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.  

 

Cancer-Sniffing Dogs

 New from the Journal of Clinical Oncology: "Canine Olfaction Combined With Bayesian Modeling for Multicancer Detection From Breath Samples: A Phase II Study in India."

Of all the ways to detect cancer, the best has to be dogs who can somehow smell it.

(I know, I know -- the "best" is the cancer detection test that works the best at detecting cancer. But a colonoscopy doesn't love you unconditionally. That would make a great slogan on my Lympho Bob t-shirts, if I actually had any for sale.)

I'm fascinated by cancer-sniffing dogs. This study took place in India. The idea is that training dogs to sniff cancer might be especially helpful in what the authors call "low and medium income countries."  Cancer detection can be very expensive. Dogs will work for very little -- a couple of biscuits and a pat on the head.

Seriously, though -- as the authors point out, dogs have been trained to sniff cancer for 30 years. The first known cancer-sniffing dog was standard schnauzer named George, who was able to detect skin cancer. Studies that looked at cancer-sniffing dogs have mostly been small, and have taken place in higher-income countries. 

For this phase 2 clinical trial, 3275 patients were enrolled. 1773 were used in training the dogs, and 1502 in the actual testing. For the tests, patients breathed into cotton surgical masks, which were then stored at -20 degrees Celsius. 283 of the patients actually had cancer -- one of seven types (head and neck, breast, lung, gynecologic, upper and lower GI, and genitourinary cancers -- there were no blood cancers among them). Each mask was sniffed by three different dogs, and the collective results were combined.  The dogs correctly detected about 90% of the samples with cancer, and about 91% of those without cancer. They were just as accurate with stage I and II cancers as with later stage cancers -- important for those cancers where early detection can increase survival.

You might not have access to the JCO article, so you can read more about it here. The company that did the testing is called Dognosis. They are working on a system that will use AI to help pick up the signals that the dog is giving. (If you've ever trained a dog to do any kind of scent work, you know it can be hard to pick up their signals on your own.)

And if you're wondering what breeds of dogs were involved, they were four Beagles, one Labrador, one Labrador-Indie mix, and one Dutch Shepherd-Belgian Malinois mix. There was less than 2% variation between the dogs, meaning it really didn't matter which dog was doing the sniffing. They all did equally well in detecting the cancers. 

The reason I find all of this so fascinating is because I have owned two standard schnauzers -- like George, the first cancer sniffing dog. Our first, Strudel, was about a year old when I got my cancer diagnosis. If she noticed anything, she didn't let me know. Our current dog is Katara, who is 5. She didn't say anything about either of my skin cancers. Maybe I just haven't been listening very well.

 

We've actually done some scent work training with Katara, just for fun. And we've learned a lot about how sensitive dogs' noses are -- about 10,000 times more sensitive than a human's nose. Out trainer explained it to us this way: when we humans smell a chocolate cake, we smell a chocolate cake. But a dog can smell the flour, the eggs, the sugar, the cocoa, etc.  Their noses are really amazing instruments.

So if you have a dog, give them an extra hug today on behalf of all the work that other dogs are doing for us.

 

 

Epcoritamab + R-Squared (+ Pharmacists)

In my quest for some Follicular Lymphoma-related reading material during this slow news time, I found an article in Pharmacy Times called "Epcoritamab Plus Lenalidomide and Rituximab in Practice: A Focus on EPCORE FL-1." 

As you can guess, Pharmacy Times is aimed at pharmacists, the folks who manage and sometimes advise on medications. That's the angle that makes it kind of interesting.

It's mostly a summary of the EPCORE FL-1 clinical trial results. EPCORE is the general name for a series of studies that have looked at the bispecific Epcoritamab. The EPCORE NHL-1 study looked at patients with several types of Non-Hodgkin's Lymphoma who were treated with just Epcoritamab. The EPCORE  FL-1 study is the one described here, and is the one that got people very very excited at last year's ASH conference.  This trial involves only FL patients, and combines Epcoritamab with R-Squared (Rituxan + Revlimid, also known as Lenalidomide).

The article provides a good overview of all of the successful trials for Epcoritamab, and especially for EPCORE FL-1. This was a phase 3 global study, with 488 patients from 30 countries. Patients had refractory or relapsed disease and had previously received a monoclonal antibody + chemotherapy. Patients were divided into two groups: one received R-squared and the other received R-squared plus Epcoritamab. 

Results were very positive. After a median follow-up of 14.8 months, The Epcoritamab group had a 95% Overall Response Rate (versus 79% for the R-squared only group). Most other measures were better in the Epcoritamab group did better than the R-squared only group -- including Progression Free Survival, Duration of Response, and Time to Next Treatment. It's easy to see why people were so excited at ASH.

Safety was also good, with low white blood cells counts (neutropenia) and infections being the most common side effects. Cytokine Release Syndrome, a major concern, occurred in 26% of patients, but all cases were manageable. Other side effects are described in the article. This isn't really providing any new data, just a summary of what was already reported.

What I found so interesting, though, were the "pharmacy" aspects of the article.

For instance, the article goes into some detail about dose escalation, something that gets mentioned in most oncology articles, but not in much detail.

In the EPCORE FL-1 trial, the dosing was changed partway through. At first, patients received a smaller dose first, and then a larger second dose. But in later studies, it was divided into three steps instead of two, so patients received it more gradually. Researchers think this probably helped lessen the severity of some side effects, including CRS. 

It also goes into some detail about "premedications" -- intravenous hydration, an antihistamine, an antipyretic (like acetaminophen), and corticosteroids (preferable dexamethasone) -- as well as "postmedications," including two to three liters of oral fluids within 24 hours after receiving Ecoritamab, plus corticosteroids (dexamethasone again) for 3 days.

I can picture an oncology pharamacist reading the results of the EPCORE FL-1 in an abstract, and thinking "That's nice, but what were the premedications?!" 

And I say that with great admiration, from one amateur Cancer Nerd to a professional one.

I don't really think about the role that pharmacists play in our treatment. 

When I had my Rituxan infusions, I had a blood draw first. Then I met with the oncologist to make sure everything was OK and I was well enough for the day's dose. Then I went to the treatment room, where the excellent Nurse Sue took care of me for a few hours. But somebody had to prepare the Rituxan. Somebody had to worry about my premedication hydration and the antihistamine I needed when I had an allergic reaction. 

It's kind of cool to think that there's someone else behind the scenes, keeping an eye on things. The size of our care team is really large.

I don't ever remember talking to a pharmacist when I needed treatment, but education is certainly a job for pharmacists, and the article discusses the role that pharmacists can play when a patient needs education about any of the medications that are a part of this treatment process. 

It's just kind of nice to have a broader perspective on things. It's one more person who cares about us, and who is looking out for us. We're lucky to have these hidden angels.  

Laughter Yoga

We're in that slow period now, as far as Lymphoma news goes. It's about six weeks until the ASCO conference, and I think researchers are holding on to all of their "good stuff" now, hoping they will make a big splash at that conference. But it's also too early for ASCO abstracts to come out, so there's nothing to read there.

What's a Cancer Nerd to do?

Go out and find something interesting, I guess.

I came across an article today about Laughter Yoga. It was emailed to me by a Public Relations group. I get lots of press releases about health issues from PR groups, and most of them have nothing to do with what I write about. I guess technically, this didn't have anything to do with it either -- not cancer or lymphoma. But I do take a yoga class once I week, and I certainly like to laugh, so I thought it was at least worth reading.

The email describes an article from the journal BMC Pediatrics called "Healing with laughter: the therapeutic power of laughter yoga in pediatric health – a systematic review."

The article describes research laughter yoga and its benefits for children. It's a review of several studies involving a total of 305 children who were taught laughter yoga.

So what is "laughter yoga"? It's a practice that combines laughter and playfulness with breathing exercises and mindfulness. It's not necessarily what many of us think of as yoga -- no downward facing dogs or warrior poses.  But it does focus on other things that are familiar to yoga practitioners, like mindfulness and breathing. 

I you would like to see Laughter Yoga in practice, here is a nice video from the Mayo Clinic. And this one from Celeste Greene reminds us to be playful for 5 minutes. No jokes -- just deliberate laughter. They made me laugh just watching them. But, honestly, I'm a very easy laugh. Ask my wife. 

The article collected data from studies about children, and it found some positive results. The children who practiced laughter yoga had a reduction in anxiety and stress levels. It did not seem to have an effect on clinical depression or self-esteem. But it did show an increase in Salivary Immunoglobulin A (SIgA), a measure of immunity. 

So there is definitely some good that comes from laughter yoga, at least for children.

I haven't looked into whether laughter yoga helps adults in the same way, but I can guess that it does. Laughter is a known stress relief, as is some deep breathing. It all kind of makes sense. 

So this is your reminder to stop every now and then and take a deep breath. And if you can, find something that makes you laugh. It might not help, but it certainly couldn't hurt.

In the meantime, I'll keep looking for any little gold nuggets of Follicular Lymphoma news that might be hiding out there.  

Take care of yourselves. 

 

Biomarkers for FL Relapse

The American Journal of Clinical Oncology published a very interesting article a couple of weeks ago that described research on biomarkers in Follicular Lymphoma. The article is called "Surveillance Strategies in Follicular Non-Hodgkin’s Lymphoma’s Using Molecular and Genetic Markers Improve Cost-efficiencies Over Routine Imaging Studies."

The idea behind the research is that we have a difficult time identifying patients who may transform or have POD24 (Progression of Disease within 24 months). Right now, about 80% of FL patients have good responses to treatment and then experience long survivals. But about 20% either transform or relapse after treatment within two years, and this 20% tends to have a shorter Overall Survival. 

The tools we now have to identify these folks are not very effective. They include things like FLIPI,the Follicular Lymphoma International Prognostic Index.  The FLIPI was never intended to be used as a tool to guess the likelihood of an individual patient's survival. If you take this little quiz, you'll see that it includes things like age, which is kind of useless -- thousands of people live long long lives with FL no matter what their age at diagnosis. The FLIPI index was developed many years ago, and has not been very effective in identifying that 20% of patients.

Over time, other prognostic models have been developed that look at factors that are a little bit more personal. For examples, the m7-FLIP which took the original FLIPI and added some possible biomarkers. This was an improvement, but still didn't completely identify that 20% as well as it was hoped. Too many of those high-risk FL patients were only identified after they transformed or relapsed within 24 months.

Other newer prognostic tools were developed in the years after that, like POD24-PI, PRIMA23, and ICA13. The authors of the article look at how effective they have been. Like m7-FLIPI, they do a good job, but not a perfect job, being anywhere from 43% to 86% effective.

The researchers looked at all of these models and essentially tried to find the best parts of them. Each prognostic model was developed from research tat looked for biomarkers, and those studies were all looking for (and finding) slightly different things. So looking at all of the data together might find some places that they overlap or that they do things that the others don't do.    

In the end, they came up with a model that they say is more comprehensive than the other models, and may do a better job of identifying high-risk patients as early as diagnosis. At this point, patients need to transform or relapse before they know for sure that they were in the high-risk group.  Identifying them early will allow doctors to possibly treat them more aggressively, and may in the future help to point researchers toward new targets for new treatments. 

The research team identified 10 biomarkers that seemed to only be present in high-risk FL patients. They did this by looking at data from patients who relapsed over a 14 year period. The biomarkers usually involve genetic mutations, which make them easier to identify.  

Of course, research like this is based on past results, so it's hard to know how effective it will be in actual patients at diagnosis. That's how these things often work -- it seems like it will be effective, but then they discover something else that their model hadn't picked up. And if that happens, that's OK -- that's how science works, and any step forward is great. But it does seem like this could be a step forward for a group that needs some help. 

I find it interesting that this study is being framed in financial terms. As the title says, a more effective model might "Improve Cost-efficiencies Over Routine Imaging Studies." In other words, a fairly simple genetic test that identifies a high-risk patient early on will mean fewer blood tests and scans and biopsies, and all the cost that goes with it. 

Lower costs are certainly important, and goodness knows that financial toxicity is a major problem for cancer patients. But all of the other benefits that come with improved prognostics matter even more  -- better Quality of Life, better mental health, and most importantly, improved Overall Survival. 

I'm hoping we see more data from this research in the next year or two as it gets applied to patients who are diagnosed now in the future.  I'll certainly be keeping an eye out.

 

When You Need to Take a Break

A long-time reader added a comment on my post about visiting the Grand Canyon last month. I always like to hear from people who have been reading for a while. 

This reader also pointed out that lately she has been stepping back from reading about Follicular Lymphoma. And that's good news, too.

It made me think about a message I got from a reader several years ago. I don't remember now if it was a comment or an email. But the reader apologized for not being in touch for the same reason as the recent commenter -- he was just not thinking about FL as much as he had.

I remember telling him that an apology wasn't necessary. It was an excellent thing that he had stepped back from reading and thinking so much about the disease.

This is one of several reasons why I don't monetize this blog. No advertisements. No subscriptions. No sponsors. No merchandise.  I know lots of health advocates who do those things, and I wish them luck. I know some of them have health issues that make it very hard for them to hold a full-time job, and the monetizing of their online accounts is an important source of income for them. I know I'm very fortunate to not have to be in that situation. 

But I also know that monetizing this blog would change things. A lot. For one thing, I'd be panicked every time I had a reader say that they were stepping back from reading so much about FL, and scrambling to figure out how to keep them. I don't want to have to put that much energy into this. I already put enough into it. 

It's always interesting to look at this blog's analytics -- the data that Google sends me about readers. To be clear, I don't receive any information about you as an individual. Unless you tell me who you are in a comment or an email, I have no idea who is reading the blog. 

But I do get information about how many people have accessed the blog every day, and I can see how many people from a particular country have read that day. (I've had readers from over 80 countries, which is really very cool to me.) So sometimes I will see a sudden spike in the number of readers from a particular country, and then maybe I'll get an email from someone in that country. I can make the connection -- that reader and maybe members of their family have gone back and read a few years' worth of entries. And then the activity from that country dies down. Maybe after a few weeks or months, I don't get much activity at all from them. 

I can see the rhythms of readership. Sometimes I get a whole lot of readers. Sometimes I don't get many. And then I get a lot again. 

And that's fine with me. When someone is newly diagnosed, they are looking for information. I'm happy that I can be a trusted source for them. Maybe I get lots of comments from them, maybe some emails. I welcome all of them. I love hearing from readers and I'm happy to help in any way I can, even if it's just listening to your story. (But I can't give out medical advice, because I'm not a doctor.)  

And that's the nature of this disease for many of us. It comes to us as a surprise, and it grows slowly enough that we can just not think about it much after a while. As much as I love to hear from readers, I also love to hear that someone has "graduated" and they don't think about me and the blog anymore. I don't take it personally. I recognize the rhythms.

For those of you who do drift away, go with my blessing. And if we've had some long communications by email in the past, but not in the present, know that I think about a lot of you and wonder how you are doing. I assume you're doing well. I'm tempted to email you sometimes to check in on you, but I also know that if you're in a good place, you probably don't need the reminder about the disease that you would get from me. 

So please drift away if you need to. I don't need the readership. I love having it, but I don't need it.

I plan on being here for a while.

Take care, everyone. 

 

Treatment Selection in R/R Follicular Lymphoma

The oncology website OncLive has another of their interesting video series on Follicular Lymphoma. They post these every few months -- a small panel of experts discussing issues related to FL. A lot of times, they discuss current treatments. I find it helpful to hear different Lymphoma specialists talk about how they handle particular situations, and explain their reasoning. 

The current video series is called "Optimizing Sequencing Strategies in R/R Follicular Lymphoma," though so far they only have one video posted. It's called "Navigating Treatment Selection in R/R Follicular Lymphoma," and as the title suggests, the Lymphoma experts talk about some of the factors that they consider when they are deciding on treatment for a patient who has Refractory or Relapsed disease (that is, the treatment they already had stopped working or didn't work at all).

The experts are Dr. Loretta Nastoupil from Southwest Oncology in Colorado, and Dr. Amitkumar Mehta from the University of Alabama - Birmingham. This is just the first part of a longer conversation, but they still had some good things to say.

Their focus here is on how they make decisions about which treatments to consider for a R/R FL patient. Dr. Nastoupil lists a few factors that she considers. She points out that FL is a very heterogeneous disease -- each patient is different. She says she sees patients in their 30s up to their 80s. Those groups will have very different goals. Some patients are extremely fit, with few comorbidities or other health issues to consider, which some are very frail. Some may have received single agent Rituxan (like me) while others had aggressive treatment that may have caused additional health issues. And of course, there is the issue of patient preference. Some patients want an aggressive treatment that gives them a chance at a very long remission. Others might prioritize a less aggressive treatment that does not affect their day-to-day lives as much but also is likely to mean treatment will be necessary within a few years. All of those factors make it hard say that there is an ideal second treatment.

Dr. Mehta briefly discusses the treatment landscape. He points out that two approved treatments have been pulled from the market for different reasons (PI3K inhibitors and Tazemetostat), but that some newer treatment regiments are also very promising. (He teases two of them, and says they will be discussing them later, probably in another video in the series. I assume they are Epcoritimab + R-squared and Tafasitamab + R-squared.) He says that in choosing a treatment, he tries to balance several factors -- how effective the treatment is, what kinds of side effects can be expected, and how those things  fit with a patient's individual goals. 

(I always like when Lymphoma experts make a priority of patient goals.) 

The rest of the series should be very good. It's not necessarily a presentation of anything new. That's usually how these video series work. It's more of  summary of where we are. I think that's really valuable, too.

One more thing that's worth pointing out. Dr. Mehta makes a comment about patient survival. He said when he was in training, they used to say that FL patients had a 10-15 year median survival. (He must be young. It was 8-10 years when I was diagnosed.) But he says that FL patients these days will probably have a "normal life span." Think about it. If the typical FL patient is 60-65 years old, and FL has a median Overall Survival of 20 years, that puts you right into the average lifespan of someone in the U.S.

And for you younger folks, remember that "median" means the midpoint. So if the median OS for FL is 20 years, that means half of FL patients will live longer than 20 years. I was diagnosed at 40. I fully expect to live to a normal life span. Dr. Mehta attributes this to having more and more effective treatments for R/R FL than we had in the past.

I've mentioned this before, and it's worth mentioning again.  Several years ago, I had a reader tell me that her oncologist said "If we can keep an FL patient alive for 5 years, we can keep them alive for 50." It's the same logic as Dr. Mehta's. The number of available treatments these days is so much greater than when I was diagnosed 18 years ago. We have options. And we have even more options being developed all the time.

That's what I like most about these videos. They give me hope.