Manufacturing CAR T Cells

The National Cancer Institute, the leading cancer research organization in the United States, put up this video a few days ago on CAR-T.

It's pretty interesting. And since the last two posts I have written were about CAR-T, I was hoping this one would make a perfect third. Given the title, "Manufacturing CAR T Cells to Accelerate Cancer Immunotherapy Research," I was hoping it would explain how CAR-T cells are made. If you look at any Lympho Bob post about CAR-T, I always skip over the part about what happens between taking the T cells from the patient and then putting them back in. 

Alas, when the video gets to that part, the voice over says, "If that sounds complex, that's because it is."

Hmm. Not much help.

But what is helpful is what they have to say about the future of CAR-T. 

Right now, there aren't many places in the U.S. that can make CAR-T cells. As you  might imagine, it takes a special kind of lab to do something like this. 

The NCI, being a part of the federal government, has been an important part of creating a central place where CAR-T cells can be made. Cells that are taken from the patient can be sent to the NCI, where they can be changed and sent back to the patient in about 7 days. For comparison, the article on the ZUMA-5 trial that I posted a few days ago said the media time to get cells back to the patient was about 17 days. Big improvement. One large facility can do the job better than a bunch of small ones.

The video says this is "baby steps" and that more work will need to be done to refine the system. 

But it does seem like a step forward. Right now, making it easier to manufacture CAR-T cells means more hospitals can take part in clinical trials. Eventually, that should man CAR-T can get to more people with more types of cancer. 

But I would hope that it could also mean it will become less expensive. We'll see.

Whatever the case, it's more evidence that the excitement about CAR-T was justified, and more resources are being put into making it better, cheaper, and more widely available.

And that's good for all of us.

ZUMA-5 Trial: Car-T for FL

The ASCO Post, a newsletter for the American Society for Clinical Oncology, has a nice piece on the ZUMA-5 trial. ZUMA-5 is a clinical trial that looks at CAR-T for indolent lymphoma, particularly Follicular Lymphoma.  It's worth reading. 

Data from ZUMA-5 was presented at the ASH conference in December, and it was very good news. This article doesn't present any new data, but it does go into a lot more detail than the ASH abstract gave.

Much of the commentary in the article comes from Dr. Caron Jacobson of the Dana-Farber Cancer Institute in Boston.

As I wrote about in my last post, CAR-T has had some success in more aggressive blood cancers like Diffuse Large B Cell Lymphoma and transformed Follicular Lymphoma. There are three different versions of CAR-T that have been approved by the FDA for these aggressive lymphomas. They are also in trials for use on indolent, slow-growing lymphomas, like the Follicular Lymphoma that most of us are dealing with. The ZUMA-5 trial is one of them.

The phase II trial 146 patients, including 124 with Follicular Lymphoma. The patients were first given conditioning with Fludarabine and Cyclophosphamide, two chemotherapy agents (Cyclophosphamide is the "C" in CHOP).  As with all CAR-T, each patient had some T cells (a kind of immune cell) removed. The T cells were changed so they recognized the cancer cells as something they should go after instead of ignoring. Then they put back into the patient so they can do their work.

The Overall Response Rate for the Follicular Lymphoma patients was 94%, with 89% getting a Complete Response. The treatment works a little bit slowly, with a median response rate of over 1 month. After 2 months, some of the patients who had a Partial Response ended up with a Complete Response.

The response rate for these indolent lymphoma patients was even better than it has been for the aggressive lymphoma patients. Dr. Jacobson said the researchers weren't sure why, though they think the conditioning agents (the chemo they got before the CAR-T) might have helped some. 

After 17 months, the median duration of response hadn't been reached yet. In other words, more than half of the patients (64%) were still responding to the treatment -- the cancer hadn't come back yet for them.

As far as safety goes, about 86% of patients in the trial had serious side effects, including drops in blood cell counts, and increased rates of infection (as white blood cell counts drop, the immune system is weakened). One patient in the trial died due to Cytokine Release Syndrome. Still, Dr. Jacobson thinks it is possible to eventually give the treatment on an outpatient basis, meaning the patient wouldn't need to stay in the hospital.

Like all treatments, the side effects can be problematic, though from what I have read, as more patients receive CAR-T, doctors are getting better at anticipating and treating them. 

My guess is that we will see some updated results about this in a few months at the ASCO conference.

As great as CAR-T has been for many patients with aggressive forms of Follicular Lymphoma and other blood cancers, it's exciting to think that a treatment with such a high response rate might be available to more us in the fairly near future. 

One more thing to be hopeful about.

Another CAR-T Approval

More FDA approval news that is meaningful for Follicular Lymphoma patients.

Last week, the FDA approved the CAR-T called Breyanzi (also known as Lisocabtagene Maraleucel) for certain types of aggressive B Cell Lymphomas, including grade 3b Follicular Lymphoma, as well as Transformed Follicular Lymphoma. The approval includes only patients whose disease is refractory or relapsed after at least two previous treatments (that is, those treatments didn't work, or did work but then stopped working). 

The grade 3b FL approval is kind of a big deal. Grade 3b is an unusual variation of FL. It is still officially Follicular Lymphoma, and hasn't transformed to another lymphoma, but is more aggressive than grade 3a, and acts like a more aggressive lymphoma like Diffuse Large B Cell Lymphoma. It isn't usually grouped with more aggressive lymphomas, but it isn't like slow-growing indolent lymphomas, so patients with grade 3b can be in a sort of limbo sometimes. So it's great that they are being included in this group.

 I won't get into what CAR-T is too much, other than to say it involves removing some T cells (a type of immune cell) from the patient, manipulating them in a laboratory so they recognize cancer cells as something that the immune system should go after, and then returning them back into the patient's body. Early CAR-T treatments showed a lot of promise, and they seem to be getting better all the time. If you want to know more about CAR-T and Follicular Lymphoma, I recommend this site. 

The approval means that there are now four different CAR-Ts approved for blood cancer, with three of them being available for some Follicular Lymphoma patients.  While the approvals are for more aggressive versions of FL, there are very promising results recently for CAR-T for slower-growing FL, and for first treatments (rather than for relapsed and refractory disease only). I'm sure we will hear more about them in a few months at the ASCO conference. I hope it turns out to be one of the big stories that gets talked about by experts.

Of course, as promising as CAR-T is, it has its share of side effects, some of them potentially serious. The FDA approval for Breyanzi was based on a clinical trial involving 192 patients. The Overall Response Rate was 73%, including 54% Complete Response and 19% Partial Response. The median duration of response for 16.7 months, but for those with a Complete Response, the media hasn't been reached yet (which is good  -- more than half have not had the disease return yet). 

But then there are the side effects. Almost half of patients had Cytokine Release Syndrome of some kind (an immune response that can be fatal, as it was for one of the patients in the trial). There were also nerve-related side effects (some very serious) and  blood count issues. Almost half of patients had what were considered "serious" side effects of some kind.

Still, despite the side effects, the treatment was approved, which suggests that the side effects maybe have become more manageable over time.

As a press release from the Leukemia and Lymphoma Society puts it, this approval "further solidifies immunotherapy as a mainstay in cancer treatment." As researchers are finding new ways to use our immune systems to control and beat cancer, we'll certainly see more treatments come our way.

Yet more to be hopeful about.

Umbralisib Approved by FDA

More good news for Follicular Lymphoma patients:

A few days ago, the FDA approved Umbralisib (also known as Ukoniq) for FL patients who have tried at least three other treatments. 

Umbralisib is a PI3K inhibitor. It is the fourth PI3K inhibitor approved for Follicular Lymphoma -- the others are Idelalisib, Duvalisib, and Copanlisib, which I just wrote about last month). They all work by blocking, or inhibiting, an enyzme called PI3K, which is part of a chain of enzymes and proteins that tell a cancer cell that it's OK to keep growing. By inhibiting it, Umbralisib (like the other inhibitors) turns off that switch and allows the cell to die like a normal cell.

The four inhibitors work the same way in general, but PI3K takes a few different forms in the body, and the different inhibitors work on one or more of those different forms. So there isn't necessarily a lot of overlap between them. They all do a slightly different job.

(Which one is best for you and your Follicular Lymphoma, should you come to a place where a PI3K inhibitor might be an option? No idea. Talk to your oncologist. She or he will know.)

The approval was granted based on a phase 2 trial that included 117 FL patients. (It was also approved for a different type of blood cancer with patients also included in the trial.) The Overall Response Rate for the FL patients was 43%, with 3% of patients getting a Complete Response. The median duration of response was just over 11 months.

Those aren't spectacular numbers compared to some other treatments. One big difference, though, is that is might be safer than other PI3K inhibitors. While it does have similar side effects, it will not come with a "black box" label, which indicates very serious side effects. That said, it still has side effects, including diarrhea, fatigue, nausea, and increased risk of infection, among others. And 18% of patients reported in the trial had serious side effects, especially diarrhea and infection.

My guess (and this is, of course, not coming from a doctor or cancer biologist) is that Umbralisib will end up being used in combination with some other treatment, and those numbers for effectiveness will increase.

The good news, though, is that there is another arrow in the quiver -- another treatment option -- for lots of Follicular Lymphoma patients. And another reason for hope.

World Cancer Day

Today, February 4, is World Cancer Day. 

I know for many of us, every day is "cancer day." But World Cancer Day is an opportunity for people around the world, dealing with many different types of cancer, to stand together (figuratively), and let others see the scope of the disease. The day is put together by the UICC, the Union for International Cancer Control, a group made up of 1200 cancer organizations in 172 countries. Truly world-wide. 

I like the theme for this year: "I Am and I Will."

The idea isn't that an "awareness" day is about being aware. It's about taking action. Ideally, the folks at UICC want us to take action in a larger sense -- doing something in our community that raises awareness and helps move toward finding cures for cancer. When we take actions locally, it all adds up to something global. There's so much misinformation about cancer of all kinds that pointing people to good sources of information, or even sharing our own story, is an important part of "awareness." We can do our part.

But to me, that "I Am and I Will" goes a little bit farther. By making others aware, we strengthen ourselves. It's so easy, as cancer patients, to feel like we have no control over our situation. It's tru that there's a lot we can't control. But there's lots that we can.

I speak from experience. Writing about Follicular Lymphoma, telling my story, learning about the disease, responding to emails from readers -- all of those things are empowering. My lymph nodes will do what they're going to do. But helping others understand the disease so they can have an informed conversation with their doctor? I can control that.

So think about ways that you can tell your story, share your knowledge, and make a difference, whether it's talking to other cancer patients, or other people who could use some help understanding what the cancer experience is about. That's what real awareness is.

Enjoy the day.

The Nest is Empty Again

My wife and I are "empty nesters" again. All three of our kids have moved out of the house, back at school.

When the pandemic started last spring, two of our kids were in college, out of state. Our daughter was fairly close, about 90 minutes away. Our middle child was in school about 5 hours away. And our oldest had finished college and was living by himself and working in the big city nearby. 

Once Covid started, our younger kids' colleges sent them back to us. They spent the rest of the spring taking classes online. Then our oldest came home, too. Since he was living by himself, it didn't make much sense for him to be in his apartment all alone, isolated.

We'd been by ourselves my wife and I, for just a few months, and we were enjoying the time together.

But for the spring, summer, and fall, we had a full house again. And that was nice, too. It's always nice to have the kids around, especially as adults, with their own opinions and beliefs and interests,  and ways of wishing the world was different.

About three weeks ago, our oldest left for graduate school, about 6 hours away. He'll be near family, which is nice.

The middle child left on Saturday. He's back at school, 5 hours away, studying bugs and forests and coyotes, and looking forward to what comes next, after he graduates in the spring.

And on Sunday, we drove our daughter to her school. They aren't letting everyone back, but there were some spaces for students who wanted to live on campus, and she got one of them. She needed the change of scenery. All three of them did.

And it's a little scary to let them go during a pandemic. But we know they will be as safe and smart as they can be, and that their lives have to go on. There schools have strict rules about wearing masks and staying distant, and we know they will follow the rules. We have a Zoom meeting scheduled with all three of them for every Sunday night. Last night was the first one. It was nice to see their faces. They seem to be doing well.

But it's still a little scary.

As for us, we're still working from home, which we are fortunate to be able to do. We're being safe, and reading the news every day about when we might be able to get a vaccine, Soon, we hope.

The good thing about all of this is that we're already used to watching and waiting that's become a part of our pandemicized lives. We know what it feels like to be "in between," not really living the life we used to have, but not really being able to live the new life that's ahead of us. It's not our favorite place to be. But there's at least a little bit of comfort in the familiar.

So we look forward to whatever good things might come next, and we try not to worry about the things we can't control. 

I hope you all find ways to stay comfortable and at ease.

Back to cancer stuff soon.

Copanlisib for Follicular Lymphoma

A couple of Copanlisib-related items have come across my screen in the last few days, so I thought I'd share.

First, to remind you (since Copanlisib hasn't been in the news much lately, from what I have seen):

Copanlisib (also known as Aliqopa) is a PI3K inhibitor. PI3K is short for phosphatidylinositol-3-kinase, which is an enzyme that cancer cells depend on to grow and live. By inhibiting it, or stopping it, cancer cells don't get the signal that they should stay alive, and so they die. There are a few PI3K inhibitors approved for FL, but Copanlisib is thought to be better in one way -- it works on two of the three different forms of PI3K in the body (others only work on one of them). It has been approved by the FDA for relapsed FL patients who have tried at least two other treatments.

As I said, it's not in the news much lately, though it usually gets mentioned by name when lymphoma experts talk about non-chemotherapy treatments and the future of Follicular Lymphoma. (Search this blog and you'll see what I mean.)

The first thing that came around this week was an article from the journal Cancer Management and Research called "Copanlisib in the Treatment of Relapsed Follicular Lymphoma: Utility and Experience from the Clinic," written by Dr. Ayushi Chauhan and Dr. Bruce Cheson. (If you've been reading for a while, you know how much I enjoy Dr. Cheson's work.)

The article isn't describing new research. It's more one of those "here's where we are with things" articles.

Still, it's very helpful in that way. 

Copanlisib was approved by the FDA after only a phase 2 clinical trial, so it is currently in several phase 3 trials. These trials are looking at Copanlisib on its own, with others looking at it in combination with other treatment.

Interestingly, one of the other studies that the authors mention says that there is some evidence that Copanlisib is less effective due to insulin feedback. The treatment may set off a reaction that uses insulin to start the PI3K enyzmes that Copanlisib has inhibited, so slowing down insulin production during treatment may help it be more effective. One way of doing this might be through a keto diet, which I know a lot of people are interested in hearing more about. 

[But let me be very clear -- this article is not saying that a keto diet will stop, cure, or prevent cancer. It is being studied as a way of making one particular treatment more effective, and even that is just a theory. Don't stop eating bread because you think it will cure your cancer. There's no evidence of that. Talk to your doctor about your diet if you have questions.]

The rest of the article talks about the best uses for Copanlisib (it's a useful treatment for patients who have already tried two things and might get some use out of a different approach), and its future (like those trials that use it in combination with other treatments).

Which brings me to the second item that came across my screen recently: a quick video from Targeted Oncology featuring Dr. Mark J. Roschewski, who makes very quick mention of a different trial, this one a phase 2 trial that looks at Copanlisib with Rituxan in FL patients that have not yet had a treatment. I think this is probably part of a larger series of videos with Dr. Roschewski, but he is excited about this trial. So far, he says, every patient in it has had a response of some kind, with fairly quick reduction in the size of tumors. 

That's exciting, especially since the FDA approval was for relapsed FL. Good to see that it has some use in untreated FL, too. Options are good.

My guess is we'll see some of the results of these trials at ASCO in June. I look forward to it. (I'm happy about anything, really, that will get me through this winter and spring.)

More soon. Stay safe.