Inside the CAR T-Cell Therapy Process for CLL

Chimeric antigen receptor (CAR) T-cell therapy has become a cornerstone treatment for several blood cancers, yet the process still feels “like science fiction,” according to Kerry Rogers, MD, associate professor at The James–The Ohio State University Comprehensive Cancer Center. In this interview with The American Journal of Managed Care^®(AJMC^®), Rogers unpacks how the therapy actually works, why patient expectations often outpace clinical reality, and what determines success across different cancers.

Rogers walks through the therapy step by step, from leukapheresis and genetic modification through lymphodepletion, infusion, and the serious adverse effects, including cytokine release syndrome and neurotoxicity, that can follow. She also addresses a growing disconnect: patients drawn in by headlines calling the therapy curative often underestimate its tradeoffs and ongoing monitoring needs. Finally, she explains why CAR T-cell therapy thrives in some diseases but not others, citing target availability, manufacturing feasibility, and the immune environment as the deciding factors.

This interview has been lightly edited for clarity.

AJMC: How is this cell-based immunotherapeutic/gene-therapy platform engineered, and what are the molecular and cellular mechanisms by which it recognizes and eliminates malignant cells?

Rogers: Every time I think about it, it still sounds very much like science fiction, like this is something that’s just really crazy that we’re able to do. The whole goal of CAR T-cell therapy is to take some of an individual’s T cells and engineer them to attack the cancer cells. The process for that is, you have to collect the T cells from the individual. That’s usually done through a process called leukapheresis. Apheresis is used for a variety of conditions, but in this particular case, it’s used to collect the white blood cells and the T cells specifically. It’s an outpatient process. The blood is taken out of the individual’s vein, goes through an apheresis machine that spins it to separate the cell components—they can actually remove the component of blood that’s white blood cells, not 100% of them—and then the blood is actually returned to the individual.

It’s a similar-type process for healthy individuals who’ve donated platelets or double red cells at most blood donation centers. It seems sort of like that, except for obviously the cell type that’s collected is different. But that’s kind of the process to get these T cells. Then the T cells are taken to a lab. For most of the commercial CAR T products, that’s the manufacturing lab with the company that makes the CAR Ts. We do have research CAR Ts that are done in-house here at Ohio State. There are various ways and places they can be manufactured, so it’s not the same for every CAR product you hear about. But [with] most of the standard approved ones, the cells are then preserved and shipped to the manufacturer and turned into CAR T cells.

This process usually takes between 5 and 6 weeks. There are some investigational products for onsite manufacture for places like our cell therapy lab that have the capability to do that. As you can imagine, [there are] not a lot of places that can. Reducing the amount of time for manufacture is kind of a goal, but right now it’s about 5 to 6 weeks in most cases.

People don’t realize, too, that CAR T, even when it’s done, you still need disease monitoring. There’s B-cell defects potentially over the rest of your lifespan. It’s not 100% curative. Your CLL could come back. It’s an ordeal to go through.

Then at the manufacturer level, they take the living T cell and insert what they call the CAR, which is a chimeric antigen receptor. That’s C-A-R for chimeric is C, antigen is A, and receptor is R. Then the T is just saying these are T cells that they’ve modified. The CAR Ts then undergo genetic modification so that they have a T-cell receptor that’s altered or not like the one they originally had. That is usually done with a viral vector, although there are other investigational ways of doing that. We use viruses to modify a lot of cells. This is not a new thing. But then in healthy T cells that are unaltered, their T-cell receptor is what tells the T cell what to attack or what to bind.

In this case, the chimeric receptor then tells it to attack some other marker. It’s kind of like you tell the T cell that you modified to attack some specific marker that it wasn’t kind of grown in the body to attack. We modify it to attack this other kind of marker. Then a lot of them actually have various ways that on the inside of this receptor, the part that goes in the cell—not the part that sticks outside of the cell and tells it what to attack—to send signals in the cell to tell it to grow and attack and proliferate and survive. They, at the laboratory level, use a virus to insert this T-cell receptor that binds and tells it to attack a different marker than it was natively designed to do in the body. Then also, the inside of this receptor, which kind of goes inside and out of the cell, tells the T cell to live, expand, and do its thing. In most CARs, that is a marker called CD19. That is on the surface of a lot of B-cell cancers, including CLL, which is mostly what I’ve used CAR T-cell [therapy] for, but also ALL and things like that.

They do have other markers, so the products for multiple myeloma, it goes after I think B-cell maturation antigen is the target. And there are a bunch of investigational ones with different targets for it to hit. The most standard is 19. That does mean that it will attack some of the individual’s healthy B cells, too. It is targeted, but not completely selective.

Then after these are manufactured, they’re quality checked and everything, then sent back to the site where the patient is. Then the patient has to receive the cells back. The current way we prepare the patient’s body to receive the cells back is to give lymphodepletion chemotherapy. This is a reasonably high-dose chemotherapy, usually fludarabine and cyclophosphamide, although, of course, there are various ways. That is an unpleasant dose of chemotherapy, but that’s necessary because if you don’t do that, the person that’s going to get their T cells back doesn’t really have space in their immune system to accommodate the new cells, and it doesn’t work well. Then you infuse the living cells back in, and that’s where all the fun starts. That is really when most of the problems start for the patient.

Their blood counts are still low from the lymphodepletion, or lowering, because that decreases the marrow’s ability to make cells for a couple weeks. The T cells grow and expand in the person’s body, that’s the goal, and they fight the cancer cells. But as you can imagine, if you have immune system cells that were just put back in someone’s body and they grow and expand, it’s kind of like having an overwhelming infection with this huge immune response you’re getting. I think that’s when really we’ve seen a lot of problems with something called cytokine release, which is, these cytokines are immune system hormones, and then that’s where we see a kind of a CAR T–specific thing called neurotoxicity, which can cause word-finding speech problems and actually unconsciousness and can be fatal, not to be dramatic.

I do think that over the past years as a field, everyone’s become better at managing these. There’s anticytokine drugs, when to use steroids, preventive measures. We’ve gotten better at knowing how to intervene or how to treat both cytokine release and neurotoxicity, so the risk of severe illness or death from these is decreased. But you will have people tell you their thinking’s not right for even months after this. You can’t drive for a while due to risk of seizure. You do need a 24-hour-a-day caregiver, similar to getting a donor stem cell transplant. You do have to stay close to the center that-s performing the CAR T [transfer] or responsible for you for this.

That used to be 30 days for some of the products. Now it’s 14 days. A lot of these are given outpatient, but people are in the hospital a lot with this. You have to have an experienced center that knows what these complications are that can manage them, to have some of these drugs like tocilizumab, which is a anti–interleukin [IL]-6, on-site to treat people. People have to know what to look for. Then ideally, when this whole process is done, usually disease is assessed at 30 and 90 days to say how well did this work to actually eliminate the cancer cells in the person’s body. Mostly these are used for blood cancer currently. Then you can see how well this might work long term for the patient. You can also now measure how well that the CAR Ts are still in the body and things like that.

AJMC: What are some of the questions you get asked most often about CAR T-cell treatment, and do they indicate any gaps in the space, such as in patient education and health literacy?

Rogers: I get a lot of questions about CAR T. Mostly, again, I see patients [who have chronic lymphocytic leukemia (CLL)]. Recently, the education and advocacy groups that really have put a lot of work into CLL, like CLL Society, Patient Power, and Blood Cancer United, I think have filled a lot of patient education gaps, but still there are a lot of questions about it.

I think one of the major questions people have is they see a popular press article, like the patients do, that say that this is potentially curative, which is true. If cure to you means never having detectable CLL for the rest of your life, these are potentially curative, and so people who have CLL that’s never needed treatment are like, “Can I get this and be cured and never come back here?” ‘'m like, “Oh.” They’re like, “I like you, but I have things to do.” I’m like, “Yeah, that’d be fun.” But then you explain all the stuff I just said about how CAR T is when it works, and people are like, “I don’t want to do that.” I’m like, “I know. I think we’ll just keep on observing your CLL,” and they’re like, “That sounds better.”

People don’t realize, too, that CAR T, even when it’s done, you still need disease monitoring. There’s B-cell defects potentially over the rest of your lifespan. It’s not 100% curative. Your CLL could come back. It’s an ordeal to go through.

I think a lot of practical questions about, “I saw a news article this is curative. Is this something that we should use to cure an individual’s CLL?” I think there’s not a lot of information as to what the process is for individuals who have questions about that. I think it’s mostly people just being excited about the potential of this and not understanding what the process is or some of the limitations of it.

Then I also get a lot of questions about why can’t this be used in other cancers, and that is also some of the reasons I was listing about why this works in some diseases and not in others. I do think as a field we should really look at when the right place is for this in a disease course. In CLL, we’ve been using it after resistance to targeted agents in a lot of them, and that makes sense because the quality of life for most people taking oral targeted agents, the years of lifespan they work for is good, the health span is usually good, at least from the feedback I’m getting from patients taking those agents. So, we might not improve their quality or quantity of life doing this early in those cases.

But you do have younger people with high-risk CLL where maybe waiting until the CLL is resistant to a lot of agents is not the right thing to do. That’s years of exposure to targeted agents that could be reduced by doing CAR T earlier. That is a potential cost-saving, too. CAR T is expensive, but so are these oral agents. When you look at [Bruton tyrosine kinase (BTK)] inhibitors, which are an indefinite therapy, you’re looking at years of taking a drug that costs over $20,000 a month, not patient cost-sharing. But to provide that if you do an expensive CAR T and it works for 5 or 6 years even, you’ve probably saved money on that potentially, depending on how well it works, what the cost of CAR T is, things like that.

I think that’s a discussion that we have as a field that people ask me about, that patients ask me about. And some of the questions there, we just don’t have answers to yet, and it really needs to be studied. I guess the only other thing is, people don’t always see what the success rate is for CAR T. Originally, the first study with liso-cel, which is the approved product, had about a 20% rate of complete remission, which is that’s who gets the really long-term benefit. And then everyone’s telling me, “Well, 20% is not good enough,” and you’re like, “Okay, but this is the only thing that I know of, other than donor stem cell transplant, which I’m certain you don’t want to do, that is likely to result you being alive in 5 to 10 years from a disease state standpoint.”

Now, also that’s not even true for what I’d expect. There’s a nice retrospective study in CLL that use of BTK inhibitors in doing this with better disease control has probably pushed the long-term remission rate with CAR T up to close to 50%, 60%. I think that misinformation or lag in what the real outcomes are, as we’re learning about it as a field, has been a problem toward patients understanding why this might be recommended for them or what the potential benefit might be.

AJMC: Why has CAR T been so successful against certain blood cancers but less so for others?

Rogers: There’s multiple layers to that. I think one component is, do you have a target that we know of that we can use? If you look at diseases where there’s monoclonal antibodies that work well, that’s where you see CAR T working well. If you look at [acute lymphoblastic leukemia], they have blinatumomab, which is like a 19, and then in diffuse large B-cell lymphoma [DLBCL], all these B-cell lymphomas, you have CD20 antibodies. Granted, there is a CD19 antibody and it’s not used quite as much, but CD19 is on all these cells. You’ve got this target that will take out B cells. It’s CD19. We can hit that. We have antibodies that hit just B cells. We know people survive having their B cells really depleted. If you look at a disease like acute leukemia, like acute myeloid leukemia, it’s really hard to find a marker on those cells that you can hit that’s specific to cancer cells that doesn’t take out most of someone’s bone marrow.

So step one is, do we have a marker that we can go after with these that work, that’s not going to cause somehow devastating consequences elsewhere in the body. A lot of times if you see a target for monoclonal antibodies or a cell population you can hit, then you could think, “Oh, hey, we could make a T cell, a CAR T product for this.” The second step is, can you make the T cells? Can you manufacture them? In CLL, which is the disease I mostly work in, manufacture of CAR T is actually quite feasible now. Most people can have a product manufactured. I think it’s less than 5% can’t with liso-cel in some of the more recent trials.

But originally, they had a lot of trouble with that and the manufacturing rate was super low, and just making the cells was a huge barrier to getting this into people. There’s T-cell changes that occur in CLL over the time people have the disease that just made it hard to manufacture. I think improved techniques in the manufacturing process, and also treating the patient with BTK inhibitors, has improved T-cell health and really increased the number of patients who could successfully have T cells manufactured.

Also, I think when we started treating patients who had received less chemotherapy over their lifespan, that probably helped in CLL. But if you look at the manufacturer success rate in diseases like ALL or diffuse large B-cell [lymphoma], [they] were never as poor as they were in CLL. Ao I think health of T cells in certain diseases matters. Then just how well it attacks the cells really matters, the immune environment, that also wasn’t overly effective in CLL compared with something like DLBCL. Part of it might be how immune evasive the cancer cells are, what else might be going on in the immune environment that would make the T cells less likely to expand. In a lot of the cancers, that’s used in our lymphomas, which are again, cancers of immune system cells, so you get this immune dysregulation inherent to the cancer.

I think all those factors kind of play into why this works for some cancers really well and why it does not work well for some others.