifically, and most commonly seen with CAR T cells used to treat multiple myeloma, a rare side effect called a movement and neurocognitive treatment-emergent adverse event (MNT) can occur, and these can include other neurologic side effects as well.  

So, let's dive a little deeper into a couple of these.  

10:27: The Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) that I mentioned earlier refers to the heightened inflammation that occurs after the cytokine release syndrome has resolved.  

We're still learning about this, but what happens is that T-cells and other immune cells called macrophages, become overactivated, which can decrease the blood’s ability to clot. So, it can increase the risk of bleeding and lead to persistent inflammation in the liver and the overall body, and is measured by a laboratory test called ferritin.  

We understand that certain CAR T-cells increase the risk of this, and having more cancer when you receive the infusion increases the risk. It's really quite rare, occurring in 1 to 3% of patients, and there is a treatment for it: typically an anti-inflammatory medication called anakinra (Kineret) as well as steroids, which are general anti-inflammatories.

So, think of this as too much inflammation that has to be countered by anti-inflammatory treatments.

11:29: With CAR T-cells used for multiple myeloma, there can be later-onset rare neurologic side effects.

One side effect that can occur is paralysis of different nerves called cranial nerves. This can lead to things like facial nerve paralysis that can cause drooping on one side of the face, or it can lead to a syndrome that looks a lot like Parkinson's disease with tremors, trouble with movement, and some memory challenges.  

We think this occurs most commonly with the CAR T-cell product called cilta-cel (Carvykti), and we're learning more about this. It typically occurs on average 50 or 60 days after the infusion of CAR T-cells.  

The biggest risk factor for this side effect is a lot of tumor, meaning a lot of cancer at the time of infusion, along with high-grade side effects. In one study, this occurred in about 5% of patients treated with cilta-cel (Carvykti), a CAR T-cell therapy for multiple myeloma.  

We're developing treatments for this, but most commonly, patients receive steroids or a chemotherapy called cyclophosphamide. Doctors and other clinicians are developing strategies to try to reduce the risk of this side effect. Usually, that involves giving treatment to lower the amount of cancer before you get the CAR T-cells and then making sure that we're doing a great job managing cytokine release syndrome and neurologic toxicity.

13:00: Now, lots of treatments for cancers can lead to other cancers. This is a known side effect after chemotherapy, for example. CAR T-cells can also be a treatment where patients can develop a new cancer after the treatment.

One study saw this occur in about 3% of patients who received CAR T-cells. The most common cancer that occurred after CAR T-cells was myelodysplastic syndrome. This is an alteration in the normal development of blood counts that sometimes progresses to an acute leukemia.

The second most common cancer after CAR T-cell therapy are various solid tumor cancers. Overall, this is very rare - 3% of patients in one study - but it is an important thing to be aware of.

13:46: I think it is important to acknowledge that CAR T-cells can be associated with prognostic uncertainty.  It is important to ensure that patients are supported through the process, because, as this quote highlights, it can be challenging not knowing what will happen with CAR T-cell therapy or whether these side effects will develop.  

Remember, not all patients develop cytokine release syndrome or neurologic toxicity, and the other side effects we talked about are quite rare.

14:14: Usually, patients are followed very closely at the treating CAR T center for the first two weeks after the infusion and usually for the first 30 days. During this time, it's common for patients to live away from home and stay very near the treating center because there must be very careful monitoring for these important side effects, most specifically cytokine release syndrome and neurotoxicity.  

14:44: It's very common after CAR T-cell therapy to have limitations in how you feel and how you move. Fatigue is the most common symptom.

Fatigue can be persistent for the first 6 months after the infusion, partly due to CAR T-cells and partly to lymphodepleting chemotherapy.

15:01: The biggest long-term risk is actually infection. That's the most common cause of patients dying from something other than their cancer, and so it's very important that patients are monitored for infection, and that everything possible is done to minimize this risk. The biggest long-term risks for infection are viral illnesses.

15:22: Now, what are we aiming to accomplish when we treat patients with CAR T-cell therapy?  

For aggressive lymphomas and for acute lymphoblastic leukemia, the goal of CAR T-cell therapy is to cure the cancer, meaning permanent eradication of the cancer. And at least in clinical trials so far, this occurs in just under half of patients, depending upon the exact disease and the study.

For low-grade lymphomas, chronic lymphocytic leukemia, and multiple myeloma, we are still learning about whether some patients can be cured. So right now, the goal of the treatment is to control the cancer for as long as possible. The average remission is typically on the order of years, depending upon the disease, the product, and the exact clinical trial

16:07: I also want to make sure that we spend some time talking about the future of CAR T-cells, because it really is very bright. We're doing lots and lots of research into expanding this type of treatment.

16:21: One key point is that we're working to expand the different cancers that can be treated with different CAR T-cells. There are innumerable clinical trials looking at just a smattering of some of the cancers listed here. You can see the theme is often other blood cancers, besides the ones that are already FDA-approved, and then lots of different solid tumor malignancies. We’re trying to develop CAR T-cells to treat cancers beyond lymphomas, leukemias, and multiple myeloma.

16:55: The second major category of expansion of CAR T-cell therapy is in non-cancer medical conditions, most commonly various autoimmune disorders.

We've seen in clinical trials that some patients with highly refractory or relapsed autoimmune conditions have responses to CAR T-cells. Some examples of non-cancer conditions under clinical investigation include lupus, systemic sclerosis, idiopathic inflammatory myositis, myasthenia gravis, multiple sclerosis, rheumatoid arthritis, and neuromyelitis optica, among others.  

17:37: There are even folks who are trying to develop CAR T-cells to treat cardiac disease, Crohn's disease, and ulcerative colitis. So, this is an exciting area of research, and hopefully, we'll see CAR T-cells available for patients in standard clinical practice for these different disorders.

17:55: I've talked about expanding CAR T-cell therapy to treat some new diseases, but what are we doing to actually improve outcomes with the CAR T-cells that we already have?  

So, one way we actually do better with CAR T-cells is by making better versions of the ones we have. We've learned how to make good CAR T-cells, but how do we improve upon them?  

18:17: One strategy is to engineer multiple latches for different proteins on the cancer cell, rather than a single latch that binds a single protein. The idea here is that it makes it harder for the cancer to escape.  

One way cancer can evade current CAR-T cells is to lose the target. So, if the target is a protein on the surface of the cancer cell, and the cancer cell loses that protein, the CAR T-cell will not be able to recognize it.  

So, what if we engineer two proteins so that the cancer cell would have to lose two distinct targets to escape? This strategy is currently under investigation in clinical trials. For some cancers, randomized trials are currently comparing standard CAR T-cells to these newer versions.  

19:12: A second way to make a better CAR T-cell is to engineer the ability of the CAR T-cell to secrete medication. So, remember, we're changing the DNA of the T-cell to make it do things it doesn't typically do. So, what if we actually engineered the T-cell to secrete a drug so it could do multiple things to treat the cancer all at once? CAR T-cells are being investigated to do this.  

19:37: Another thing we're trying to do is to make CAR T-cells that have a “kill switch”.  

So, what if you get one of the side effects that we don't want you to have with CAR T-cells? If the CAR T-cell is engineered with a way to turn off the side effect, which is what a kill switch is, then we could administer something to eliminate this side effect. And so there are CAR T-cells under development that have built-in kill switches.

20:01: The second way that we're trying to improve CAR T-cells is by giving CAR T-cells in a more personalized way.

Right now, we tend to follow a pretty standard script in how we give CAR T-cells, and in terms of eligibility.

One example of this is a clinical trial that took patients with aggressive lymphomas and no prior treatments. They tried to pick out particularly high-risk lymphomas, and they're comparing giving CAR T-cells very early, basically in the first-line setting as the first treatment for the cancer, versus our standard treatment, which is chemotherapy.

And so this clinical trial is ongoing, and it has the potential to say, ‘let's give CAR T-cells very upfront in a particular group of patients that are at higher risk.’

20:50: A third way that we're trying to improve upon CAR T-cells is to actually change the way we manufacture CAR T-cells. Right now, the way we manufacture CAR T-cells follows the steps I shared with you before, but there are ways to speed up the process. And so there are clinical trials looking at new manufacturing techniques to make these much faster.  

And there are also clinical trials evaluating CAR T-cells derived from another person. So that's called an allogeneic CAR T-cell, where instead of the CAR T-cells being made from the individual patient, they're being made from T-cells from another healthy individual. And then, as soon as that patient needs CAR T-cells, we could ship them directly. Clinical trials are evaluating the use of these allogeneic CAR T-cells.  

21:42: The fourth way that CAR T-cells are being studied as a potential improvement is called in vivo CAR T-cells. And what this does is totally turn manufacturing on its head.  

I shared the typical manufacturing process with you on the left side of this screen. And that's where we collect the patient's T-cells, modify their DNA in the laboratory, and give them back.  

But what if we injected patients with technology that allows CAR T-cells to be manufactured directly within the body, meaning we never have to take the T-cells out? That's called in vivo CAR T, meaning it’s all happening inside the patient.

The advantage of this would be that you might not need lymphodepleting chemotherapy, and it makes the logistics much easier, which could make the therapy more widely available to patients.

There are clinical trials already underway to assess whether this potential technology could be equal to, or even better than, current CAR T-cell therapies.

22:46: The last thing I want to talk about is how we can continue to improve the quality of life of patients who are receiving CAR T-cell therapy. As part of that, I want to think about the most common symptoms patients experience and what the lived experience really is for patients receiving CAR T-cells.  

23:05: This is a list of the most common symptoms that patients can face when they're going through CAR T-cell therapy. By far, the most common symptom is fatigue.

Other common symptoms are loss of appetite, headaches, chills, neurologic toxicity, which can lead to feelings of confusion and memory loss, and then other symptoms like pain, vomiting, diarrhea, and lightheadedness.

23:36: I, along with my colleagues, led a study to measure physical symptoms during the CAR T-cell process. And we found that about half of the patients reported severe symptoms, particularly in the first week after the CAR T-cell infusion.

Thankfully, we did see a decrease in this percentage. Patients seemed to have improvements in their symptoms by the time they were a month out from CAR T-cell therapy. And by the time that they were three months out, the percentage of patients with these symptoms had decreased significantly.  

But there are still patients who have symptoms even three to six months after their CAR T-cell infusion. So, I think this highlights that there's room for improvement.  

24:16: We also looked at psychological symptoms. You know, this is a lot to go through for any patient and any family.

And we found that six months after the CAR T-cell infusion, about 20% or so, even as high as a quarter of patients, had persistent significant psychological symptoms. This is important because it highlights that there's significant room for improvement in making this process as smooth and patient-friendly as possible.

24:43: We tried to measure quality of life, which is typically done by surveying patients and asking them questions about their quality-of-life. We found in a study looking at multiple different types of CAR T-cells with multiple different types of patients and cancers, that over time, quality of life decreased during the acute phase of the CAR T-cell therapy, meaning about a week or two after the CAR T-cell infusion. This is the period when patients typically experience the highest percentage of burdensome symptoms. Remember the cytokine release syndrome and the neurologic toxicity that we talked about.

25:19: We did see that quality of life, on average, tended to rebound by one month after the CAR T-cell infusion. By three months after the CAR T-cell infusion, quality of life, on average, had actually improved compared to before the CAR T-cell infusion. And this appeared to persist, in other words, be preserved even six months after the CAR T-cell infusion.  

Encouragingly, patients rated their quality of life at a level similar to the United States population average, and we didn't identify a group with a particularly poor quality-of-life trajectory.  

So, despite the fact that there's room for improvement, I do think this is encouraging information about what patients can expect, on average, for their quality of life after CAR T-cells.  

25:59: Now let's think about survivorship. Survivorship refers to what it's like after you have the CAR T-cell infusion. And this is obviously very important for any cancer treatment.  

26:15: This slide, which I think is very helpful, summarizes the main things we like to think about medically after patients have received CAR T-cells.  

Remember, the most important cause of problems long-term after CAR T-cell therapy is infection - bacterial, viral, or fungal.  

Fungal infections and a rare type of pneumonia called pneumocystis typically occur in the first couple of months after CAR T-cell infusion, whereas viral infections are typically a long-term risk.  

Low immunoglobulins, which are proteins that help fight infections, can be a problem for months to even years after CAR T-cell therapy, and it can take a long time for the immune system to recover.  

Cytopenias refer to low blood counts, and we can see, in a subset of patients, low blood counts for months to even years after the CAR T-cell infusion. So, this needs to be monitored and managed by doctors and the rest of the care team.  

And then I mentioned to you previously some of the rare neurologic events that can occur even months after the CAR T-cell infusion.  

It’s very important to stay up to date on cancer screenings because secondary cancers that can occur after CAR T-cell therapy.  

So, I think this highlights the very important survivorship issues that can occur and the importance of having long-term monitoring after CAR T-cell therapy.  

27:41: Here are some of the research strategies that I worked on, along with other investigators and researchers across the world, to improve the CAR T-cell experience for patients.

One avenue is helping with how we educate and support patients through the CAR T-cell process.  

The second avenue is thinking about how we can reduce side effects.

The third avenue is asking ourselves, can we just prevent these from happening in the first place?

And the fourth avenue is trying to optimize logistics and make this experience as smooth as possible.  

So, let's think about each of these avenues.

28:14: It’s critical to know that CAR T-cell therapy is actually relatively rarely used, even amongst eligible patients in the United States.

This study showed that less than 20% of eligible patients aged 65 to 69 actually received CAR T-cell therapy. And this number is even lower for patients older than 69 years of age.

This is probably because of some of the logistical challenges of CAR T-cells. Remember, these are typically available in a relatively limited number of centers across the United States because of the specialized nature of this therapy. And CAR T-cell therapy also requires a caregiver. It requires you to be relatively close to the treating center.

We certainly would like to get higher than 20% of eligible patients receiving CAR T-cell therapy.  

29:08: One thing we're looking at to improve the process is using digital technology, such as mobile applications for iPhone, iPad, or other devices, to educate patients, manage side effects, and improve access.

This is just a screenshot from an iPad application that we're working on developing, and we're testing it in clinical trials to see how effective it is.

29:33: A second thing that we've already studied and we're still in the process of studying is whether video technology can help educate patients through the process. You can imagine, just from this discussion, that there is a lot to tell patients in a short one-hour or two-hour visit.

So, videos may help patients understand the treatment process, 30:the logistics, and prepare them for the side-effect experience. This is from a study I ran, where we found that over 90% of patients felt that a video was actually helpful in the consent and education processes.

30:12: The third thing is thinking about whether we can integrate other disciplines to help minimize the side effects that patients experience.

One type of specialist is a palliative care specialist. Palliative care refers to specialists who help mitigate side effects and symptoms and help maximize quality of life during treatment.

We and others are looking at a clinical trial to test whether adding palliative care specialists improves quality of life and reduces the side-effect burden for patients and caregivers undergoing CAR T-cell therapy.

30:44: Similarly, for older adults undergoing CAR T-cell therapy, adding geriatricians who specialize in the management of older adults may reduce the risk of side effects and improve the process for these patients. Most clinical studies have shown that CAR T-cells are very effective in older adults, and so it's very important that we ensure that this therapy is available for these patients as well.

31:11: Finally, one other avenue that we're seeing is the development of survivorship programs for CAR T-cell patients.

Survivorship programs help patients who receive CAR T-cells minimize long-term side effects and maximize long-term quality of life.

So, research is ongoing to determine how to integrate these survivorship programs into various medical programs, so that local oncologists and CAR T-cell centers can collaborate and ensure that patients receive the most up-to-date management to minimize these long-term complications.

31:48: There are also studies ongoing to prevent side effects. I mentioned that we obviously want to manage side effects, but it's even better to prevent them in the first place.

One ongoing study is examining whether giving intravenous immunoglobulins, which are proteins that fight infections, can prevent infections from occurring in the first place.  

There are also clinical trials evaluating the use of anti-inflammatory medicines with CAR T-cell therapy to prevent neurologic toxicities and cytokine release syndromes.

And then some of these newer CAR T-cells that we've talked about previously actually can potentially have fewer side effects. And so just having a better CAR T-cell can lead to a better outcome for patients.  

32:36: The last thing to mention with this is how we’re changing the logistics of CAR T-cell therapy to make it a better process.  

The FDA, which is the government, has actually reduced the burden on patients by shortening the time required to have a caregiver. Previously, it had to be 30 days; now it can be as short as 14 days.

Previously, we had an eight-week driving restriction. That's now been shortened to two weeks.

Now, this must be personalized. It should be discussed with the treating oncologist because, in some cases, it should be longer than this. But the point is that the bare minimum has been decreased.

In addition, we're actually doing more and more outpatient CAR T-cell therapies. As CAR T-cell therapy becomes safer, we're able to do much of this outpatient, so patients don't spend as much time in the hospital, where they could be at risk of infections from other hospitalized patients.

There are ongoing studies looking at remote monitoring equipment to see if we can make it safer to give CAR T-cells.

For example, we all know about Apple Watches and other wearable devices. Can these wearables make it easier for us to identify side effects faster and allow patients to receive treatment closer to home?

And finally, we really want CAR T-cell therapy to expand to new locations so that patients can receive it closer to home, with less of their lives uprooted.

33:53: I'd like to conclude with a few statements.

Hopefully, I've shared that CAR T-cells are currently available for patients with lymphoma, multiple myeloma, and certain types of leukemia, and have really transformed the outcomes and treatments available for these patients.

I've shared that some diseases can even be cured with CAR T-cell therapy, and for others, we're seeing prolonged remissions that, in many cases, have not been seen with any other type of therapy.

I think the future of CAR T-cell therapy is extremely bright.  

I've shared with you new CAR T-cell designs, new ways that CAR T-cells are being made, and ways that we're personalizing who receives CAR T-cells, and hopefully, how we manage these short-term and long-term side effects.

I think it's very important to be aware that CAR T-cell therapy is actively being studied, both in solid tumor cancers and in non-oncologic indications, such as various autoimmune conditions, and that CAR T-cells will hopefully one day be available for these patients as well.

There's a lot of research ongoing on how to optimize the quality-of-life experience for patients going through CAR T-cell therapy. Some of what I shared with you were digital health strategies, palliative care strategies, geriatrics, survivorship programs, and prevention.

And with that, it's really been a privilege to have the opportunity to share this presentation.  I'm looking forward to some terrific questions.

Question and Answer Session

35:19 (Marla): Thank you, Dr. Johnson, for that excellent presentation. There is a lot to learn about CAR-T for the future, so we'll get started here.  

35:28: First question is, how long do these modified CAR T-cells stay in the system to fight cancer, and when they are gone, what takes over if the cancer returns?  

35:39 (Dr. Johnson): That's a terrific question, and to be honest with you, we don't have a standard assay to measure this, in practice. You might think, ‘Oh, why don't you just have the treating team check your CAR T-cells and see how many you have?’ We currently don't have that type of assay. In research studies, it varies a lot, but CAR T-cells often live for months and occasionally for years.  

Remember, we also don't know how long the CAR T-cells need to live to actually do their job. For example, if the CAR T-cells kill all the cancer and it took 3 months, they don’t need to live for 10 years. They really only need to be there for three months. So, I think for every individual type of cancer or condition, how long the CAR T-cells need to be there probably varies. And we're trying to learn that.

The key point is that, from what we understand, most of the time, CAR T-cells are likely present for months. But it can range significantly.

Now, what do you do when the CAR T-cells die? Again, when the CAR T-cells die, it may be that the cancer is in such a deep remission that you don't need anything else. The cancer may be eradicated, or the cancer may be so deep in remission that there's simply nothing else needed.

In some cases, when the cancer returns, we commonly turn to other treatments. Usually, retreatment with CAR T-cells hasn't shown as much effectiveness as we would like, although some clinical trials are ongoing to determine whether, after a long time, additional doses of CAR T-cells can be helpful. Most of the time, we're adding in other medications to try to treat the cancer in that circumstance.

37:24 (Marla): What is the future outlook for CAR T-cell therapy for AML (acute myeloid leukemia)?

37:34: (Dr. Johnson): Yeah, that's a great question.

So, AML refers to acute myeloid leukemia, and that's different from acute lymphoblastic leukemia (ALL). It's an acute leukemia, but the actual cancer cell is from a different type of blood cell.

The challenge with AML is that myeloid blood cells are responsible for protecting us from bacterial infections. For example, if the CAR T-cells completely kill all of the healthy myeloid blood cells, guess what? Patients get really sick with infections. So that's why it’s a little trickier to develop a CAR T-cell for AML. You need CAR T-cells to kill cancer cells, but preserve enough healthy blood cells to prevent bacterial infections.

Right now, there are clinical trials ongoing to develop CAR T-cells that bind to very specific targets on AML cells, and are engineered to secrete a drug. It uses a multi-step process.  

So, I think the future of CAR T-cells in AML is these novel, new CAR T-cell designs that I shared with you - a CAR T-cell that binds, but also secretes a drug. I think that's where we're going to see CAR T-cells tested in AML.

38:52 (Marla): Will CAR T-cell therapy induce injury to intestinal mucus layers and then lead to something like leaky gut?

39:02 (Dr. Johnson): So that's a great question.

There is a specific entity called enterocolitis. And what that refers to is inflammation directly in the intestine. It's most commonly seen with BCMA-directed CAR T-cells, which target multiple myeloma. It was seen most often with cilta-cel (Catvykti). In one study, it occurred in about 5% of patients, so it's rare.

What happens in that scenario is that some of the CAR T-cells go into the gut, and they create inflammation right at that layer. It tends to lead specifically to a diarrhea syndrome.

So, I would say, yes, it has been seen, usually with a very specific CAR T-cell product, and it's rare, but we do see that.

I think the main strategies to prevent that are what we talked about before, which is really trying to make sure the cancer is well controlled at the time the CAR T-cells are given.

40:17 (Marla):  A patient is wondering: they've had one stem cell transplant. What are the risks if they go to CAR T? Are they allowed to have CAR T? Is it different for every situation?

40:31 (Dr. Johnson): So, there are two types of stem cell transplants. One type of stem cell transplant is an autologous stem cell transplant. This is a transplant from self. And that's used in both lymphoma and multiple myeloma.

CAR T-cells, when they first came out, were used for patients who had had a prior autologous transplant. So, it's absolutely, completely fine to get CAR T-cells after you've had an autologous transplant. That has been studied and is a very standard practice.

Now, the second type of transplant is an allogeneic transplant. That means a transplant from another person.

The original clinical trials of CAR T-cells didn't include many patients who had had a stem cell transplant from another person.  

That said, it's been done. That's not a contraindication to receiving CAR T-cell therapy. It can still be used. But just know that fewer patients who had an allogeneic transplant have received CAR T-cell therapy than those who received CAR T-cells after an autologous transplant.

In terms of how you think about CAR T-cells, it would be very similar. You would still be engineering CAR T cells. The difference is that they're engineering T-cells that came from your donor for the transplant.

And you would engineer the CAR T-cells the same way. You administer the CAR T-cells the same way. So, the logistics and how you manage them are very similar. It's just being done on T-cells that came from another person.

42:00 (Marla): The chemo for stem cell transplant was horrible. It was melphalan. How does the chemo at the start of CAR-T compare?

42:10 (Dr. Johnson): In general, it all depends, of course, on what you've had before. The chemotherapy experience can be completely different depending on which chemo you had.

But in general, the chemotherapy for CAR T-cell therapy is easier to tolerate than the chemotherapy for an autologous transplant and most of the standard chemotherapies for aggressive lymphomas.

I certainly think compared to chemotherapy for an autologous transplant, the chemotherapy for CAR T-cell therapy is significantly easier to tolerate, on average.

Remember, the goal for the chemotherapy and an autologous transplant is to completely ablate the blood counts and then give back stem cells. The only goal of chemotherapy with CAR T-cell therapy is to lower blood counts enough for the CAR T-cells to grow. You're just trying to prevent the body from killing off the CAR T-cells quickly.

I don't want to say that there are no side effects from lymphodepletion. People do, on average, get tired and potentially have diarrhea, fatigue, and some nausea, but in general, patients find that the chemotherapy for CAR T-cell therapy is easier to tolerate than chemotherapy for a transplant or a multi-agent chemotherapy for aggressive lymphoma

43:25 (Marla):  Do NK cell-based CAR T-cells have a better safety profile than CD19-based CAR T-cells?

43:44 (Dr. Johnson): In general, the clinical trials of NK-CAR cells have shown very, very good side-effect profiles, although a lot of the new CAR T-cells also show very good side-effect profiles. So, I think it depends on what you're comparing.  

In some clinical trials comparing original CAR T-cells with some of the original NK-CAR cells, the CAR-NKs seem to have a gentler side-effect profile. However, NK-CAR cells have generally not demonstrated the long-term durability of CAR T-cells.  

There are no FDA-approved NK-CAR cells. They've been tested in clinical trials, but have not shown enough efficacy, meaning effectiveness against the cancer, to lead to an approval. But we do see, in general, very favorable side-effect profiles with CAR-NK. That said, though, remember that for all the new CAR-T-cells we're talking about, part of what we're trying to do is keep the CAR-T-cell side effects as low as possible.

44:45 (Marla): What's the best way to rebuild muscle after CAR-T?

44:51 (Dr. Johnson): You know, I think when we talk about the most common issues after CAR T-cells, fatigue is by far the most common. So, I think muscle rebuilding after CAR T-cell therapy is pretty similar to muscle rebuilding after various cancer therapies, such as chemotherapy for lymphoma, multiple therapies for multiple myeloma, i you had an autologous stem cell transplant.

Usually, the best thing to do is to try to get back into an exercise program. You want to be steady with how you recover.

I think the number one mistake with fatigue is what I'll call the roller coaster, where you feel a little bit better one day, so you go all out. Then you're exhausted for days, and you do nothing, and then you go all out, and you end up with this up and down, up and down, up and down that's hard to ever move past.

And so, I think the better strategy, in general, is to try to start with an exercise program and steadily build over time. That's probably the number one way to rebuild.

I think the other things to think about are making sure that your nutritional program is good, that you're getting all the nutrients and vitamins, you're getting fruits and vegetables, and you're getting lean protein so that you're actually able to recover.

And then, if there are ongoing issues, like fatigue, you're making sure you're seeing the primary care physician so that the “bread and butter” things that can also cause issues aren't forgotten during this process.

So, an exercise regime that builds steadily, ensuring that nutrition is appropriate, and having a primary care physician engaged to make sure that other issues are not causing the problem.

46:33 (Marla): For how many months after CAR T-cell therapy will a patient require IVIG?

46:40 (Dr. Johnson): So, this varies considerably depending upon which CAR-T-cell product you got and what kind of cancer you have. It's hard to generalize, but let me give you a few examples.  

And I should add that, depending on where you are in the country or the world, it may be managed a little differently. Doctors have not established a single one-size-fits-all strategy that everyone should follow. So, I'll give you what I do, but I'm also going to tell you a couple of other things.  

Some practitioners will give multiple myeloma patients IVIG once a month for six months after CAR T-cell therapy, regardless of IgG levels. IgG is how you measure the immunoglobulin protein. So that's one strategy for multiple myeloma: give IVIG monthly for six months and then reassess.

In my practice for lymphoma patients, I usually check immunoglobulin levels monthly for the first six months, then every three months. If the patient’s immunoglobulin levels are below 400, I typically give preventative IVIG on a monthly basis. If the immunoglobulin levels are above 400, I typically don't, and I'm usually just monitoring.

If a patient has borderline immunoglobulin levels, say 400 to 500, and they call me, and they have an infection, maybe they have a sinus infection, they developed a virus, I'll typically administer a dose of IVIG in that case.  

Remember, there is no one-size-fits-all practice yet. We are doing clinical trials to learn how to give IVIG prophylactically to prevent infections. So, in the future, we may have a very standardized practice. But for now, there's a lot of variability.

48:22 (Marla): This person had CAR T-cell therapy in 2025, and their white blood cell count, red blood cell count, and platelets remain low. When will the counts return to normal?

48:38 (Dr. Johnson): It depends on the CAR T-cell product you received and exactly what disease you had. In general, about 25% of patients, or so, will have persistent low blood counts one month after infusion. In that group of patients, about two-thirds will recover blood counts by six months after the infusion. So, depending upon when in 2025 you received the CAR T-cells, there's a decent chance that blood counts will recover in the first six months after infusion.

If it's been more than six months, some patients will have persistent low blood counts that last for years. If it's been more than 3 months and a patient still has low blood counts, I would recommend a bone marrow biopsy to ensure we have a clear understanding of the cause.

49:35 (Marla): This gentleman had a transplant for multiple myeloma in 2019, and he's doing well, but he was wondering if his myeloma recurs at this age, whether CAR T-cell therapy is a possible next step for him?

49:51 (Dr. Johnson): CAR-T-cell therapy for multiple myeloma is absolutely available. There are multiple products. The specifics of when you can receive CAR T-cell therapy depend on how many lines of prior therapy patients had, and exactly what they had before, but absolutely, in general, CAR T-cell therapy would be very appropriate to consider for any multiple myeloma patient when it comes back after a transplant.  

Many, many therapies have been approved over the last several years for patients with multiple myeloma. So, whether it should be the next line of therapy or whether it should be something that's kept in people's back pocket, that's really something that should be discussed with the treating oncologist, but it's absolutely on the list of therapies that are available.

50:34 (Marla): So, the age of 77 is not an issue. Great.

50:41 (Marla): Next question is, and I'm going to address this first, and then I'll let you do it. Someone asked about CAR T-cell therapy locations in San Francisco and Silicon Valley. And I will just say that BMT InfoNet has an online CAR T-cell directory that lists all centers in the United States that currently do CAR T-cell therapy. So that would be a place to look. And if Dr. Johnson has something to add to that, that would be great.

51:11 (Dr. Johnson): I think UCSF is a wonderful cancer center right in San Francisco. So that might be a natural fit. But I would fully support looking at the website and at the various centers. A lot of times, you know, convenience is important.

51:31(Marla): Which CAR-Ts have shown efficacy in systemic sclerosis?

51:36 (Dr. Johnson): So really, there are a number of CAR-T-cell products that are being tested in systemic sclerosis. Remember, they're all in clinical trials. So, we're still trying to get to the point that there's actual approval. But the focus has been on CD19 CAR-T-cells, which are similar to the CAR-T-cells used for lymphomas and leukemias, and several are in clinical development and clinical trials.

51:59 (Marla): Does administering CAR T-cells make our body generate more CAR T-cells?

52:07 (Dr. Johnson): When you receive CAR T-cells, they are alive, so they will engage proliferate. Essentially, what you're doing is getting them kick-started, and then the CAR T-cells live and can proliferate on their own in your body. And these CAR T-cells, because they are autologous, meaning from the patient, they are able to do that.

52:35 (Marla): I have two types of lymphoma, LPL (lymphoplasmacytic lymphoma) with Bing-Neel syndrome and large B cell in my left chest. Am I a candidate for CAR T-cell therapy?

52:45 (Dr. Johnson):  So, in the case of something like that, you're usually going to be managed based upon diffuse large B-cell lymphoma. And so for diffuse large B-cell lymphoma, CAR T-cell therapy is FDA-approved in the second-line setting. So after a prior line of therapy for DLB-cell, you absolutely could receive CAR T-cell.

53:07 (Marla): Does the prevalence of mental health complications indicate that the T-cells can access our brain across the blood-brain barrier, or is it the consequence of their lived experience after treatment?

53:21 (Dr. Johnson): CAR T-cells can absolutely get into the brain, and CAR T-cells are available for patients with primary central nervous system lymphoma. So, if you have a lymphoma that's in the brain, CAR T-cells are completely available for that. We certainly know that CAR T-cells reach the brain.  

In general, it seems like the neurologic side effects of CAR T-cells are fully reversible and recover. So I think a lot of the long-term psychological symptoms that patients experience are probably related to everything that they've been through. Remember, these are patients who have had multiple lines of different treatments, and that can include some prior chemotherapy, which can also cause some cognitive side effects.  

Interestingly, patients who have baseline depression seem to have a higher risk of some of the neurologic toxicities. So, there's ongoing research trying to understand how the inflammation associated with depression can potentially affect the risk of. It's a really good question, and I think we still don't know for sure.

54:23 (Marla): How close are you to creating CAR T-cells internally with a virus?

54:31 (Dr. Johnson): So that's what in vivo CAR T-cells are, and those are in phase one clinical trials, meaning they're just now being tested for how safe they are.

Once that's done, if they are safe, they would move on to see how efficacious they are, meaning how well they work. So, we are at the point of testing them.

54:52 (Marla): How long does CAR T-cell therapy work for plasma cell leukemia? Is there any sort of definite answer there?

54:59 (Dr. Johnson): I wouldn't say there's a definite answer other than to say that plasma cell leukemia is essentially multiple myeloma. So, I would consider it in the bucket of patients who are receiving it for multiple myeloma.

55:15 (Marla): Someone asked about an increased risk of GVHD after transplant. And I'm not sure if they're talking about whether this will affect CAR-T. Is there any correlation? There is no GVHD with CAR-T, correct?

55:33 (Johnson): Yeah, with CAR T-cells, there has been no graft-versus-host disease seen,  either with autologous CAR T-cells or allogeneic CAR T-cells, which are CAR T-cells from another person. We really have not seen graft-versus-host disease from that, though it is a potential concern with allogeneic CAR T-cells.

55:53 (Marla): And I think at that point, we will close this off. I want to thank Dr. Johnson and our partners for this very helpful presentation, and thank you, the audience, for your wonderful questions.