For many blood cancer patients, CAR T-cell therapy is game-changing

Transcript:

Bonnie Rochman, senior editor/writer (00:02.494)
Hi, today we're speaking with Dr. Mazyar Shadman, a blood cancer specialist and medical director of cellular immunotherapy at Fred Hutch. Thank you so much for joining us.

Mazyar Shadman (00:22.734)
Thanks for having me. Great to be here.

Bonnie Rochman (00:26.002)
So we're going to be talking mostly about CAR T-cell therapy, which is a really groundbreaking treatment approach that involves removing T cells from a patient and engineering them to better detect and fight cancers. Did I get that right? OK, perfect. So as we talked about when we spoke last week, CAR T was first developed to treat blood cancers. And that's really what we're going to be focusing on today as we talk about a white paper, kind of an overview, that you recently published in Transplantation and Cell Therapy. And the name of that white paper is titled, “Who is eligible for CAR T-cell therapy? Expert perspectives on overcoming referral barriers.” But before we dive into that — it feels pretty self-explanatory what that's going to be all about, and I'm going to want you to elaborate — but I thought it would be a great idea to talk about what CAR T therapy is in the first place. So take it away.

Mazyar Shadman (01:28.62)
Yes, happy to talk about CAR T cell therapy. So CAR T, or chimeric antigen receptor T-cell therapy, is a form of immunotherapy, a form of cellular immunotherapy where we take advantage of T cells. T cells are very strong immune cells that we all have. And these T cells do a great job against infections. And that is the principle of what they do. The idea was to train these T cells and educate them to also attack cancer cells. And that process has been very successful. So CAR T therapy, which is a general term for a number of drugs that we now have available, is now standard of care for a number of blood cancers, lymphomas, multiple myeloma, some of the leukemias. You know, although we still continue research trials that bring more and more novel CAR T approaches, CAR T is already part of our standard treatment portfolio.

So the process starts by, as you mentioned, taking the T cells out or some very small number of T cells out of a patient's body and through a genetic engineering process, which takes a few weeks, two or three weeks, we modify those T cells in a way that when they go back to the patient's body, they're able to recognize and attack cancer cells by causing an immune storm within the body. So that is basically CAR-T therapy in a very general term.

Bonnie Rochman (03:03.05)
So that sounds like science fiction and it's amazing that it works. Now, how many approved CAR T cell therapies are in existence today?

Mazyar Shadman (03:16.226)
Yeah, great question. As you mentioned, this treatment modality, CAR T-cell therapy started with blood cancer. So we now have FDA-approved standard of care CAR T treatments for lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma. We also have it for a couple of leukemias, chronic lymphocytic leukemia, acute lymphoblastic leukemia and also for multiple myeloma. Now for each disease, we may have more than one specific CAR T product approved, but that's kind of the coverage we have. 

In some cases, and I would say in most of these cases, CAR T is not just an option. It is considered to be the best option. And I'm sure 
we'll talk about that. And that kind of takes us to the paper. So we have CAR T approved for all the diseases that I just mentioned.

Bonnie Rochman (04:09.659)
OK. And is this CAR T-cell therapy something that is exclusive to academic medical centers such as Fred Hutch?

Mazyar Shadman (04:20.256)
It's not exclusive to academic medical centers, but in general, major sites. I would say there are some non-academic but highly specialized centers that also deliver CAR T therapy, but it's definitely not a type of treatment that you can get in any practice or medical oncologist setting where you're being treated. So in most cases, patients have to relocate for a short period of time to be able to get this treatment.

Bonnie Rochman (04:48.528)
OK, so I think that's a nice segue into your paper. So let's talk a little bit more about your paper and what you see as some of the key takeaways.

Mazyar Shadman (05:00.214)
Of course. So before I get to the paper, I wanted to highlight two points. So first, this is a treatment that should be the highest priority for, again, some and most of the diseases that I outline. What does that mean? It means that when you look at the treatment options, either when you look at guidelines or when you talk to your physician, it's not uncommon that a physician would list a number of options. And sometimes these options are equally effective and  we don't necessarily know which ones are better than the other ones. And you think about the logistics and feasibility becomes — it's always an important factor — but it becomes the major factor if you don't know which drug is better in terms of how good it works for cancer.

CAR T is a unique situation; I will use a couple of examples. So for large B-cell lymphoma, which is the most common type of lymphoma that we use CAR T for, CAR T is a treatment that helps patients live longer and is better than some of the standard or the standard of care that we used before CAR T. For example, the majority of patients with large B-cell lymphoma who have relapsed disease, meaning that the disease comes back after initial treatment, the high-risk group, the ones who would have their disease coming back early, historically had a very limited chance for living beyond six months.

Now we're curing 30 to 40% of those patients with CAR T therapy. So it's very important for patients to understand that if you have a disease like that, I mean, I use large B-cell lymphoma as an example, but you can argue the same thing for many other diseases. But it's important for patients to know that this is a treatment that comes with what we call overall survival advantage, number one, and patients regardless of their disease stage or some of the more classic features that we often talk about when we talk about cancer treatment, these patients can be cured potentially. 

So 30, 40% may, it's not perfect, it's not 100, but we're looking at a much smaller number of patients not being able to live beyond six months. So that's number one. Number two, the unfortunate fact is despite being such an effective and revolutionary treatment for lymphoma, if I tell you that only 15 to 20% of patients nationally who should be getting CAR T are getting it, that is a really eye-opening number. That is concerning for us in the CAR-T community. You have a treatment that's life-saving, has been shown in head-to-head randomized trials, the highest level of evidence in medicine, to provide cure in some patients, yet we are looking at best 20% utilization in the country. And there's a problem there.

So that takes us to the paper: Why? And many of us are looking at access and why is it that 80% of our patients are not even considered or treated for CAR T-cell therapy, and there are many factors. I would put them in two big categories.

Number one, logistically, it's not easy. You asked a great question to patients. Can patients receive this treatment at home? Most of the time, the answer is no, they have to for a short period of time, a month or two, they need to relocate to another place to get the treatment. So that comes with a lot of logistical challenges and that's a different discussion.

The second is lack of education about what CAR T involves and what are the requirements for CAR-T therapy, both for some of our colleagues who don't necessarily work with CAR T and are not very familiar with it, which is expected, and also our patients not necessarily knowing how different this option is compared to the other ones. I mean, it's not that you either go to Seattle to get CAR T, or you take this pill at home and they're both the same. No, they're not the same. So what you're trying to do is to educate our patients. 

This paper is specifically focused on our physician colleagues. One of the misconceptions is, OK, well, CAR T-cell therapy is a process that I send my patients to Seattle. Oh, it reminds me of a stem cell transplant. And for stem cell transplant, which is a very different procedure, there are very strict requirements for patients in terms of medical fitness. You need to have a very strong heart muscle. You need to have lung function that is above a certain percentage. Your kidney function needs to be perfect or near perfect, and the list goes on, right? Those are absolutely needed for stem cell transplant. But what we're...

Bonnie Rochman (09:38.398)
I believe what you said, I think just something I just wanted to point out, something really surprising to me that you said was that CAR T has no age limit.

Mazyar Shadman (09:52.974)
Yes, so age by itself should not be a reason for a patient not getting CAR T and age by itself is a reason for some patients not getting an autologous stem cell transplant. So these are the contrasts that we're trying to highlight in this paper to say, OK, if you have a patient who's let's say, just pick a random number, 82, and historically you wouldn't even discuss autologous transplant because we don't do transplant, but we would absolutely do it.

Bonnie Rochman (10:18.558)
That wouldn't be an option.

Mazyar Shadman (10:22.862)
And again, we would still make the assessments and know if there are other reasons not to consider CAR T, that's a medical decision. But age by itself should not be a reason for not getting CAR T therapy. And what you're doing in this paper, which is there are a number of experts from major academic CAR T centers that came together. And the idea is to say, OK, age, yes, you know that for transplant, you don't do it. For CAR T, that should not be the reason not to do it. Heart function, we have this absolute cut-off of whatever percentage for echocardiogram or ejection fraction. We don't have that for CAR T. We can work with our colleagues in cardiology and optimize the patient for it. Kidney function, it needs to be really, really good, near perfect for transplant. Guess what? We do CAR T on select patients on hemodialysis. So the idea is don't assume that because there are medical problems beyond lymphoma or myeloma or leukemia, CAR T is not an option.

We convert a very, very high percentage of our patients who are referred to us to actually getting CAR T-cell therapy. We have no control or hopefully we can get some more collaboration with our colleagues, but we don't get what we don't get in terms of that initial assessment. So we're trying to educate or really spread the word about how feasible these CAR T products in general are for even patients with medical problems.

Bonnie Rochman (11:52.606)
Right, so what I understood from talking to you previously is that really no matter what medical condition a person has, they should at the very least have a conversation with a CAR T-cell therapy expert to say, am I a candidate, am I eligible for this?

Mazyar Shadman (12:07.352)
Exactly.

Mazyar Shadman (12:10.732)
Yeah, every patient with relapsed blood cancer deserves an official consultation with a CAR T expert. Don't assume that you're not eligible because of medical problems.

Bonnie Rochman (12:23.366)
Now why is this not a first-line therapy? This is so, so miraculous. Why aren't we going straight to this?

Mazyar Shadman (12:30.37)
Well, I mean, we are probably heading that direction. So in cancer treatment in general, you try a new treatment in later lines of therapy. You want to make sure that the treatment is safe and it works in patients who don't have other options. Then for some treatments, you see amazing responses and you say, OK, well, why don't I try it in second line? That has happened already in lymphoma. It has been studied in a second-line trial and was the winner. So now we are at the second line for lymphoma. And there are actually ongoing studies that are looking into using CAR T-cell therapy in the first line. Getting a treatment to first line requires a process, but that is already happening in multiple myeloma. Same thing, it's coming to earlier lines of therapy in mantle cell lymphoma. We are working on studies to utilize it as part of first line, but that's the natural process of getting new drugs. Yeah.

Bonnie Rochman (13:25.31)
Yeah, that's the progression. OK, got it, got it. And then some of these CAR T cell therapies are administered as part of our research program at Fred Hutch, specifically clinical trials. And I was hoping you could talk a little bit about what clinical trials are and how many we have. I believe it's 20 to 30 that are currently using CAR T.

Mazyar Shadman (13:51.062)
Yeah, yeah, absolutely. Basically, first of all, clinical trials are, that's how we got here. So one of the most commonly used CAR T products that's out there for lymphoma, for example, was developed at Fred Hutch. And imagine patients who benefited from that treatment 10-plus years before it was available on a commercial basis, right? So number one, it's a way of having access to potentially life-saving treatments years before they're available. And clinical trials come in different flavors, right? You have an unmet need and you have to at some point start a very novel approach and you don't know much about how good it works and you learn from just offering it to patients.

But many of the studies that we have, we already know that these treatments work and it's just, we are either using them in combination with other drugs or we're trying to make the progress we've made even better. For example, I told you we can cure 40% of patients with relapsed lymphoma. The goal is to make it 90%, 100%. 

So there are different types of clinical trials. One group are diseases for which we already have a CAR T product, trying to make things better. But there is a much larger category of diseases for which we don't have CAR T. And we're trying to bring these novel treatments to diseases where we don't have an approved drug right now. Prostate cancer is a very common cancer that we're now studying CAR T-cell therapy in that disease. And it's interesting that it's even going beyond cancer. We have autoimmune diseases that we use the same CAR T products that we use for cancers and they're shown to be effective for treatment of autoimmune diseases like lupus, like systemic sclerosis. Soon we will have studies with multiple sclerosis. Clinical trials are a way of having access to these new drugs before they're available.

Bonnie Rochman (15:54.374)
OK, well, thank you. I wanted to see if there's anything else you wanted to emphasize, but this is, I think this is an incredible overview and really the theme that I'm picking up on is getting the word out about CAR T and how it's an option for all sorts of patients.

Mazyar Shadman (16:12.686)
Exactly. Any patient with a relapsed blood cancer or any type of cancer deserves a dedicated conversation with a CAR-T expert; most patients are eligible. So don't assume you're not.

Bonnie Rochman (16:27.55)
Perfect. Thank you so much.

Mazyar Shadman (16:29.55)
Thank you.