Wednesday, September 14, 2016

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.


Anonymous said...

This was just on OncLive yesterday as well:

Seems to work in all settings of NHL.

Terrilyn McCormick said...

Thank you for sharing this exciting study and also just a word a gratitude to you for your blog. It has been an excellent resource for me as I'm less than a year into my FL diagnosis.

I just read the article and was struck by how few women were included in the study (5 of 32 participants). As I've spent so much time in the medical world this last year, I've been struck on numerous occasions of how sexism pervades my experience as a patient and how doctors respond to me. I know men are more likely to have NHL but its definitely not at this ratio of the study. Had me wondering was this a study design flaw or maybe men are more likely to have more aggressive cancers or resistance to treatments. Any thoughts on that?

Lymphomaniac said...

Hi Terrilyn.
To be honest, I didn't even look at the graphic for patient characteristics -- I tend not to, unless the authors point out that age/sex/race/etc. seemed to be a factor. Of course, their not pointing it out doesn't mean that it isn't actually a factor.
As I understand it, sexism has a long history in medicine, and in medical research. And that has some serious implications. I know, for example, that symptoms for heart attacks are different in women than in men, so a medical professional who was taught that only "male" symptoms are real symptoms is not going to treat a female patient in an appropriate way. Those sex differences can matter a lot.
Is that the case in cancer, particularly Follicular Lymphoma? I don't know. For the study that's being discussed here, I don't know if this was a registered clinical trial, and if that would have made a difference in balancing sexes. It's a pretty small study, so it would be a stage 1 or 2 study, most likely, and maybe with the focus being less on how a treatment fits a large population, they just took the first 32 patients they could get. Maybe a larger study will seek out more balance in the patient population.
The FDA is certainly aware of the issue. This summer, they posted a statement on how sex differences can have an effect on clinical trials and other research:

As for the kind of day-to-day sexism that you see as a patient, I'm not surprised by it. It's hard for me to see as a man, but I don't doubt that you are treated differently because you are a woman. I'm sorry it happens. I wish I knew how to make it better -- for my wife and daughter, as well as for you and other patients.

Anonymous said...

Hi Bob,

Sorry for not posting sooner. I've written here before. As you mentioned, I'm one of your readers with Follicular Lymphoma and direct CAR-T experience. For what it's worth, I am now over a year out from CAR-T infusion and still in complete remission, something that hasn't happened for me in over 3 years. For me, it has been a miracle.

I don't remember if I mentioned this before, but while I was considering participating in a CAR-T trial in early 2015, my wife learned through her brother of someone else in the Southwest who had been diagnosed with fNHL the year before, and was unresponsive to all treatment (R-CHOP, R-Bendamustine, etc.). She persuaded him to find a CAR-T trial in his area, even before I enrolled in mine!

It turned out to be the right decision for him, too. I'm only mentioning it because he is one of the 32 in the study you just cited. He ended up driving all the way to Seattle to participate in the CAR-T trial at the Fred Hutchinson Cancer Center. He is 1 of the 3 Follicular patients cited, and 1 of the 2 to get a complete remission, which he is still enjoying.

I cannot close this reply without at least mentioning that CAR-T is not without risk. I don't remember if you covered this already, but there was a case a few months back where 2 patients died from CRS as a result of CAR-T. That trial had to be modified, where they no longer give patients a Fludarabine/Cytoxan combination prior to infusion, only single-agent Cytoxan. It remains to be seen if this will be just as effective, as I think the best responses seem to come from patients like our Southwestern friend and myself, who received the Fl/Cy combination.

With all the work and $$ being poured into CAR-T, hopefully they find a way to reduce the CRS complications.

All the best,

-- Ben

Anonymous said...

Bob - thanks for all the great follicular lymphoma posts. I follow your blog daily looking for more good information. Bill

Ben - My 69 year old wife was diagnosed with follicular lymphoma in 2011. After progressing after R-CHOP, BR, Ibrutinib, and Idelalisib/rituximab she enrolled in a NIH CAR-T trial (NCT02659943) and was infused on March 2, 2016. She is now in complete remission. She had low blood pressure for 2 days following infusion and low IgG for which she has had two IVIG infusions. Otherwise no side effects. Except for some afternoon/evening fatigue she feels great. We'd like to talk with you about your CAR-T experiences - please contact me at Thanks, Bill

Wisks said...

My husband has FL DBCL and we are trying very hard to get into a Car T trial. Can you tell me how long it took to give the cells and then how long your wife was in the hospital for the infusion? What was it like for her? Thank you for sharing in advance.