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.