Helping Create a New Treatment

I mentioned a few posts ago that a lot of what I write about, I get from Google Alerts. And the Follicular Lymphoma-related sites that I am alerted to can be anything from medical journals to business analysis to local news. Last week, I got another one of those local news articles that i thought was worth sharing.

The article is from a local news site called the Tri-Cities Area Journal of Business in Washington state, and the article itself is called "Richland native has hand in development of new cancer drug."

It's a short piece about a woman named Jackie Tyler, who grew up in the area, went to school to study biomedical engineering (she was fascinated by Biology and Chemistry, but knew she didn't want to be a doctor or nurse). She went to graduate school, and then got a job with the company Genentech. After a couple of years, she was put on a team that was developing a new cancer treatment. After 7 years, that treatment was given FDA approval last December -- the bispecific Mosunetuzumab (also known as Lunsumio). 

Her job on the team is as a technical development principle scientist. She works with the molecules in a drug to figure out what should be added to it to make the drug stable as it travels from the manufacturing plant to the hospital or clinic, and from a shelf to the patient. 

A few things kind of struck me from the article.

First, she was on the team for 7 years. It takes at least that long to develop a treatment and get it through clinical trials to approval. It probably takes even longer -- I've heard it's about 10 years for most treatments. Mosunetuzumab maybe was a little faster because it received accelerated approval. 

Second, did you ever think about something shelf-stability in a treatment? I focus on effectiveness and safety, and I imagine scientists in lab coats working hard at it all, but I never really thought about a whole separate team working on making sure that the treatment doesn't "go bad" before it gets to a patient. That's a whole different level of safety and effectiveness -- whatever gets added needs to work, but also needs to be safe.

I think many of us who are cancer patients, or who deal with any kind of chronic health issue, probably have mixed feelings about the companies that make drugs of all kinds. Especially in the United States, where so many people have to pay their own bills for their health, or might be denied by an insurance company because a particular treatment costs more than they are willing to pay. Pharma companies make lots of money from their products, and making money is obviously their goal.

But the company isn't the same as the people who work for it. I've had the opportunity to speak to a whole bunch of people who work for pharma companies, from Vice Presidents on down to entry-level workers. And there are definitely some people whose job is to make sure that the company makes money, and that's their priority. But so many others got into their jobs for personal reasons -- a relative with cancer or another disease, and they decided to devote their own lives to improving others' lives.

It's nice to read a story like this one, and remember that there are dozens of people involved in a process that brings a treatment to us. I'm grateful to them.

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.

Treatment Options for Relapsed/Refractory Follicualr Lymphoma

The website OncLive is doing one of their video series on CAR-T and Lymphoma. It's a follow up to the discussions of CAR-T from the ASH conference a couple of weeks ago. The conversation is between DR. Marc Hoffman from the University of Kansas Cancer Center and Dr. Loretta Nastoupil from MD Anderson Cancer Center.

The series looks at CAR-T in all lymphomas (especially DLBCL), but two of the videos are devoted to Follicular Lymphoma.

The first video is called "Available Treatment Options for R/R Follicular Lymphoma." At the start of the video, Dr. Nastoupil asks Dr. Hoffman to walk her through current treatment options for Relapsed/Refractory FL and where CAR-T fits in. Dr. Hoffman smiles and "This is a really complicated question." 

That seems like a bad sign for Follicular Lymphoma -- none of us want our cancer to be complicated. (But we also know how true it is.)

But there's a good reason for it being complicated -- basically, there are lots of options. With an aggressive lymphoma like DLBCL, CAR-T makes a lot of sense. It's probably the best option for an aggressive lymphoma. But for patients with FL, that might not be the case -- some of us have a more aggressive version when it returns, and some of us don't. And it's hard to identify those patients from the beginning. For a patient who is transformed or POD24, then CAR-T makes sense. For other R/R patients with FL, maybe another option would make more sense, and save CAR-T for those who need it later (maybe because they are refractory to Rituxan or to a chemo like Bendamustine or CHOP). 

So, according to Dr. Hoffman, about 20% of R/R FL patients will need CAR-T right away. About 35% or so would do fine with a less aggressive treatment -- maybe just Rituxan. The complication comes for those "in the middle." They don't have an aggressive disease, but don't have an indolent one, either. there's no easy answer. Dr. Hoffman says in those cases, his question is "What's your appetite for toxicity?" In other words, there are probably going to be options that have more mild side effects (more mild -- every treatment has side effects), but won't last as long, but CAR-T may have harsher side effects but last longer until another treatment is needed (if it's ever needed).

All of those percentages are based just on his experience with FL patients, but I think the approach makes sense, and I appreciate his involving the patient in the decision. He says that he has "very few takes" for CAR-T in Follicular right now. If he presents it as a kind of risk/reward decision, I can see why. They seem to want something milder that allows for a decent Quality of Life, rather than taking a chance with one big shot.

It's a very interesting insight. I think most of us who have been able to watch and wait have a kind of mindset that lets us live with the disease and be at peace with it. It will be interesting to see how many patients choose CAR-T in the future, when the options are laid out for them in this way.

The second video in the series is called "CAR-T Cell Therapy for Patients with R/R FL," and gets more directly into what happens when patients do make the choice to go with CAR-T. There are now two options for CAR-T for R/R FL, and while the two types are very similar, there are some differences. Dr. Hoffman finds that when people are ready to make the choice, they have already done their homework and know a lot about the choice they are making. He thinks more patients will pt for bi-specifics than for CAR-T, based on what we know about the two choices right now. 

The final challenge is how to sequence treatments -- what to offer first, and then second, and then third (if a patient needs a series of treatments over time). One issue, for example, is how Bendamustine might affect T cells. The order becomes important.

I think there are probably one or two more videos in this series. It's worth watching. Dr. Hoffman and Dr. Nastoupil seem like great oncologists who focus a lot of their patients' needs. If nothing else, they are a great reminder that we should be making sure our doctors ask what we want and need from treatment, and listen to us when we tell them.

 

Looking Back at the Rituxin Era

The Follicular Lymphoma Foundation published a short article by its Chief Medical Officer, Dr. Mitchell Smith, looking back at the "Rituxan Era" in Follicular Lymphoma. It's aimed at patients, and it has a very hopeful message.

The Follicular Lymphoma Foundation was started just a few years ago, with the main purpose of trying to cure Follicular Lymphoma. the foundation raises money and the  gives it to researchers to help them keep their work going. You can read more about them at their link.

Dr. Smith wrote his article, "25 Years in FL -- The Rituximab Era," in response to the article in the Journal of Clinical Oncology last month that celebrated the 25th anniversary of Rituxan being used as a single agent for Follicular lymphoma patients. Rituxan (also known as rituximab and Mabthera) has been a hugely important treatment for FL patients. There have been great improvements in Overall Survival and Progression Free Survival for FL patients since Rituxan was introduced. (To give you an example, when I was diagnosed 15 years ago, the median Overall Survival for FL patients was considered to be 8-10 years, and that was based on old data from before Rituxan's approval. Now it's generally considered to be about 18-20 years.)

When researchers look back at the history of FL, they often talk about the "Rituxan Era." Chemotherapy became widely used after World War II, so we had about 50 years of the "Chemotherapy era." With Rituxan's approval, we are now 25 years into the "Rituxan Era." (It will be fascinating to see what cancer historians have to say 25 years from now -- are we in the "CAR-T Era" and we don't even realize it? I plan to be around in 25 years, so I'll let you know.)

In his article, Dr. Smith shows just how influential Rituxan has been. Think about it. Rituxan can be sued as a single agent, by itself (which is how I had it, and it's given me 13 years of not needing treatment). It has been recognized as making traditional chemotherapy better (which is why most patients get R-CHOP instead of CHOP, or R-B instead of just Bendamustine). It was the basis for RIT, RadioImmunoTherapy, where a small drop of radiation is attached to Rituxan, and then delivered to cancerous cells. And now it's the basis for bi-specifics, where a Rituxan-like antibody can deliver a T cell directly to the cancer cells.

Check the links to the RIT and bi-specifics. They're both from 2022. Rituxan continues to play a huge roll in Follicualr Lymphoma treatment.

And that doesn't even get into the other monoclonal antibodies and biosimilars that are based on Rituxan.

Pretty amazing. 

In the past, I've written in this blog about "My Best Friend Rituxan." I was being playful, but it's clear that we all owe a huge debt to this treatment, and to the many many people who have done research on it -- and continue to do research. 

Can Diet Cure Lymphoma?

I came across an article from the Cleveland Clinic, and excellent hospital in Ohio, with this very provocative title: 

"Can Diet Cure Lymphoma? Foods to Eat and Avoid."

Before we go any further, I'll give you the answer: No. Diet can't cure Lymphoma. That's the answer in the article, and it's the answer that any other article that's actually based in science will give you. Other answers are probably trying to sell you something, or are being very optimistic. But as much as I'd love to tell you that eating tons of broccoli or tumeric or something else will cure your Lymphoma, there's no evidence that shows that it will.

I have mixed feelings about that title. It's very close to being "clickbait," the kind of title for an online article that promises something that it doesn't deliver. I don't think a hospital should be doing that. 

On the other hand, if the point of clickbait is to get you to read, then maybe it's a good thing. If someone is looking online for information on diet and Lymphoma, better that they get accurate information from the Cleveland Clinic than from someone who is telling a personal story about their experience. 

(If you've never read such a story, they go like this: "I have eaten a bean sprout sandwich, and nothing else, every day for two years, since the day I was diagnosed with Follicular Lymphoma, and my FL has not progressed. In fact, my nodes have gotten smaller."  But the problem is, FL is slow-growing, and nodes can shrink on their own, so the bean sprout sandwich doesn't have anything to do with it. And as I written before, I have a hamburger and french fries about once a week, because it makes me happy. But I'm not going to claim that I've gone 13 years without treatment because of red meat and fried foods. That would be ridiculous. But it's the same logic.)

So what does the article say about diet?

A few really good, useful things.

Some diets can help prevent cancers like Lymphoma. (That's prevent them -- keep you from getting them. That's not the same as curing them once you have them.) Diets that are heavy in plants are especially good for you. The article recommends the Mediterranean Diet. Lots of fruits and vegetables, legumes, whole grains, nuts and seeds, and fish. Cut back on red meat, animal fats, and sugar. (And yes, I know I just told you that animal fats and red meat make me happy. Do as I say, not as I do.)

Also, if you're in treatment, it's important to eat a healthy diet. If your treatment makes it heard for you to eat, then eat the things that you are able to. Fruits and vegetables are especially important -- find the ones that you like. And if you are losing weight, focus on calorie-dense foods like nuts and full-fat diary.

In addition, diet is important after treatment as well. For many patients, treatment results in muscle loss. More protein can help get it back.

As for supplements, if a patient is eating a healthy diet, then supplements probably aren't necessary. But it's important to pay attention to Vitamin D levels, says the article.

Finally, the article mentions some diets that Lymphoma patients should NOT follow, especially if they are in treatment. These include the Keto diet, which the Cleveland Clinic says s the opposite of what they recommend for some Lymphoma patients. Also not recommended: an "alkaline diet," where a patient only eats non-acidic foods, on the theory that cancer likes an acidic environment. But the body doesn't work that way -- it keeps a balanced pH (not too acidic and not too alkaline) no matter what you eat. Diet just doesn't have that kind of effect. Other diets that people read online can be problematic because they don't provide a balance of nutrients.

The bottom line: Our bodies are complicated. And cancer is complicated, too. As much as I would love to be able to eat one thing, or avoid a few things, to cure my cancer, it's just not that easy. If it was, we'd all be cured by now.

And as helpful as this article is, the best person to talk to about all of this is your oncologist. As I've said many times, I am not a doctor or a cancer researcher. Don't take cancer advice from me alone. Your oncologist can offer advice about diet, or can get you the name of a dietician who can work with you. Lots of cancer hospitals have Survivorship offices that offer just this kind of advice, so ask if it's available to you.

But if you want my advice, then here it is -- eat healthy all week and get some exercise every day. And when you do have that hamburger once in a while, don't feel bad about it. You have enough to worry about.

The Biology of Follicular Lymphoma

I know a few of you are very science-literate, and can understand some very dense science about cancer, and especially about Follicular Lymphoma. I consider myself pretty science-literate -- good enough to understand the basic ideas and explain them to others, even if the details can be a little fuzzy for me sometimes. (Though you should trust that if I don't understand something, I'll either tell you so, or I just won't write about it.)

With that in mind, I want to share the basics of a really important article from the ASH Education Program, which provides on specific topics. The article is called "Biology of Follicular Lymphoma: Insights and Windows of Clinical Opportunity." For those of you who are Science Nerds, and can understand the science, I encourage you to read it. If that's not your thing, I'll do my best here to give you a summary.

It's an important article because it's about as up-to-date as you'll find on the biology of FL -- the basics of what happens to our genes, our cells, and what surrounds them, and why it makes Follicular Lymphoma such a tough cancer to deal with.

The main point of this article is that Follicular Lymphoma is a heterogeneous cancer -- it can take a slightly different form for each patient, and one patient's cancer can change over time. It's kind of a constantly moving target. It's why (as is true for lots of cancers) one FL patient can get a great response to a treatment, and another can get no response at all. That's because FL has both a genetic and epi-genetic component. In other words, problems with our genes can cause FL, but the Tumor Micro-Environment (TME) -- all of the things happening around the cancer cells -- can create problems that keep the cancer cells alive.

The good news is, in the last 10 years especially, researchers are identifying more and more genetic and epi-gentic issues with FL. And identifying them, and then figuring out how they affect the FL, can lead to new and effective treatments (though they can take years to develop, test, and approve).

A little more detail, if you're interested:

About 85% of FL patients have a genetic mutation involving t(14;18) translocation, leading to BCL2 overexpression. In other words, two pieces of our DNA switch places. When that happens, a switch gets turned on, and a gene called BCL2 (which stands for B Cell Lymphoma 2) stops doing its job. As a result, B Cells stop dying. And the result is a B Cell Lymphoma like FL.

What complicates things is that there are more genetic mutations that can come into play. The article has a nice chart to show them all, and how common they are (anywhere from 6% to 40% of FL patients might have one of these mutations -- are several of them, which is one of things that makes it hard to stop FL).

 

Another complication of all of this is what these mutations do. A lot of them affect the cancer cells' behavior, in terms of growing and staying alive. The signals that tell a cell to die off are never received, and the cells just keep living and dividing.

The other complication is that the mutations also mess with the immune cells that might normally go after a rogue cell (different types of T cells). So the cancer cells don't just multiply; they also create an environment that makes it much harder to kill them off. And that contributes to FL being considered incurable -- those cells can just hang out for a while and become activated again years later.

Another complication -- as those cancer cells stick around over time, they can develop new mutations. The likelihood of that happening is really hard to detect at diagnosis. This may be why some FL can transform to a more aggressive lymphoma, and why it's hard to predict which patents' cancer will transform.

The bad news is, FL is a really complicated disease, and there are lots of factors that influence the type of FL we will have and how it will behave over the long term.

But the good news -- and I think it's really good news -- is that researchers are identifying those factors and figuring out how to develop treatments that target those factors, whether they are genetic or epi-genetic. They take time to develop, maybe years, but they're coming.

A lot of what we need to do is just be patient and wait. Most of us with FL get used to all that waiting.

But if you want to be a little more active, talk to your oncologist about the kinds of  clinical trials that are nearby, and that your doc might think would be appropriate for you, if and when the time comes for treatment. That's the only way new treatments can get developed.

I hope some of you will take a closer look at the article. To me, it's fascinating, and knowing what's happening to my body just makes me feel more empowered.