CAR-T: What's Next?

The medical journal Cancers published an article recently called "CAR-T: What is Next?"

I thought it was pretty interesting, given what I wrote in my last post -- that experts were kind of torn about when to give CAR-T to Follicular Lymphoma patients, given some of its limitations (like its potential effects on Quality of Life). 

This article, by three authors from King's College in London, is a review of how CAR-T is used, not just in FL, or even in blood cancers, but in solid cancers, too. And as the title suggests, it also looks at the future of CAR-T, and how researchers are working to overcome some of its limitations. As the authors point out, one of the limitation is the dangerous side effect called Cytokine Release Syndrome, the body's response to a surge of immune cells. But another is a lack of durability for patients with some cancers, where as many as 60% of patients receiving CAR-T will relapse. Basically, CAR-T has limitation in both of the areas that cancer treatments are evaluated by -- how effective they are, and how safe they are.

Of course, every cancer treatment has limitations on how effective and safe they are. If they didn't have limitations, then we'd all be cured, with no side effects. It seems to me that this is an issue for CAR-T because it holds so much promise. 

It turns out there are a whole lot of attempts by researchers to make CAR-T more effective and more safe. If you look at the article, focus on Table 2, which gives a summary of all of those attempts. It's too big a table to copy here, but I want to mention a few of the research approaches that are discussed. 

•  To try to make CAR-T more effective, researchers are developing Artificial Antigen-Presenting Cells (AAPCs). CAR-T works by training T Cells (a kind of immune cell) to recognize the cancer cells. When the cancer cells are gone, the T Cells might die off, since the threat is gone. It is possible that, if there is a relapse, those trained T Cells aren't around anymore to go after the cancer cells. In this research, AAPCs are given to the patient after relapse. these might be "fake cancer cells" or other substances that stimulate the trained T Cells, so those trained cells don't die off. If an actual relapse happens, those T cells will be ready to recognize them and go after them.
• Other research combines CAR-T with Bi-Specifics. A Bi-specific works by bringing a cancer cell and T Cell next to each other, making it easier on the T Cell. Researchers are trying to develop B-specifics that would seek out the specific T cells that have been trained in the CAR-T process, making them even more effective.
• Still other research is trying to develop variations on CAR-T. There are lots of immune cells in the body besides T Cells, and they can be even more powerful. So some researchers are trying to develop treatments like CAR-NK (training Natural Killer cells they way T Cells are trained now) and CAR-M (using Macrophages in place of T cells).
  
• Other research is focused on safety, trying to reduce the side effects that come with CAR-T. One problem with CAR-T is that once it starts working, it's hard to control. That's why Cytokine Release Syndrome is a problem -- it's a side effect of having too strong an immune response. In a weird way, it's almost as if CAR-T is working too well. T cells work in two ways -- they kill the cancer cell, but then also signal the body to create more T cells. So one strategy to help with safety is to separate those two functions -- keep the "kill the cancer cell" part, but not the "signal the body to make so many that the patient gets CRS" part. Another strategy is to add something to the T Cell as it is being trained that will act as a kind of brake. If signs of CRS are starting, doctors can give the patient another treatment that will tell the T cells to slow down, and thus avoid CRS.
  

I'm not trying to give a complete list of the research being done to improve CAR-T -- there is a while lot more that is discussed in the article. But I think it's pretty fantastic that there is so much work being done on this. Oncologists are very excited about the possibilities of CAR-T; as I've mentioned before, CAR-T and Bi-specifics seem to be the two things that get doctors most excited these days. And patients are just as excited -- I see lots of discussion in online groups for FL patients about CAR-T being "The Cure."

As this article makes clear, that might be a little premature. We're not there yet. But I love that there's so much work being done to move us in that direction -- far more than I was aware of. Lots of reasons for hope.

T Cell Lymphoma After CAR-T

I may get back to a couple more ASCO presentations, but for now I want to write about three articles in the New England Journal of Medicine this week. You probably remember that in January, the FDA issued a warning about CAR-T. There seemed to be an increased risk of developing secondary cancers, especially T Cell Lymphoma, after CAR-T. Some research a few months later looked at how common those T Cell Lymphomas were.

Now the NEJM has published more research on this topic. Two studies looked at groups of CAR-T patients who developed T Cell Lymphoma after treatment. The researchers in both studies were especially interested in where the secondary T Cell Lymphomas came from. There had still been some uncertainty about whether the new cancers came from the manipulated T Cells. (Remember that CAR-T involves removing T Cells, a kind of immune cell, from the patient; then changing the cells so they can recognize cancer cells; then putting them back into the patient.) The concern is that changing the T Cells makes them more likely to become cancerous themselves.

I'll give you the bottom line -- it's possible that the treatment can lead to the secondary cancer.

One of the studies, "Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy," looked at 724 patients who had received CAR-T at their center. Only one of them developed T Cell cancer -- a patient with Diffuse Large B Cell Lymphoma. The researchers performed a number of tests on samples of the two lymphomas, and found that they were genetically unrelated. However, both were positive for Epstein-Barr Virus, a very common virus that does have a connection to some cancers, including Burkeit's Lymphoma and Hodgkin's Lymphoma. The study isn't suggesting that DLBCL is caused by Epstein-Barr, but there may be some issue that ultimately leads to cancer forming -- in this case, independently of one another. In other words, the T Cell Lymphoma might have come about from the same general conditions as the B Cell Lymphoma, but they are genetically unrelated to one another.

In the other study, "Indolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy," researchers looked at a different group of patients who were given a different type of CAR-T. This study looked at a single patient who had received CAR-T as a treatment for Multiple Myeloma, a different type of blood cancer. In this case, the researchers did find a genetic connection between the new T Cell Lymphoma and the T Cells that had been changed as part of the treatment. The researchers looked deeply at the samples and seem to have found the genetic alternations that resulted in the T Cell turning cancerous.

To be clear, these two studies weren't comparing the same samples or the same patients -- or even the same CAR-T treatments. And while I say it is possible, I mean that they aren't coming right out and saying CAR-T will definitely lead to cancer, because that's just not true.There have been thousands of patients who received CAR-T who have not had any issues with secondary cancers. They're saying there's a possibility -- but they still don't know why or how.

That's why the third article that issue of NEJM, "T-Cell Cancer after CAR T-Cell Therapy," tries to bring together what the two studies say and add it to what we already know. They point out that there is a connection between the treatment and the new cancer in that second study, but still don't know how it arises. That single case of T Cell Lymphoma came from a pool of 587 B Cell Lymphoma patients, making the rate of incidence 0.17%. That's in line with the data that the FDA reviewed, which identified 354 cases of T-cell lymphoma in 288,478 patients with B-cell lymphoma, an incidence rate of 0.12%.

The important part of these studies is their attempt to identify whether or not the treatment causes the secondary cancer. Patients (like us) with B Cell Lymphomas are about 5 times more likely than the general population to develop a T Cell Lymphoma, meaning the conditions for someone receiving CAR-T are already greater.

In the end, I can't imagine that this research will cause the FDA to change its recommendation about CAR-T. The Black Box Warning will remain, and patients will still need to have that conversation with their oncologists. But the FDA will likely conclude that the benefits of CAR-T far outweigh the risks.

ASCO Part 2: CAR-T News

A little more from the ASCO Virtual Education session. 

There was, of course, a session on CAR-T treatments at ASCO part 2 -- CAR T-Cell Therapy: Strategies to Expand Access.

I'm going to assume that, if you're reading the blog, you have heard of CAR-T. But maybe a quick reminder would be helpful, just in case. CAR-T stands for Chimeric Antigen Receptor T-cell therapy. Basically, T cells are a type of immune cell that help clear out any invaders in the body (like bacteria or viruses). Cancer cells, while they don't belong, are not attacked by the immune system because they are not "invaders" from outside. They are our own cells that have gone rogue. The system for finding outsiders just ignores them. CAR-T therapies take T cells from the body, change them in a way that lets them recognize cancer cells as invaders, and then puts them back into the body to find and clear out the cancer cells. Ideally, like any immune cell, they grow in numbers to deal with the cancer cells, and then remember the cancer cells so they can go back to work on them if the cancer returns.

Lots of patients have had success with CAR-T, though not all of them, and researchers continue to work on making CAR-T more effective and safer (which is important because CAR-T has the potential to create some very serious side effects). If you want to read more about CAR-T and Follicular Lymphoma, I recommend this site.

There are two CAR-T treatments that have been approved by the FDA, and about 600 clinical trials around the world that are testing CAR-T (newer versions, different diseases, etc.). One of the big issues with CAR-T, though, is the cost. Because each treatment is created specifically for one patient, using that patient's cells, the cost is very high -- potentially close to $500,000 per treatment. 

The ASCO session on CAR-T focused on issues of access -- how to get the treatment to patients who might be helped by it. ASCO put out a nice summary of the session in the daily newsletter they published during the conference. But basically, the issues include things like cost, of course. But there are others.

For example, side effects can be a major problem, one that is potentially life-threatening. As one presenter pointed out, some smaller clinics may be able to administer the CAR-T treatment, but they don't necessarily have the facility to deal with some of the side effects. She hoped that researchers would be able to make CAR-T treatments better in the near future, in ways that reduce the severity of side effects, making them more available to those clinics that can't handle those safety issues.

Another issue, in addition to cost, is the time that goes into creating the T cells. Right now, they are removed from the patient and taken to a lab, where the cells are changed and then left to grow in large enough numbers to be effective. This can take weeks, and some patients can get worse or die during that time. Improvements to the process, to speed things up, may come in the near future, and may help accessibility.

But cost seems to be the biggest barrier. In the United States, this means creating a better system for private insurance and Medicare (the government-run healthcare system for older patients) to reimburse the cost of the treatment.

The good news is that all of the speakers at the session seemed hopeful that the problems they pointed out were solvable, and that making people aware of the problems was a good first step.

This is especially important for us as Follicular Lymphoma patients. CAR-T treatments that are currently available are approved for aggressive blood cancers, including Transformed Follicular Lymphoma. But a few weeks ago, early results from a phase 2 clinical trial of CAR-T for Relapsed and Refractory FL patients showed some good results. (These are FL patients whose last treatment stopped working, or didn't work at all. They aren't necessarily patients with Transformed or aggressive Follicular Lymphoma, a much larger group of patients.) Earlier this summer, a different CAR-T treatment also showed good results for the same group of patients.

Ideally, as CAR-T trials move along, and eventually get approved for more FL patients, the accessibility issues with CAR-T will also approve, so the people the treatment is meant for will actually be able to afford it, be treated with it, and do so safely.

CAR-T is one of those treatments that get lymphoma experts very excited. Here's hoping that all of their wishes come true in the next few years.

ASCO: CAR-T

First of all, a Happy Cancer Survivor's day to everyone!  The National Cancer Survivors day Foundation defines a survivor as anyone who has been diagnosed with cancer who is still alive today. It's a day worth celebrating. In fact, it's a reminder that every day is worth celebrating -- we should be sure to take some time, every now and then, to remember that.

I'm not going to spend too much time on Cancer Survivor's Day today (if you want to look back at what I had to say in the past, feel free -- it still holds true, especially the part about having a crush n figure skater Katarina Witt when I was a teenager).

More importantly, there are ASCO abstracts still waiting out there to be discussed.

My friend William asked me to check out what's being said about CAR-T. (William and Ben write a blog on CAR-T and Follicular Lymphoma. Ben had CAR-T, as did William's wife.)

There is a LOT of stuff on CAR-T at ASCO. It's an exciting treatment that shows a lot of promise. I've written about it before (a lot), but here's a reminder of how it works:

One of the body's defenses against invaders is a kind of white blood call called T cells. There are actually a bunch of different kinds of T cells, but there basic job is to figure out that there is an invader (like a bacteria or a virus) and attack it. T cells can multiply rapidly, so millions of them go on the attack.

But T cells don't work on cancer cells. Cancer isn't an invader from outside -- it's our own cells that have gone wrong. So CAR-T is a way of using T cells to go after cancer cells. Some T cells are removed from the body and changed in a way that lets them treat cancer cells as outside invaders. The new T cells can multiply and overwhelm the cancer just like they would any invader.

CAR-T is still in developmental stages (though it has been approved for aggressive transformed Follicular Lymphoma). Right now, about one third of patients have a long response to CAR-T, about one third have a response that lasts less than a year, and about one third do not have a response. My own oncologist thinks it will be much more effective in about 5 years. Another problem is that it is expensive -- it is basically a personalized cancer treatment, made just for each specific patient. It can also have some serious side effects, as the body is overwhelmed by the army of T cells, causing a reaction that could be fatal if not treated.

With so many presentations on CAR-T at ASCO, I won't get into too much detail about them, but here are some of the highlights:

• One studied looked at Quality of Life in CAR-T versus Stem Cell Transplants. Unfortunately, aggressive treatments can result in severe side effects and lower QoL. The study found that CAR-T patients had the same QofL as the STC patients, and may have had fewer physical side effects in the month that followed treatment/
• Another looked at Cytokine release syndrome, also known as CRS. That's the potentially deadly reaction that the body has when so many T cells kill off other cells at one time. the body has a reaction that's almost like getting a really bad flu. One presentation offered a way to detect CRS and deal with it before it becomes too harmful. (This has been a big area of research for the last few years, and it seems like doctors are able to watch for CRS and deal with it early.)
• Another used PET scans as away to predict how effective a CAR-T treatment would be. By looking at a PET 30 days after CAR-T treatment, and comparing it to PETs taken after 90 days, researchers could figure out how to tell if the 30 day PETs could predict whether or not the CAR-T would be successful. early predictors like this are important; rather than waiting another 2 months to see if it worked, some patients can start a new treatment much sooner, saving valuable time.
• Another looked at outcomes for DLBCL patients who had CAR-T. they found that patients who relapsed within 3 months of treatment had poor outcomes. But those who relapsed 3 months or longer after getting CAR-T did much better with the treatment that followed.

There weren't any presentations that looked at only Follicular Lymphoma and CAR-T. The clinical trial series that focuses on CAR-T and lymphoma is called ZUMA. So ZUMA-1 looked at DLBCL and Transformed FL, and the results of that trial were the reason CAR-T was approved. There are a bunch of trials (at least 8) that are looking at CAR-T and other blood cancers. One of them is looking at FL (not transformed FL, but just regular old FL). No results yet, at least not anything worth presenting at ASCO. Maybe at ASH in December, or ASCO next year.

I'm looking forward to seeing how CAR-T improves over the next few years. There is certainly a lot of research that's looking into making it happen.

CAR-T: Behind the Scenes

Fierce Pharma published a story a few days ago about Kite Pharma, the makers of the CAR-T treatment Yescarta, also known as Axicabtagene ciloleucel or Axi-cel. It's one of the three different types of CAR-T treatments that are approved for use on Follicular Lymphoma patients. (The others are Liso-cel or Breyanzi, and Tisa-cel or Kymriah). I know I often write about CAR-T as if it was just one thing, but it's a class of treatments, with a bunch of different options, not just one treatment. It's like referring to "chemotherapy" when there are a bunch of different specific types of chemo. 

The story reports on an interview with Kite's Senior Vice President in charge of technical operations. I'm not suggesting Yescarta is a better version of CAR-T than the others (I have no idea which is best, and it probably depends a lot on each patient's situation). But I thought some of the behind-the-scenes information was really interesting, and gives some hope for CAR-T maybe being more widely available. 

If you're new to the world of FL, or in case you just need a reminder, CAR-T stands for Chimeric Antigen Receptor T-Cells. If you know your Greek Mythology, you know a Chimera is a monster made of parts of different animals (a lion, a goat, a snake, and a dragon). A Chimeric Antigen Receptor T-Cell is also made up of different parts.  

The Kite website has a cool short video on the process. Basically, T cells are removed from the patient. T cells are immune cells, so their job is to find and eliminate invaders like viruses. They can't find and eliminate cancer cells, though, because cancer cells are not "invaders" -- they are our own cells that won't die like they are supposed to. So the T cells that were removed from the patient are taken to a laboratory where they are changed by adding a CAR gene. The CAR gene helps the cells create a receptor -- a little spike on the surface of the immune cell. Normally, T cells have receptors that allow them to attach to antigens on the surface of the invader. The CAR gene creates a receptor that lets them do the same thing to a cancer cell. They find the antigen on the cancer cell and attach to it and eliminate it.

So after the T cells are changed in this way, they are grown in the lab so they multiply. They are then shipped back to the hospital and infused back into the patient. This whole process can take 3 to 4 weeks. Once they are back in the patient, hopefully they will work as intended. And the great thing about T cells is their memory. Months or years after they encounter a virus (or a cancer cell), they will remember the antigen and send a signal to the body to create more T cells with that receptor. So when CAR-T works, it can work for a long time from just that one dose.

CAR-T treatments are exciting, but they have some downsides. For one thing, they don't always work, either in the short term or the long term. When they were first approved, they were described as being unsuccessful about 33% of patients, successful for about a year for 33% of patients, and successful long term for about 33% of patients.  Those numbers have gotten better as CAR-T treatments have been developed, but they still certainly are not perfect. 

Another issue is the potential side effects, like Cytokine Release Syndrome, or CRS. Cytokines are basically those proteins that signal the body to make more T cells when an invader is discovered. But too aggressive a response from the immune system all at once can create unintended problems, even death. This was more of an issue when CAR-T was first introduced, but doctors have done a much better job of recognizing it and managing early on. (And CRS is an issue with lots of immunotherapies, including bispecifics.) 

One of the biggest issues, though, is the cost. Because this is a bespoke treatment -- the T cells can only be used for one patient -- CAR-T can cost up to $500,000 per dose. It's a one-time cost, and some studies have shown that a successful CAR-T treatment can actually end up being less expensive than three or four unsuccessful courses of other treatments like chemotherapy. But it's still a lot more than most health insurers or health systems are willing to pay when cheaper options are available. That seems to limit its use.  

Back to the behind-the-scenes article. Another issue with CAR-T has been in the manufacturing process. It's a tricky thing. The T cells have to be stored properly and then shipped to a specialized facility. Ideally, there would be lots of those facilities so the cells wouldn't have to travel too far, and there could be lots of patients helped all at once. But that takes some time and money, and without a large group of patients paying for it, the building was slow (for all of the companies that have a CAR-T treatment). 

Apart from buildings for laboratories, the CAR-T companies also dealt with the supply of viral vectors. These are viruses that are used to carry the genetic material to the T cells. Viruses survive by getting int healthy cells and then multiplying. Viral vectors are viruses that have been changed so they won't do harm, but will carry the new gene material to the cells. But they needed to be produced, too. The CAR-T manufacturers have been improving all of those processes. 

These are some of these behind-the-scenes issues that are described in the article. I think we forget everything that needs to happen to actually make a treatment. We see it in a bag on an IV stand, but it went through a lot to get there. 

The last issue that is discussed in the article is to me the most exciting. CAR-T manufacturers are working on "in vivo" versions of CAR-T. Right now, CAR-T treatments are "ex vivo," meaning "outside the living body." T cells are removed from the body and shipped somewhere else to be changed into a form that can treat cancer. And this all adds to the cost.

But an "in vivo" version -- "in the living body" -- is one where the CAR genes are put into the patient, where they can find the T cells and change them. This is a whole lot harder. "Ex vivo" T cells are isolated in a container, all by themselves. "In vivo" T cells are floating around in the bloodstream with lots of other cells, so the "in vivo" process needs to find them first, and then go through everything that happens now in a laboratory.  That's a big challenge.

But if they can overcome that challenge, it might change the game in big ways. The process would be much less expensive -- the patient is the laboratory. 

That's not going to happen anytime soon -- the interview mentions this process happening "over the next decade." But it would be a huge change to FL treatment. 

It's fascinating to me to look a little deeper into a process that we don't think much about. And I love to see how excited people are about possibilities. It's a constant moving forward.

There's so much to be hopeful about.  

 

FDA Designation for Kymriah CAR-T

I'm catching up on this:

A couple of weeks ago, the FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation for Kymriah (also known as tisagenlecleucel), a type of CAR-T therapy. This would be the first CAR-T for Relapsed or Refractory Follicular Lymphoma, if it is approved.

Let's break all of that down.

First, as most of you probably know, CAR-T stands for Chimeric Antigen Receptor (CAR) T-cell therapy. T cells are a kind of immune cell that do an excellent job of attacking invaders in the body. Cancer cells, however, are not invaders; they are our own cells that have been messed up so they don't know how to die like a normal cell. So T cells leave them alone. With CAR-T treatments, some of a patient's T cells are removed, taken to a lab so they can be changed to recognize cancer cells, and then put back into the patient, so they attack the cancer cells. Every treatment is made individually for a specific patient, so it's kind of expensive. Early CAR-T treatments work really well for some patients, pretty well for others, and not at all for some. But it shows huge promise.

(If you want to learn more about CAR-T, go to CAR-T and Follicular Non-Hodgkin's Lymphoma, a blog run by a CAR-T patient and a CAR-T caregiver. Good stuff.)

Right now, there are two CAR-T treatments that have received any kind of FDA approvals. The first is called Yescarta (also known as axicabtagene ciloleucel). It has been approved for some aggressive B cell lymphomas, including Transformed Follicular Lymphoma.

The second is called Kymriah. It has been approved for certain aggressive lymphomas and leukemias. But not Follicular Lymphoma.

The makers of Kymriah have applied for FDA approval, based on a Stage II clinical trial called ELARA. The FDA has granted a particular type of designation called Regenerative Medicine Advanced Therapy, or RMAT. This basically means that it is a type of therapy that is created from cells (like T cells), changes cells, or changes genes within cells. It was created to recognize that something like CAR-T is different from other types of treatments like traditional chemotherapy. the designation is only a few years old, but over 40 treatments have applied for it, which says something about where medicine is heading.

One last thing -- "Relapsed or Refractory" means the disease has stopped responding to the last treatment it received, or the last treatment just didn't work at all. This, to me, is the most important part of this approval. It means that anyone who has received treatment for Follicular Lymphoma would potentially be eligible to receive this CAR-T treatment, if it is approved. Right now, CAR-T is only available (outside of a clinical trial) to patients whose FL has transformed into a more aggressive lymphoma.

Now, a word of caution here. When results of CAR-T trials get announced, I see lots of people in online groups who say "I want this treatment! It looks great!" And they are right -- it does look great.

But it is expensive (roughly $400,000, from the numbers I have seen), since it needs to be created for each individual who gets it. It also can have some pretty rough side effects for some patients (though doctors have gotten better about anticipating them). And early trials found long-lasting effects for about 1/3 of patients, short-term effects (less than a year) for about 1/3, and no effects for the last 1/3. Those numbers seem to be getting better as researchers learn more about how CAR-T works.

But the point is, as with most FL news, there is a lot of great stuff in this, and it should give us a lot of hope.  But so far, there is no magic formula for FL treatment, and CAR-T doesn't seem to be. Keep that in mind in a few months when you hear about this being approved (assuming it happens).

But that doesn't mean this isn't worth being happy about.  Every arrow in the quiver is a victory for us. So I have hopes this this one will end up helping a lot of people, too.

CAR-T in Advanced Lymphoma

An article was published last week in Science Translational Medicine called "Immunotherapy of non-Hidgkin's Lymphoma with a Defined Ratio of CD8+ and CD4+ CD19-specific Chimeric Antigen Receptor Modified T-Cells." It has some people in oncology very excited.

The study involves lymphoma patients (including a few Follicular Lymphoma patients) who have had lots of treatments that just haven't worked. But this one did for a lot of them.

The main treatment is called CAR-T (Chimeric Antigen Receptor T-Cells). I've written about them before, and there are at least a couple of readers out there with direct experience. CAR-T is a treatment that is being used in a bunch of trials, with a lot of success.

Cancer cells are able to do their nasty job so well because they can fool the immune system into leaving them alone. Instead of seeing the cells as the unwanted invaders that they are, our immune system (which normally gets rid of invaders) just lets the cancer cells hang out like they are normal cells. CAR-T works by letting the immune system know that cancer cells are bad, and should be gotten rid of.

A cancer patient's T cells are collected. T cells are immune cells in the blood stream that track down invaders. They can recognize invaders because of the features on the T cell surfaces (called Receptors) match up with features on the invader (called Antigens). When a T cell Receptor finds something with an Antigen that matches it, the T cell destroys it. So After the T cells have been collected, they are changed in a laboratory, so they have a special Receptor that will recognize the Antigens on the specific cancer cells that it is after. (This is why they are called Chimeric Antigen Receptor T-Cells. A Chimera, is you remember your Greek Mythology, is an animal made up of different parts: a lion's head, a goat's body, and a snake for a tail. Made up of different parts, and deadly -- a good name for this engineered T cell.)

So the CAR-T cells are created in the lab, and then grown so there are a few billion of them, and then put back into the patient. If they do their job well, they look for the specific Antigen on the cancer cell and kill those cells. But even better -- like all T cells, they also multiply in the body and stay there, so if new cancer cells grow, they can wipe them out, too. It's a great example of Immunotherapy -- using the body's own immune system to defeat the cancer.

What makes this study a little different is the way they used the CAR-T cells.

First, they gave the patients a combination chemotherapy called Lymphodepletion, a combination of Cyclophosphamide (which is the C in the CHOP chemo combination) and, for some patients,  Fludarabine (another chemo drug which has fallen out of favor in recent years). They call this combination "Lymphodepletion" because the purpose is to wipe out some of the White Blood Cells in the blood (including some T Cells), because there are so many of them that there's no room for the CAR-T cells. This seems to have been a big improvement over other attempts at using CAR-T cells. The patients in the study who had the two chemo drugs before the CAR-T cells had much better results than those who didn't have them: a 72% Overall Response Rate, and a 50% Complete Response Rate (the others who didn't have the chemo had a 50% Overall response and just an 8% Complete Response).

The other big change they made in this study was in the type of T-Cells that they engineered into CAR-T cells. There are a few different kinds of T-Cells in the body, and they do different jobs. This study used a mix of Helper T Cells (the CD4+ in the title of the study) and Killer T-Cells (CD8+). As you can guess, Helper cells help other cells by secreting proteins that help with the body's immune response. Killer cells do the actual killing. Both are necessary for a complete response (there are other types of T cells, too, but these two do a lot of the work in the immune system). By making sure that there were the same number of Helper and Killer T-Cells in the CAR-T sample, the researchers increased the odds that the treatment would work.

So in the end, it study found that CAR-T results are improved when the patient first makes some room for the CAR-T cells with some chemo, and then uses the right mix of cells.

In my EFS12 post from a few days ago, an anonymous reader pointed out that about 80% of patients will probably die with FL, not from it, and that the other 20% will be helped by CAR-T and some other therapies. I absolutely share that enthusiasm. As I said, there are a lot of people excited about Immunotherapy, and CAR-T in particular, and this study seems to have hit on some ways of making CAR-T even more effective.

There's still a way to go, of course. This was a small study (just 32 patients), and there were some side effects (including Cytokine Release Syndrome, where the body is overwhelmed by dead cancer cells and can't clean them up fats enough). But there is a lot of reason to be hopeful, as researchers will continue to refine things and develop even more effective ways of using the body's immune system to protect itself.

CAR-T Hospitalization

Interesting research about the hospitalization of patients who receive CAR-T treatments.

First, a reminder of what CAR-T is, because it has gotten quite a bit of attention in blood cancer circles in the last few years.

CAR-T stands Chimeric Antigen Receptor T-cell therapy. It involves T cells, one of the types of immune cells in the body. T cells are one of the ways the body fights invaders, like bacteria and viruses. But cancer cells are not invaders -- they are part of the body that won't die. So T cells need to be taught to fight them. With CAR-T, some T cells are removed from the patient's body and changed in a lab so they will recognize and fight cancer cells. Then they put back into the body to do their job. One of the great things about the treatment is that T cells have a memory -- if they find an invader that they have already encountered, they will know to fight it again. So if a CAR-T treatment is successful once, it should keep on recognizing and fighting those cancer cells whenever they come back.

As always, if you want to learn more about CAR-T and Follicular Lymphoma, I highly recommend the site CAR-T and Follicular Non-Hodgkin's Lymphoma.

CAR-T also has some potentially bad side effects. When the body fights off and kills huge numbers of cells all at once, it can have a reaction called Cytokine Release Syndrome. This can be severe enough that a few early CAR-T patients died from it. Doctors seem to be better at controlling it now. CAR-T can also cause some neurological problems.

Because of the seriousness of the potential side effects, CAR-T patients often need to stay in the hospital after treatment. That's what two recent studies focused on. Both were published in Biology of Blood and Marrow Transplantation.

One of the two studies deals with very young people (under 25) who have had CAR-T treatment. I'm going to skip that one; it's extremely rare that a young person gets Follicular Lymphoma.

The other study looks at patients who at 18 and over; I think that covers everyone who reads this blog.

The study is called "Emerging Trends in Chimeric Antigen Receptor T-Cell Immunotherapy in Adults from the Vizient Clinical Database."

The study looks at data that is being compiled by Vizient, which tracks information about patients in clinical trials. They tracked 735 patients who had CAR-T between October 2017 and August 2018. For the study, they were interested in what kind of follow-up was needed by the patients. 61.5% of patients has Diffuse Large B Cell Lymphoma. About 4% had Follicular Lymphoma, and the rest had other blood cancers.

They found that the median hospital stay was 15 days, and the media cost of the stay was $82,059. (That's for the hospital stay only -- the treatment itself can cost around $400,000.) During the hosital stay, almost 70% of the patients had a reaction to the treatment, and 12% had other complications. Other side effects: 56% had fever, 55% had a change in blood pressure, 25% had nausea, 18% had headache or migraine, 15% had kidney failure, and 1.5% had in-hospital death. Within 30 days, 16% of patients had to be readmitted to the hospital -- 6% within 7 days.

I find the study interesting for a couple of reasons. First, I see a lot of patients online who get excited about treatments like CAR-T. They should be excited, in some ways. Early results are very good, and should get even better -- my oncologist said CAR-T will be improved in 5 yars as researchers learn more.

But CAR-T isn't a miracle. It works very well for about 1/3 of patients, pretty well (for about a year) in 1/3, and not at all for the other 1/3. Those numbers should get better. But they aren't there yet. And more importantly, as this study reminds us, EVERY cancer treatment has side effects. And some of them are severe. We have to expect some bad with the good.

Second, I find the cost analysis interesting. Vizient is a company that deals with analytics -- they look at data from clinical trials and elsewhere and help their clients deliver "exceptional, cost-effective care." Their job is to help businesses be successful in helping patients, but also do it for the least money possible. I'm not criticizing Vizient. But the study is a reminder that cancer treatment costs money. One of the big criticisms against CAR-T's manufacturers has been the cost of the treatment. The study is a reminder to me that, as treatments get better, cost is going to continue to be a factor. Patients aren't going to be able to bear that cost, so there will need to be some structure in place that helps them. Health care costs are going to continue to be a political problem. If you're looking for an issue to get excited and involved in, that's a good one.

So CAR-T has certainly given us some success. But like every other treatment, we still have a way to go.

CAR-T for NHL

OncLive has an excellent video series on CAR-T. They usually spread their video series over a couple of weeks, with a new installment every few days.

Today's installment is called "Expanding the Role of CAR T in Non-Hodgkin Lymphoma," and it features comments from Dr. Nilanjan Ghosh of the Levin Cancer Institute in North Carolina; Dr. Leo Gordon from Northwestern Memorial Hospital in Chicago; and Dr. Matthew Lunning from the University of Nebraska Medical Center.

This video is fourth in the series. The others cover some basic information about how CAR-T works, and some practical issues like cost. It's a good introduction to CAR-T. (And, of course, if you want to learn more, especially from a patient's perspective, you might consider checking out the CAR-T and Follicualr Non-Hodgkin's Lymphoma blog, run by some folks with first-hand experience as patient and caregiver.)


I found this video on expanding the role of CAR-T especially interesting. In one of the online groups I am in, someone complained this week about not being eligible for CAR-T because her disease wasn't aggressive enough. Lots of grumbling followed. People seemed to think that the treatment was being kept from them unfairly.

That is not the case. A couple of versions of CAR-T have been approved by the FDA, but approval, of course, is always for very specific situations. And for Follicular Lymphoma, that means patients with a particularly aggressive form, who have already tried a certain number of treatments.

There are trials that are looking to expand who can get CAR-T, but it's going to be a little bit of time before we know how well it works for those folks.

This particular video gets into some of the issues that surround making CAR-T available to me people. There are a couple of trials looking at CAR-T after the patient has had a transplant. There are questions about whether CAR-T could work for someone with MRD -- Minimal Residual Disease (in other words, how many cancer cells need to be around for the CAR-T to attack in order for it to work?).  Is it better to use this on POD24 patients (those who have the disease come back with 24 months after they have had chemoimmunotherapy)?

Lots of questions about CAR-T, and only time will give us the answers.

My new oncologist, Dr. H, thinks CAR-T will be much more effective in 5 years. We'll have more data from more trials, and we'll get a better sense of just who this treatment will work for. We've had lots of success stories so far (and a few failures). Maybe in 5 years we look forward to more of thsoe successes.

Click above for the video. If the link doesn't work (or if you need a transcript for translation), OncLive provided a very helpful transcript, which I am including below:




Nilanjan Ghosh, MD, PhD: One of the future directions for CAR T-cell therapy in relapsed/refractory B-cell lymphoma is to see if it can be moved up from second-line, and after failure of second-line to an earlier line. It has good activity in most patients, so this is a natural evolution. The question is, can it be compared to transplantation? There are 3 clinical trials that have been planned for this possibility. There’s ZUMA-1, in which axicabtagene ciloleucel [axi-cel] is being compared to salvage therapy followed by transplantation. There’s a trial called BELINDA in which CTL019 [Kymriah] is being compared to salvage therapy followed by transplantation. All these trials are going to see whether patients who are failing first-line therapy, have relapse, and thereafter can receive CAR T-cell products compared to other salvage therapies.

Leo Gordon, MD: The timing of CAR T therapy is an evolution. Currently, it’s for patients with refractory disease, but perhaps consolidation for patients with responding lymphoma who are high risk for relapse would be a good fit. Should it be used as consolidation for patients in complete remission? This begs the question: Do you need antigen in order for this to work? In other words, do you need some tumor present in order for CAR T-cell therapy to work? Will it work with minimal residual disease with no obvious antigens that are there for the CARs to attach to? We do not know the answer.

At the moment all the patients treated have had visible disease on PET [positron emission tomography] scans and physical exams. Whether it works in patients with no obvious disease, we don’t know. Saying it might be used as a consolidation treatment would probably be premature.

As we try and advance the use of these, ultimately the CAR T therapies themselves are going to be better; there are going to be better costimulatory molecules. There’ll be more educated cells that might be targeting a variety of different targets on tumor cells. Additionally, we’re exploring the so-called Platform study, which is being done with Celgene-Juno with the same JCAR017 molecule cell product. We’re looking at the use of adding certain agents to CARs, such as PD-L1 [programmed death-ligand 1] checkpoint inhibitors.

We’re looking at immunomodulatory imide drugs [IMiDs], a variety of other drugs that we think might enhance the efficacy of these CARs, perhaps by reducing the number of T-regulatory cells, which might get in the way of the CARs working. In the future, there are going to be better CARS and costimulatory molecules, and there will be perhaps the use of combinations of treatment—maybe radiation, which will help release antigens and make the CARs more effective radiations to certain sites of disease.

Matthew Lunning, DO: Clinical trials are ongoing in follicular lymphoma, mantle cell lymphoma, and chronic lymphomatic leukemia [CLL] looking at CAR T cells in these spaces. If you take each one of those diseases—it’s a spectrum—it’s just like large B-cell lymphoma. Patients with follicular lymphoma receive an anthracycline-containing bendamustine [Bendeka] regimen, which in the refractory setting is a front-line therapy that becomes more intensive in the second-line setting as the lymphoma progresses. This is an acceptable patient for CAR T-cell therapy, I think, on a clinical trial.

One could argue that a patient who relapses within 2 years from front-line anthracycline-based chemotherapy is a big deal. Fifty percent of those people are not alive in 5 years, and their likely cause of death is lymphoma. That’s a population in follicular lymphoma that I would want to study with CAR T cells. Mantle-cell lymphoma is another population I would like to study. It can definitely behave like the most aggressive lymphomas in the relapsed/refractory setting.

You have to be able to discern which one of these it is behaving like. The same thing goes for CLL. In mantle cell lymphoma, again, if you’ve gotten front-line chemotherapy and consolidated with an autotransplant, and you relapsed quickly after an autotransplant, that might be an area where CAR T-cell treatment would be a reasonable strategy. Some may argue that that patient should at least get a trial of ibrutinib [Imbruvica] tyrosine kinase inhibitor prior to going to CAR T cell.

The answer, if you look at the efficacy that’s been displayed across the 3 constructs, is that if it’s going to work, if it’s agnostic to double-hit or triple-hit refractory in 6 months, or after autotransplant, you can still see responses with durability in that patient population. Even in indolent lymphomas where you’re talking about that tough population, there may be the opportunity for efficacy, but you have to be mindful of the potential toxicity. It’s always a risk-benefit discussion with the patient and family regarding CAR T-cell therapy

More CAR-T at AACR

I'm writing about CAR-T again because I find it so fascinating.

And once again, OncLive has an interesting piece on CAR-T.

There has been some great news ab out CAR-T lately about clinical trial results, but this OncLive piece reports on additional infomation that we are learning about how CAR-T works. Researchers found two biomarkers that could help predict whether or not CAR-T will work well for particular patients. In other words, if researchers examine the cells, and they find that they have certain properties, that may predict whether CAR-T will work.

Before we go on, a little background to remind us f what we are dealing with.

CAR-T is not a single treatment. It's more of a general term for a treatment approach that several research terms are taking. CAR-T stands for Chimeric Antigen Receptor T cells. T cells are immune cells that attack invaders in the body in different ways. CAR-T involves removing those cells from a patient and changing them so they recognize and attack cancer cells the way they would attack a virus or other invader.

One of the biomarkers that researchers discovered is called Polyfunctional Strength Index, or PSI. Let's step back again for this one. T Cells do a lot of different things, and there are a lot of different types, with each type playing a different role in the immune system's attack against an invader. So, for example, there are Effector T Cells, which respond to the invasion; Helper T Cells, whicn help out other white blood cells; Killer T Cells, which do the actual attacking; Memory T Cells, which remember an invader so a more efficient attack can be made next time. There are others, but you get the point -- different T Cells do different jobs.

Except some don't do just one job, but two or more jobs. These are called Polyfunctional T Cells -- they serve many functions, or do several jobs. According to the research, having more Polyfunctional T Cells meant a better chance at a Response.

The other biomarker was post-infusion T Cell proliferation, or how much the T Cells multiplied after they were put back into the patient. One of the really great things about CAR-T treatments is that they take advantage of T Cells being living things. Unlike chemo or other treatments, where the amount of treatment stays the same after it is put into you, T Cells naturally multiply -- if the invader is big and bad, the body produces more T Cells to attack it. According to this research, the ability to cteate more T Cells is another good sign of a response.

Put those two things together -- T Cells that do more than one job, and T Cells that multiply well -- and you have an even better predictor that the patient will have a response to the treatment.

As I said, T Cells are fascinating to me, even when they are working normally. They can learn to detect an invader, remember what it is, and beat it up in the future. B Cells are fascinating, too. And what's even more fascinating is that my own are turning against me. And now we have some very smart people figuring out how to reverse that and have them work to protect me.

We have pretty amazing bodies, don't we?

And amazing people who are figuring out how they work.

effector, stimulatory, attractor, regulatory, and inflammatory, - See more at: http://www.onclive.com/web-exclusives/car-t-cell-functionality-correlates-with-outcomes-offering-a-biomarker-for-response#sthash.ui4zrnEB.dpuf

http://www.onclive.com/web-exclusives/car-t-cell-functionality-correlates-with-outcomes-offering-a-biomarker-for-response

Who Should Get CAR-T?

A few days ago, a video was released called "Who Should Receive CAR-T Therapy for Lymphoma."

It's a presentation by Dr. Caron Jacobson, from the Harvard Medical School and Dana-Farber Cancer Institute in Boston. She gave the presentation as part of the Great Debates and Updates in Hematalogical Malignancies virtual conference this past summer.

In the presentation, Dr. Jacobson goes through the results of some of the clinical trials for CAR-T use for lymphoma patients, as well as some "real world" studies of CAR-T that happened after it was approved by the FDA. Based on that data, she has some suggestions for which lymphoma patients might benefit from CAR-T.

I'm not going to go too deep into the data -- the video does that well, and it's fairly dense in the material presented, and a lot of packed into the 22 minute video. But I'll offer some highlights.

The message that I think Dr. Jacobson wants to get across is that CAR-T is "quite revolutionary" and more patients should be encouraged to try it. The message that I am getting is sightly less positive. More on that below.

Dr. Jacobson first looks at three trials, two of which (the Zuma-1 trial and the Transcend-CORE trial) involved patients with B-cell lymphomas. (The other involved patients with T-cell lymphomas, so I'm going to ignore that, since Follicular Lymphoma is a B cell lymphoma). Both trials involved patients with aggressive lymphomas (like transformed FL).

The Zuma-1 trial's CAR-T was Axi-cell, and 82% of patients in the trial had a Response, with 54% having a Complete Response. After 6 months, 41% maintained that Response, including 36% that has a CR.

The numbers for the Transcend-CORE trial, which used the CAR-T treatment called Liso-cel, 73% of patients had a Response, and 53% had a CR. There was not enough data to give a 6 month follow-up.

Dr. Jacobson also commented on the Zuma-5 trial, which looks at patients with Relapsed/Refractory indolent FL -- not aggressive or transformed, but just your regular old FL, the kind that most of us probably have. That data was presented at ASCO over the summer.  Results are great. After about a year of follow-up, 93% of patients had a Response, with 80% having a Complete Response. Of the FL patients in the trial, the response was even better -- 95% Overall Response, with 81% getting a Complete Response.

Those numbers stayed roughly the same in "real world" studies -- doctors who kept track of how patients were doing outside of clinical trials, after FDA approval. See the video for more on the actual studies, but the Overall Response/Complete Response for them were 70/50, 82/64, and 74/54, with one of them finding 41% of patients maintaining the response after 6 months (same as the Zuma-1 trial).

All of this sounds excellent, and it is. However, it gets trickier when we look at  toxicity -- the side effects that come with CAR-T.

In the Zuma-1 trial (the trial for aggressive FL), 93% of patients experienced Cytokine Release Syndrome, with 16% having grade 3 or higher (that is, very serious). 70% experienced neurological toxicities, or nerve issues, with 35% at grade 3 or higher. In the Transcend-CORE trial, 83% had CRS (9% grade 3 or higher), and 53% had neurological toxicities (17% grade 3 or higher).

As with all treatments, there were side effects, and sometimes very serious side effects. The good news, according to Dr. Jacobson, is that doctors have learned how to manage those side effects much better, and those numbers seem to be going down.

Dr. Jacobson also looked at data from patients who were not included in the trial. They received CAR-T, but the results weren't included in the data for lots of reasons, including that they had a "bridging therapy" -- that is, in between the time their T cells were collected and the time they were put back into their bodies, they received another treatment. This makes sense to not include them -- they got something "extra" that might have messed with showing how well the CAR-T worked. 

Those patients who received a bridging therapy were tracked anyway, and the data shows that the CAR-T didn't work as well for them, though it worked better than lots of other treatments. This might have been because their disease was already very far along, and the CAR-T was getting to them too late to hep as much as it could have.

That's really important information to have.

So, based on all of the data, which lymphoma patients should get CAR-T?

Well, CAR-T gave a durable remission (one that lasted longer than 6 months) to about 41% of patients with aggressive lymphomas. Among the reasons it didn't work? Patients has elevated LDH (the disease was behaving aggressively) or had co-morbidities (other health issues that might have influenced the outcome). 

So it seems like CAR-T works well for many patients with aggressive FL, but not too aggressive or too advanced. 

And for patients in the Zuma-5 trial (relapsed/refractory FL), 83% had a response that remained after 15 months. Longer follow-ups and a larger study are necessary, but it seems kind of intuitive here -- CAR-T works better on disease that isn't too aggressive, so maybe indolent, slow-growing FL is an even better target than aggressive FL? [That's a complete guess by me, someone who, I should remind you, is not a doctor or a cancer researcher.]

Dr. Jacobson is calling for more "real world" study of CAR-T, beyond trials, because trials can sometimes be too restrictive. That makes sense -- to compare patient responses accurately, you need clinical trial participants to be as alike as possible. But outside of a trial, after a treatment has been approved, it's easier to pay attention to other variables. Expanding access makes a lot of sense.

OK, so my take on all of this (again, recognizing that I am not an expert, just a patient who reads a lot):

I agree with Dr. Jacobson that CAR-T is "quite revolutionary," and has the potential to really change things for Follicular Lymphoma patients. I look forward to seeing what the FDA thinks about CAR-T for R/R FL patients, those with less-aggressive disease. I know my oncologist s excited about this, too, and thinks it could be a game-changer for FL.

However, we can't ignore a bunch of things: there needs to be more long-term follow-up for the Zuma-5 trial. Side effects of CAR-T, while becoming more manageable, can still be very serious. CAR-T is really expensive, and some health insurers may not like the idea of paying almost a half-million dollars for a treatment when cheaper options exist.

I'm saying this from a patient advocate perspective. I see lots of patients online who think CAR-T will solve all of our problems. And you know, it just might. But we have lots of hurdles to overcome until then. It might not work for everyone, it might not remain working for everyone, and it might not be available to everyone. 

That said, there is lots to be excited about, if we can keep a long-term perspective on things. 

(And since I plan to be around for a very long time, I think I can do that. I hope you can, too.)

 

CAR-T Information

I've across two very recent sources of information  about CAR-T that I'd like to share with you.

As I'm sure you know, CAR-T is a blood cancer treatment, and it's one that is getting a lot of attention lately. CAR-T stands for Chimeric Antigen Receptor T-cell. A T-cell is a part of the immune system. T-cells track down and fight infections (like viruses or bacteria) in the body. But they don't fight cancer cells. So to create CAR-T, some of a patients T-cells are removed from her body, and then changed in a laboratory so they will recognize cancer cells the same way they would recognize other invaders like viruses and bacteria. then they are put back into the patient, and they do their work.

(Personally, I really like that it's called "chimeric," which comes from Greek mythology. A chimera is a monster with a lion's head, a goat's body, and snake for a tale. I always thought that was a cool monster. The Chimeric Antigen Receptor does the same thing, squishing a few different parts into one cell, so it can find and attach to cancer cells and then attract T cells to the cancer cell. But it's a good monster.)

CAR-T therapy is one of those treatments that get oncologists very excited. It works for a lot people (including a couple of readers of this blog), though not for everyone. I read recently that about one-third of patients will have a long-lasting remission with CAR-T (including those two readers), one-third will have a shorter remission (maybe a year), and one-third will not get any remission. My own oncologist is one of those experts who is excited about it, and thinks that in about 5 years, we'll see a much higher effectiveness rate.

Like all treatments, CAR-T has side effects, including Cytokine Release Syndrome, in which the body reacts to so many cells being killed off at once. It can be dangerous, even deadly, though doctors seem to be doing a much better job of expecting this side effect and dealing with it right away. CAR-T can also cause some long-term nerve problems.

And right now, it is only approved in the U.S. for patients with aggressive blood cancers, including Transformed Follicular Lymphoma.

That's a quick look at the basics. Now, those two sources.

The first is a British documentary called War in the Blood, which is running on the British TV station BBC2. I follow a lot of folks in that part of the world on Twitter, and they are all very excited about this documentary. It follows two blood cancer patients who receive CAR-T, and it sounds like an amazing and uplifting piece of work.

Unfortunately for me, the link above will only let people in the UK watch online (and on BBC2). So all of you residents of the UK, please let us know if you've watched the documentary, and what you thought of it. And if anyone outside the UK has found a way to watch it online, or knows of when it might be on TV elsewhere (maybe BBC America?), let us know that, too. (In the meantime, I'll just go to BBC America and happily watch whatever Idris Elba show happens to be on.)

The second source of information is much more accessible: The local radio show Yale Cancer Answers just did an episode on CAR-T, and it is available online. You can either listen to the hour-long show, or read (or translate) a pdf of the transcript.

This link will take you to all of the Yale Cancer Answers shows, listed by date. The CAR-T show is from July 7, 2019.

The show is sponsored by the Yale Cancer Center, which is where I see my oncologist. The expert who talks about CAR-T is Dr. Iris Isufi (she is not my doctor, though she oversees a lot of the clinical trials at the hospital, and so is probably the most up-to-date person on new treatments at Yale). The show is meant for a non-medical audience, so they explain things very simply. I think it's as good an introduction to CAR-T as you'll find anywhere.

Of course, if you're looking for ongoing information about CAR-T, I highly recommend the blog CAR-T and Follicular Non-Hodgkin's Lymphoma, written by those two readers I mentioned above, Ben (who received CAR-T himself), and William (who is actually a caregiver for his wife, a CAR-T recipient).

Good stuff.

**************************

UPDATE 7/16/19: "War in the Blood" is now available on YouTube:
https://www.youtube.com/watch?v=0Nu2qe-Gf_c
Thanks to William for the link.

More CAR-T Awesomeness

Lots of people are getting excited about the things that CAR-T treatments can do. Just when you thought it couldn't get more awesome, a new study in Cell gives us reason more reason to be excited about CAR-T for Follicular Lymphoma.

(But before I go on, I want to thank a reader named Ben for sharing his experiences with CAR-T in the comments section of a post from a few weeks ago. I didn't get a chance to respond to the comment, which is a great mix of hope for the future of this treatment, and caution about some of the side effects. Please do read Ben's comment when you get a chance.)

The article is called "Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells." Here's what it says:

So far, CAR-T cells are used as ways to help the body's immune system recognize and attack cancer cells that would otherwise get past those defenses. T cells, which usually attack invaders, are removed from the body and changed so they recognize the cancer cells as invaders. It's been a pretty effective treatment so far (again, I suggest you read Ben's comment).

But CAR-T cells can do other things, too. Because they focus in on cancer cells, they can also be used to deliver things to those cells. It's kind of like RIT, which identifies cancer cells and delivers a tiny dose of radiation. CAR-T can deliver things that don't just kill the cell, but repair it instead.

The researchers know that many cases of Follicular Lymphoma cases involve a gene called HVEM. Whn HVEM is mutated (as, of course, it is with Follicular Lymphoma), it cannot interact with a protein called BTLA. When that happens, bad things happen -- cancer cells go crazy.

(This is another of those pathway things that we're learning more about. When everything is working OK, calls behave themselves. Mess with the pathway, and all hell breaks loose. It's like a fence that keeps pigs on a path between two pens. If the fence breaks, that path gets messed up, and the next thing you know, there are pigs all over town.)

So here's where CAR-T comes in. The researchers figured out that the HVEM gene can be repaired if the HVEM protein can be delivered to the cell.  The CAR-T cells can be told to find cells that have the CD19 protein on the surface, which is a protein Follicular Lymphoma cells have. When the CAR-T cells find it, they can deliver the HVEM protein to that cell, and the cell can be repaired. No more HVEM mutation, no more messed up pathway, no more cancer. The pigs stay in the pen.

But here's what makes CAR-T so amazing.

In addition to changing T cells in CAR-T cells, researchers were also able to program the cells to keep producing the HVEM protein. T cells are meant to find an invader and then multiply and find any other similar invaders. CAR-T cells are no different, and neither are these special CAR-T cells. They will keep producing that HVEM protein, finding other cancer cells, and getting the protein to them, too. One article calls them "mini-pharmacies" -- they keep traveling around and producing the treatment that the cancer cells need. Very cool. Because the CAR-T cells are delivering a protein that only mutated cells will need, the thinking is that healthy cells will be spared, and there will be fewer side effects.

As exciting as this is, right now, it has only been tried on animal models. No humans yet. But the researchers think that their work justifies carrying on with this approach to see how well it really works.

There's definitely reason for hope with CAR-T. As relatively new as it is, we're already seeing variations of it, like this one, that seem to improve on it.

Lots to look forward to.

New FDA Warning for CAR-T

There was some bad news for CAR-T treatments issued yesterday -- the FDA called for  "Black Box Warning" for CAR-T treatments. These would include the CAR-T treatments that have been approved for Follicular Lymphoma. 

This follows reports from November that some CAR-T treatments were leading to T Cell malignancies. In other words, with the treatment that involves changing T cells to find and eliminate cancer cells, those T cells could turn cancerous themselves. 

There's a lot to unpack here, and I'm trying to be rational about it all. 

First, the FDA's action. Issuing a "Back Box Warning" means they are adding a literal black box or border to the packaging insert of the treatment. The black box is meant to make it stand out and be noticed. The warning is considered the highest safety-related warning that the FDA gives, and it usually means that the treatment can lead to severe side effects. There are currently over 400 approved treatments, including many cancer treatments, that have Black Box Warnings, and the warnings can be changed or removed over time as new data becomes available.

The FDA warning came because a large number of patients who have taken CAR-T treatments have developed T cell cancers. In the letter that the FDA sent to manufacturers of CAR-T treatments, they said that they have become aware of this risk and that the new cancers have "serious outcomes, including hospitalization and death." How many patients have developed new T cell cancers? I can't find a definitive number, but it may be as high as 22. That doesn't seem like a lot compared to the thousands who have received treatment, but it's enough to issue the warning, especially since they develop over time. Doctors have been asked to be especially vigilant with CAR-T patients and continue to monitor them, even after they have been in remission for some time. 

The call for the Black Box warning isn't complete. The manufacturers have 30 days to respond to the FDA, with changes they will add to the labels, or a statement of why they think the label warning isn't necessary. 

So what does this mean for Follicular Lymphoma patients?

I'm not really sure. As I have said before, I'm not an oncologist or cancer researcher.

But really, I'm not sure even oncologists know at this point. It's very new, and they seem to be digesting the news (at least in the conversations I am seeing online).

Any new Black Box warning makes doctors take notice, obviously. They need to rethink the kind of risk/reward calculations that they always make when considering a treatment for a patient -- essentially, will this treatment create more problems than it solves? Every treatment has side effects, some more severe than others, some that affect certain patients more than others. That's not going to change. But they're going to have a lot more to think about.

Some interesting reactions online that I have read:

• This may lead some doctors to recommend CAR-T for older patients, if T cell cancers develop many years later, rather than younger patients who will be at greater risk.
• This may lead researchers to create "kill switches" on the T cells, so if they turn malignant, they can be more easily killed off (don't know if that's even possible).
• There is still a lack of data over the relationship between CAR-T and the new cancers. In other words, researchers are still looking to see if the T cells that were changed as part of the treatment are even the same T cells that turned cancerous. That's extremely important data to have. 
  
• At least one oncologist who I respect a lot says CAR-T will still be a great help to many of his patients, and that the new cancer is "low risk."
• Another said the rewards of CAR-T far outweigh the risks, especially since CAR-T is often used now for patients with "dire prognosis."

So as I said, I'm trying to be rational about it all. In my own case, CAR-T isn't something that my oncologist and I have discussed for me right now. Maybe that changes over time. And maybe by then, there's more data about this issue to help make a decision.

So, the same advice applies as always. Have an oncologist that you trust, and have honest conversations about treatment -- your goals, your fears, and your needs. Then make the best decision you can.

CAR-T

A couple of items related to CAR-T that are a little bit older, but worth looking at:

First, the online magazine CureToday has an article on CAR-T, specifically the ZUMA-1 trial that was reported on at the ASH conference in December, and in the journal Blood.

The article described the results from the ZUMA-1 trial, which looked at CAR-T in patients with aggressive lymphomas, mostly Diffuse Large B Cell Lymphoma (which is why I didn't write about it earlier), but also transformed Follicular Lymphoma (which is why I'm becoming aware of it now). I'll let you read the articles yourself, but basically, the patients were given a CAR-T treatment called KTE-C19, which targets lymphoma cells that have the CD19 protein on their surface. With a CAR-T treatment, the patient's T-cells (a kind of immune cell) are removed from the body, changed so that they recognize the cells with CD19, and then put back into the patient's body, where they hunt down the bad guys.(Lymphomation.org updated their section on CAR-T about a week ago; you can find some nice links there to find out more about the treatment.)

For cohort 1, the DLBCL patients, the results were excellent -- about 76% of patients (51 patients overall) had a response. Just as  importantly, the "manufacturing" process was successful, with 99% of patients being able to get their T cells changed and put back into their bodies. The average time for patients to receive their changes T cells was about 17 days, which is important because they were not all st the same site. And the CAR-T cells expanded within 14 days to the point where there were enough of them floating around to be able to do their job, the way naturally-occurring T cells do. So, lots of successes.

Cohort 2 included the transformed Follicular Lymphoma patients, and was much smaller -- 6 patients total, 3 of them with transformed FL. But the results were just as good. All 6 patients had a Complete Response, and all were still in complete remission after a median of 3 months of follow-up.

Now, 3 patients measured over 3 months is enough to give us some hope, but certainly not enough to make us think we have The Answer. This trial will continue, and I'm sure we all look forward to long-term results with a larger population.

Which brings me to another article: "Immunotherapy Cancer ‘Cure’ Headlines Distract from Fascinating Science." This was posted in the comments about a week ago by a reader named Popplepot (great name!) and it's worth revisiting. It was published about a year ago in the Science Blog published by the organization Cancer Research UK, soon after the first results from a CAR-T trial. The results were fantastic, and some of the experts commenting on it said things like "CAR-T might lead to a cure some day." Media reports heard the word "cure" and that became the focus, leaving out that the experts said "might" and "some day." The article reminds us of what makes CAR-T so fascinating (and it really is fascinating, given that it overcomes the basic problem with cancer -- why doesn't the body recognize cancer cells as invaders?).

But the Cancer Research UK article also makes us aware of some of the problems with early CAR-T trials -- they are small, and they also point to some nasty side effects (which resulted in a couple of deaths of patients).

So it's a good reminder for all of us to pay attention to some of the problems that come with new treatments. I know I'm guilty of this. I'm naturally upbeat and positive, so I ignore some of the negatives that come with reports of new treatments and clinical trial results. I'm working on it.

We're going to see more and more CAR-T results, I'm sure. Which reminds me of another reader's recent comments. William May, whose wife has had great success with CAR-T, was expecting the recent OncLive Peer Exchange video series to address CAR-T. It looks like they've moved on from Follicular Lymphoma treatments to CLL treatments, and no mention of CAR-T. I share your disappointment, William.

But that's OK. As I said, there will be plenty of stuff to read about CAR-T in the months and years to come. Looking forward to it.

(And thanks, Popplepot and William, for you comments.)

More Cool CAR-T News

I'm going to assume you read the last post, and learned all about CAR-T treatments. If not, go do some reading and listening.

Now that you have the basics of CAR-T down, here are a couple of other cool new studies about it.

The first is called "The Tyrosine Kinase Inhibitor Dasatinib Acts as a Pharmacologic On/Off Switch for CAR T Cells," published in Science Translation Medicine. As you may know, one of the real dangers of CAR-T is Cytokine Release Syndrome, which happens when the body reacts to all of those T-Cells swimming around and killing things. It can be deadly. Doctors are better about identifying and treating CRS before it gets too dangerous.

But this study has found a way to deal with CRS by temporarily turning off the T-Cells. Dasatinib is an inhibitor that is used to treat some types of Leukemia. Like all inhibitors, it inhibits -- gets in the way of a process that cancer cells need to survive. The researchers found that giving Dasatinib to CAR-T patients can turn off the T-Cells. So if the T-cells are working too hard, and the body is reacting by releasing too many Cytokines, the Dasatinib will turn off the T-Cells for a few days and slow down any CRS possibilities. When the Dasatinib wears off, the T-Cells go back to doing their job of finding and killing off the cancer cells.

The other study is called "High Rate of Durable Complete Remission in Follicular Lymphoma after CD19 CAR-T cell Immunotherapy," published a couple of days ago in the journal Blood.

This article reports on a phase 1/phase 2 clinical trial that used CAR-T on patients with Tranformed Follicular Lymphoma (which are the patients that have FDA approval for CAR-T), but also some with Relapsed/Refractory Follicular Lymphoma (they have not transformed, but their last treatment stopped working, or didn't work at all).

In the small trial, 8 R/R patients and 13 Transformed patients were given a chemotherapy combination of Cyclophosphamide (that's the "C" in "CHOP") and Fludarabine. Then they were given the CAR-T. Results were good: 7 of the 8 R/R FL patients had a Complete Reaction, and 6 of the 13 Transformed patients had a Complete Reaction. (There were no Partial Reactions.) All R/R Follicular patients who had a CR were still in remission after a media follow-up of 24 months, and the Transformed patients had a median remission of 10.2 months. Side effects were manageable and in line with what we've already seen with CAR-T.

To me, it seems like the big news here is the Relapsed/Refractory Follicular Lymphoma patients. CAR-T is not yet approved by the FDA for these patients, and this shows that it could be effective for this group.

HOWEVER, this is a very small study, with only 8 patients. It shows that it's worth doing more research on this group (which is already happening anyway).

Another HOWEVER: there is a lot of excitement about CAR-T, and it's worth being excited about. But the news is mixed, in many ways. Not all of the patients had a Response. In fact, is was 13 out of 21 who had a Response, or about 62% -- pretty good, but not a miracle cure. Same with duration -- many had a 2 year response, but many had less than that. Still good, but again, not a cure.

My point is this -- there is lots of to be excited about with CAR-T, and lots of research going on that is helping doctors figure out how to make it better. As I've said before, my own oncologist thinks that, in 5 years, CAR-T is going to be a lot more effective.

In the meantime, we can still be excited about it, and we'll keep an eye on all of the good research that's being done. And, as always, if you want to know more, I recommend the blog CAR-T and Follicular Non-Hodgkin's Lymphoma.

Happy reading!

ASCO Review: Lots of CAR-T Stuff

I had hoped to write something about what I learned on Day 3 of the ASCO conference, but I've been busy with work and I've barely had a chance to think about it. I did learn a lot that day, it had a lot to do with the place that patients have in the oncology community. I'll get to it.

For now, a quick look at one of the hot topics of the ASCO conference: CAR-T. There were dozens of presentations about various CAR-T treatments. Not all were about Follicular Lymphoma. But it's clear that CAR-T treatments are one of those approaches that oncologists are excited about, and are putting a lot of hope into.

(And looking back at what I write about day 1 and day 2 of the conference, it seems like most cancer folks are going with the "we should be excited!" approach to CAR-T form day 1, rather than the "we need to learn a lot more!" approach of day 2, which is interesting.)

So here's a quick run down of some more of the CAR-T stuff that came out of the ASCO conference (and this is just some, not all, by any means):

•  One of the ways around the high expense of CAR-T is by developing an "off the shelf" version. In other words, instead of a treatment that is made for each individual patient, there could be a version that works for everyone who wants it. Results of a phase 1 study trying to do that: "First-in-human data of ALLO-501 and ALLO-647 in relapsed/refractory large B-cell or follicular lymphoma (R/R LBCL/FL): ALPHA study." In a very small study of DLBCL and aggressive FL patients, patients were first given a treatment to wipe out most of their existing T cells. Then they were give the "off the shelf" CAR-T. Like personalized CAR-T, this one targets lymphoma cells. But the pre-treatment makes sure that the patient's immune system doesn't get in the way of the new T cells as they go after cancer cells. The treatment was effective (9 patients were evaluated, with 3 Complete Responses and 4 Partial Responses, for a 78% response rate). As a phase 1 trial, safety is a primary concern, and it was shown to be safe, with expected side effects. 9 patients is very, very small, but the results are enough to continue on a larger group. Definitely worth watching.
• Most CAR-T treatments involve targeting of the CD19 protein on the cancer cells. Those kinds of targets are common -- Rituxan goes after the CD20 protein. While targeting CD19 seems effective, some researchers think it contributes to CAR-T being able to work well at first, but then stop working. One presentation, "Safety and efficacy of optimized tandem CD19/CD20 CAR-engineered T cells in patients with relapsed/refractory non-Hodgkin lymphoma," described a CAR-T treatment that targets both CD19 and CD20. Two targets might be better than one. The study described a combined phase 1/phase 2 trial with 99 patients with several different lymphomas, incuding some with FL and transformed FL. Overall, the early results look good, with 84% getting a response after a follow-up of 13.5 months, and the treatment being fairly safe. If the goal, though, is to produce longer responses than CAR-T with only one target, then longer-term follow up is going to be really important. Another one to keep an eye on.
• On the other hand, there was one study of long-term follow-up of CAR-T patients, called "Long-term follow-up of anti-CD19 CAR T-cell therapy for B-cell lymphoma and chronic lymphocytic leukemia." The study describes a group of patients who were given early versions of CAR-T treatment at the National Institute of Health between 2009 and 2015 -- 43 patients in all. They had a variety of lymphomas, including 5 with FL. The overall remission rate was 76%, with 54% complete remission and 22% partial. Long-term side-effects were minimal. Of the patients who had a CR, 15 of the 25 were still in remission. While the long-term effects for some patients were excellent (the FL patients did especially well), they were still limited -- close to the breakdown I have heard (1/3 of patients have a long remission, 1/3 have a shorter remission, and 1/3 have no remission). But these are also patients who had an early version of CAR-T, and the treatment does seem to be improving as researchers learn more from patients who have had some version of it.

Lots more for me to work through. I'll start getting at the non-CAR-T stuff soon. As interesting and promising as it is, there is also some good information about other treatments for Follicular Lymphoma.

The Current State of CAR-T and Bispecifics for FL

Great article a couple of weeks ago from the journal Blood Advances, which is published by the folks at ASH. The article is called "The rules of T-cell engagement: Current state of CAR T cells and bispecific antibodies in B-cell lymphomas." 

This isn't giving a description of original research. It's one of those "Here's where we stand today" articles that sums up everything that's happening with a topic. In this case, it's looking at two types of treatments, CAR-T and bispecific antibodies.

If you've been a regular reader lately, you know that, at least in my view, the these are the two treatment types that get lymphoma oncologists/hematologists most excited. They have been around for a few years, so their effectiveness is pretty well-known. And there is more and more research happening to improve them in different ways, whether by finding new targets for them or reducing their side effects.

A quick reminder: CAR-T stands for Chimeric Antigen Receptor–modified T cells. CAR-T works by removing some of a patient's T cells (a type of immune cell) and changing them in a laboratory so they more easily recognize cancer cells. Then they are put back into the body and allowed to do their job. It's been a very successful treatment for many (though not all) patients. CAR-T can have some severe side effects, though as CAR-T is used more, oncologists are getting better at identifying them and trying to manage them.

Bispecifics are different. They are made up of two parts (that's why they are called "bi," meaning "two." One part seeks out a protein found on the surface of a B cell, similar to what Rituxan does. But the other part seeks out a protein on a T cell (there's that immune cell again). By bringing the T cell next to the cancer cell, it allows the T cell to eliminate it. This also can have some serious side effects, and has also been very successful for many (but not all) patients.

The article provides some of this background, but also looks specifically at which CAR-T and bispecific treatments have been approved for use with certain types of lymphoma. Of course, Follicular Lymphoma is one of those types, which is why I'm writing about it.

As the chart from the article shows, there are three CAR-T treatments approved for FL (at least in the U.S.) -- known as Axi-cel, Tisa-cel, and Liso-cel. And there are two bispecifics currently approved -- Mosunetuzumab and Epcoritamab. The chart shows which line of treatment they have been approved for (it's third line or later for all five of them, at least for now), gives some data about effectiveness (the Overall and Complete Response Rates), and some information about safety (the percentage of patients who experienced particular side effects).

It's a really nice chart (if you're into that kind of thing. And I am.)

There's also a bit of a longer discussion for each of the different types of lymphoma, and the section on FL is very interesting. 

The authors talk a little bit about sequencing of treatments. For advanced or bulky disease, they usually go with immuno-chemotherapy (something like R-CHOP or B-R, I assume), if that seems appropriate for the patient. They typically go for R-squared (Lenalidomide + Rituxan) for a second treatment. And then they express their happiness that CAR-T and bispecifics are now available for a third line, which have greatly increased the options that patients have.

I appreciate their careful discussion of third-line treatment decisions. As they say, neither CAR-T nor bispecifics are shown to cure FL, so patient choice becomes very important. And there are lots of factors to consider, from cost (CAR-T is much higher) to side effects and quality of life. They also mention that younger patients might prefer CAR-T, since there is a greater chance of it being a "one and done" treatment. Patients who have transformed might also prefer CAR-T, since it is very effective against transformed FL.

Finally, the article describes some of the current and future research happening with CAR-T and bispecifics. This includes using either of them in combination with other treatments, using bispecifics after CAR-T as a type of maintenance, and using either of them as a first or second line treatment.

As I said, it's a good article in that it brings a lot of stuff together in one place, and it's clear why these two are so exciting. I don't have a sense of whether there are other types of lymphoma treatments being developed that also use T cells to go after B lymphocytes, but my guess is that with the success of these two treatments, there are plenty of ambitious and innovative researchers who are looking.

The bottom line is, once again, that we have options, and there are more coming. That should make us all a little bit happier.

Managing CAR-T Side Effects

I don't think my friends at the CAR-T and Follicular Non-Hodgkin's Lymphoma blog have gotten to this one yet, but they'll forgive me if I look at it first.

Some folks at MD Anderson, along with colleagues at some other institutions, have published "Chimeric Antigen Receptor T-cell Therapy — Assessment and Management of Toxicities" -- a plan for watching and responding to the potentially fatal side effects that can come with CAR-T therapy.


CAR-T has been in the news in the last few weeks because the FDA approved the treatment for some Leukemia patients. CAR-T thrapy involves removing a patient's T Cells (part of the immune system that attacks invaders) and changing them so they can recognize cancer cells as invaders and take care of them. The results in clinical trials have been excellent -- good enough to justify FDA approval, with more approvals possible in the future (including one, potentially, for some Follicular Lymphoma patients).

The problem with CAR-T is some of the side effects. In a way, CAR-T can work too well.

The potential side effect that causes the biggest problem is Cytokine-Release Syndrome, or CRS. CAR-T has been called a "living cancer treatment," because unlike something like  chemical treatment, T Cells do their job by not just attacking invaders, but by overwhelming them -- when they sense an invader, they signal to other T Cells to attack. So an effective response means a whole army going against the invaders.

Those T Cells are activated by Cytokines, which are proteins whose job is to signal cells. The problem is, the Cytokines signal the T Cells, which then produce more Cytokines. Which signal more T Cells. Which produce more Cytokines.

The body can usually keep this cycle in check, so it doesn't cause too many problems. But sometimes it can't do that. And this results in CRS. The body is overwhelmed by Cytokines and T Cells. At best, it can make the patient feel really horrible (like having the flu, I have read). At worst, it can be fatal, and there has been at least one patient in a CAR-T trial who has died as a result.

Another side effect is neurotoxicity, or toxicity that affects the nervous system. CAR-T treatment can cause a specific type of neurotoxicity called CAR-T-cell-Related Encephalopathy Syndrome, or CRES. This affects the brain in particular.

These very nasty side effects have been dealt with since CAR-T treatments (and other Immunotherapies) have been in trials.

The folks at MD Anderson and their colleagues looked at published studies and about 100 patients to develop a system for identifying CAR-T side effects early, and dealing with them quickly before too much damage occurs. Cytokine release Syndrome does not have to be fatal, but it does have to be treated quickly to keep the worst from happening.

The system involves monitoring the patient for symptoms, grading the symptoms (determining how severe they are), and treating immediately. The treatment could involve "aggressive supportive care, anti-IL-6 therapy, and/or corticosteroids for severe cases." Anti-IL-6 are antibodies that target the Interleukin-6 Cytokine. Corticosteroids are commonly used to stop allergic reactions. Basically, the treatments are used to slow down the immune system response.

Interestingly, one researcher who was not part of this team pointed out that other approaches are also being used in other places, and that the ways to deal with CAR-T side effects are still evolving.


So while there is no guarantee that the system will stop a CRS reaction, but I find it comforting that there is a system being recommended. Lots of very good minds worked together for this, and it sounds like even more good minds will keep working to make it better.