November 26, 2019

CAR T cell therapy: how it helped 2 brave young women fight cancer

By Conor McKechnie and Dodi Axelson

CAR T cell therapy: how it helped 2 brave young women fight cancer

This is a serious but inspirational story where a few brave souls blazed the trail and are now paying it forward. This is the story of Emily Whitehead, the first CAR T pediatric patient. And this is the story of Nicole Gularte, the leukemia patient who received CAR T cell therapy three times! You can support the Emily Whitehead Foundation here.

CONOR: Dodi, today I’m going to tell you a story that I've been following personally for a number of years. It's more immediately serious story than some of the other topics we've covered. But it is a story about discovery. Some of them that we've talked about so far have been accidental discoveries, many through harmless means. But this one's really interesting in that to get to a discovery that can then be shared to the benefit of others. A number of people have had to go through unimaginable pain and suffering before that discovery could become useful for others. So, we might cry a bit but I'm just gonna let you know, it's okay. It works out in the end in this case. But what's really interesting is how the players in this story interconnect with others to form new possibilities.

DODI: All right. Well, I feel warned and comforted at the same time. I'm going to grab the tissues because well, it's probably still a story worth exploring and life and death stories are really the ones that matter. And that's why we're going to talk about that during this episode. Let's do this. I'm Dodi.

CONOR: and I'm Conor and this is Discovery Matters.

[Intro music]

CONOR: So, in 2010, in early May, a 5-year-old girl called Emily Whitehead had a doctor's appointment, a yearly check-up and she was told that she was completely healthy. Soon after the appointment her mother Kari started noticing bruises all over Emily's body.

KARI WHITEHEAD: So, I said to my husband Tom have you noticed that Emily has these bruises? She has 21 of them on her body. And he said well she and her cousins bought these Nerf swords that they were fighting each other with, and they were hitting each other, and he said so it probably, that's probably where they came from.

CONOR: Then one day Emily tripped and fell.

KW: Within a couple of minutes, there was this huge bruise. It was very dark and ugly, and it was at that moment that I realized that something isn't quite right. She had bruises, her gums were bleeding whenever she brushed her teeth, and I remember she had a couple of nosebleeds over the past week.

CONOR: So, Kari was worried. She texted these symptoms to her sister, who's actually a nurse.

KW: When I got home that night Tom said to me, what did you tell your sister? Because she called here crying and said that Emily has the classic signs of leukemia, and it was at that moment when we kind of realized that maybe this was something more than just the typical black and blue marks.

CONOR: They took Emily to the doctor and eventually she was diagnosed with acute lymphoblastic leukemia. What followed was 26 gruelling months of unimaginably painful chemotherapy. Once all of that treatment was exhausted it was actually looking hopeless. Kari and her husband Tom were told that they should really prepare for the worst, that they should take Emily home and think about hospice care and that soon she was going to go into organ failure. They were told about a trial that was usually only open for adults, and that didn't feel quite right for Kari and Tom. So, they decided to leave, but just as they were leaving a nurse stopped them.

KW: And she said before you leave, I want to tell you about something that’s upcoming. It's called T cell therapy. Unfortunately, it's not approved yet. We're kind of stuck on the paperwork. We don't think it's going to be approved in time for Emily. But because we were talking about the toxic effects of chemotherapy on children, she said this is going to use your own immune system to fight leukemia. And I thought, that's exactly what we need. Emily’s leukemia is different, and we need a different treatment. You know, we were looking for something different, but unfortunately it wasn't available. Her doctors came to us and said we’re sorry, but we've run out of weapons to fight Emily's cancer. We don't have anything left and we think it's time for you to take her home, and at this point you probably have a couple of weeks left.

DODI: There's just no way that you can feel good about hearing any of that. It's the worst thing a parent could hear.

CONOR: Yeah, you're right. And Kari and Tom weren’t going to give up. She phoned Philadelphia and she said that they were willing to sign Emily up for the trial that was previously offered to them. The one that didn't feel right in the beginning.

KW: And they said unfortunately you no longer qualify for that trial, and my heart just stopped because I knew that that was the end. And her doctor said, however yesterday I received an email that the T cell therapy clinical trial has been approved and we think that Emily might qualify, and we couldn't believe that it open because this was absolutely perfect timing and I said this is it. This is what we've been waiting for.

DODI: So, Emily was about to be the first child to undergo CAR T therapy. I think we need to talk more about CAR T therapy and what it is. Can we get a definition?

CONOR: To answer that it's time to talk about how we can use viruses to deliver therapies. And how we can use them to teach our bodies how to heal themselves.

PHIL VANEK: I like to think of viruses as evolutionarily conserved, or they've been with us for hundreds of thousands of years for the most part. I’m Phil Vanek, I'm General Manager for Cell and Gene Therapy Strategy and Business Development.

CONOR: Phil Vanek is someone whose job it is to make cell therapy simpler to manufacture and scale up and improving access for patients and families in that way. People like Kari, Tom and Emily, of course.

DODI: All right got it. But does CAR T therapy work?

PV: Let me break it down probably into three steps. The first step, extracting a cell from the patient. And that cell in our world just becomes the raw material for the therapy that will ultimately be manufactured. So, the first step following the collection is to do something to the cell. So, I liken it to installing a new circuit board into a computer and in the biology world, basically, that means they're installing a new feature a new capability into a cell and that's somehow have lost that capability. It may have had that capability damaged along the way or it may be something that the patient was born with that needs correcting. And so, the first step of an advanced therapy manufacturing cell and gene therapy is to install, if you will, a kind of a therapeutic benefit into the cell.

Step two, once that process is completed, we have to make enough cells for a therapeutic dose. And that's a process basically in a laboratory under very controlled conditions. We take the few cells that we took out from the patient, that have been modified or engineered and we put them into a culture vessel where we can grow more and more and more cells. This can take anywhere from a few hours to a few days. But ultimately, we end up with a large number of cells that will ultimately be used as the injectable therapy, the injectable product for the patient.

So now that we have these cells grown up in a bioreactor, we have to process them and prepare them for both administration into the patient, but also delivery and distribution back to the clinical center. So, that three-step process, collecting the cells and engineering them, extending them to the point where we have a therapeutic dose, and then ultimately freezing them and shipping them to the patient are kind of the three key stages I see in most of the cell and gene therapies we make today.

DODI: Alright, so to recap and just so I understand, CAR T cell therapy basically uses a part of the immune system, these altered T cells to fight cancer.

CONOR: That's the basic idea. Yes. T cells all collected from the blood and using a virus to deliver the genetic payload they’re modified to produce these chimeric antigen receptor structures on the surfaces. And these modified CAR T cells can then track down the cancer cells in the blood and destroy them!

DODI: Amazing. So, Emily was the first child to try this and that makes me wonder about dosage. So how do you use this method on a patient, who is so young?

PV: Most medicines today are prescribed per kilogram of body weight. So, you know paediatric patients versus adult patients. That’s step one in determining what a therapeutic or an effective dose is. Then it comes down to what is the therapeutic potential or what is the therapeutic index. That's determined either by whatever we've done to engineer the cell. The higher potency element we introduced into the cell, potentially the fewer cells we need. Then it comes down to what's the mode of administration, is it something that has to be implanted into a patient through surgery. Is it something that is just put in through an IV drip or an intravenous drip in a bag in the hospital. Or is it something that gets administered sort of through a specific type of injection into intramuscular or into the muscle like you might get a flu vaccine. So, all of those elements have an implication in how many cells we need.

The other question we certainly ask is how durable is the treatment? So there are some treatments that, like an Aspirin™ or a small molecule, will only stay in your body for a certain amount of time. Therefore, you either have to repeat those to continue the therapeutic benefit. For cell and gene therapies, where these potentially have the capability of being introduced to a patient and then becoming part of the patient, right? Surviving with the patient through old age that also impacts the dosage that's required. So, it really comes down to those few elements. It's the size of the patient. It's how the material is administered. It is how durable is the therapy and then finally it's how powerful is that therapeutic index. How many cells do we need to get the effect we’re looking for?

DODI: It sounds like what Phil is describing can be compared to the way we buy orange juice. So, you buy orange juice either as a concentrate or ready to drink or maybe even fresh-squeezed.

PV: I like that. The fresh versus the frozen, you know, that's the Holy Grail in our industry. It's how do we take these therapies that today are fresh-squeezed, you know, the little boutique stand on the side of the road driving through the sunshine in Florida. This is where much of the industry is today, but it's that same process of industrializing. It is about looking at how can we work on distribution, the storage of the material, the preservation of the material. All that goes, of the same thinking that goes into frozen concentrated orange juice is how the industry has thought about bioprocess in the past, but also thinks about cell and gene therapies going forward. It's a great analogy. I like it.

DODI: So we know how it works in theory, but does it work? Did it work for Emily?

CONOR: Well, eventually yes. She was told that this CAR T therapy had made her cancer-free. It's just extraordinary.

DODI: That sure is amazing. And I guess with any good science what's coming next is that we have to see that it works on more people.

CONOR: Well, I'm glad you asked that because that's what's so interesting about this story. I want to tell you about Nicole. In 2010, the very same year that Emily found out that she had leukemia, Nicole was 26 years old fresh out of grad school and she receive the equally horrifying news that she'd been diagnosed with the same type of cancer.

NICOLE GULARTE: As soon as I found out, I went into a wheelchair and was wheeled across the street to a hospital. From that moment on I didn't see the outside for about 90 days.

CONOR: And it was a similar story. Chemo, knee surgery, which meant she had to learn how to walk again, two years of initial treatment that ended in 2013, but in April 2014, she relapsed.

NG: I always knew that if you went into remission and your cancer didn't come back the rate of success was good. It's when a child or an adult with this type of disease relapses that things start to get very, very difficult.

CONOR: Doctors told Nicole the same things that they told Emily's mother and father.

NG: They said, well Nicole your only option at this point is to go through what you just went through, get you into remission again, and then do it all over again with a bone marrow transplant. And so, I thought about the past three years and what I had already been through and I told the doctors at Stanford, I said look, there's got to be something better. This is Stanford. I'm not going to go through everything I just went through all over again. If I physically make it, I don't think I can mentally handle it. I really don't. And I said it has to be something else. One doctor looked at the other and I was in my hospital bed. Both doctors facing me and one said what about CAR T? And the other said no that I thought was going to be here, you know, like two years ago. It's I said, what's CAR T? Hello. I'm in the room and my one doctor said he said Nicole look don't even think about it, don't waste your time. You're never going to see it. Not in your lifetime. I looked at the look on the other doctor’s face and her expression showed me that she did not agree with what that male doctor was saying. I knew at that time, I had to take into my own hands.

CONOR: So, she did. She tried a different trial and for a time the leukemia went away, but in the end once again, the disease came back. So, this is 2016 now. And finally she got herself on to a CAR T clinical trial at UPenn. And as soon as she got there the doctors asked her…

NG: Have you heard of Emily Whitehead? And I said, no, who's Emily Whitehead?

CONOR: The doctor told Nicole what we'd heard earlier from Kari.

NG: I cried, my mom cried, and I was also caught off guard because I hadn't heard about this story. And so, it was very, very hopeful she from this point on was definitely my hero.

CONOR: The doctors froze her cells and they waited for the inevitable relapse. That relapse resulted in her losing the ability to see colors in her left eye and then they found the leukemia in her spine and in her brain, which tragically meant that she did not qualify any longer for the CAR T therapy.

NG: And I was given three to five weeks left to live. And, sorry, so I wanted to be buried next to my father who had passed when I was a teenager and he was buried in a Catholic cemetery. And I had not been baptized as a child. I don't know why, because both my mom and dad are Catholic. But, so I decided to get baptized and it was a beautiful ceremony. I've never been married. I don't have kids. This was equivalent to a wedding. It was gorgeous and it was very uplifting. I felt like a different person. I reached out to the Whiteheads during this time. I had actually sent a message and I said look, I heard about your daughter's story two years ago, and I've been, I give speeches and talks, I believe in her story. I believe in CAR T and I've been trying to access the adult trial but I don't qualify now. After talking to Tom, or I had messaged Tom, Tom had called me and he said Nicole, you know, I'll do whatever I can in my power to help you get into either the clinical trial the children's one at CHoP or the adult one. He did whatever he could.

DODI: So, Emily's family was now helping Nicole get CAR T treatment. This is just an incredible tragic connection. I mean now it's turned around and become life-sustaining literally.

CONOR: That's exactly what's so interesting about these stories. This is how very often these ground-breaking therapies get championed by a community of patients who've had successes in clinical trials. Lastly, Tom gave Nicole a piece of advice.

NG: He said, Nicole I urge you to go back to Stanford and get one more lumbar puncture one more. And I said, you know what? I'm going to go ahead and I'm going to do that. So, I went to Stanford, I sucked it up and I did one more lumbar puncture and usually it takes a day or two to get those results, but Stanford really wanted to know. So I got them back in two, three hours and I was declared there was no cancer in my spinal fluid.

DODI: Wait what?

CONOR: I know, no one could really work out why, but it meant that Nicole was not going to die in a few weeks.

DODI: And surely it meant that she now qualified for CAR T treatment?

CONOR: Exactly. So, Emily's father, Tom, flew Nicole out to Pennsylvania for the trial.

NG: When I entered the trial it was September of 2016, I had an immediate reaction with this CAR T 19. So, it's the same exact drug that Emily received, except for it's been kind of perfected or they’ve learned to improve it let's say. But it was still very new, especially for an adult, not very many adults have received this. I was one of the first at UPenn. On the 10th day I regained 100% color vision. I was cancer free on the 28th day and I was able to go back home.

DODI: So scientifically, what does this all mean? And what is the future of industrializing this cell therapy?

PV: If you think about the bioprocess industry 30 years ago, people were pulling equipment off the shelf and trying to make it work for the industry as it was. Today, the industry is laden with technologies that are designed specifically for the manufacturing challenges that the bioprocess or biologics industry faced over the last 30 years. Cell and gene therapy is in that same level of infancy as an industry. Today, we have tens, if not hundreds, of different cell types that we’re looking at that would have therapeutic benefit. Looking at all the different ways to engineer them. Some of these cells grow attached to the side of the pool, some grow in suspension in the middle of the pool, right?

All of those things will have to be combined in ways and there will be a certain amount of standardization that say in five or ten years there’s really ten different manufacturing methods. I still believe they'll be largely modular methods because that allows scale with enough flexibility for the variety of cell types. But at the same time there will be a consolidation of technologies. Just to make this a more streamlined and a much more straightforward manufacturing process.

CONOR: Well, that's it for today.

DODI: Yeah, heavy.

CONOR: I just want to point out that even though we told Emily and Nicole story in about 20 minutes, there's a lot more to what they went through. Join us next time for more...

DODI:Discovery Matters, bye for now.

CONOR: Bye bye.

[Outro music]

CONOR: Our executive producer is Andrea Kilin. Discovery Matters is produced in collaboration with Soundtelling. Production and music by Thomas Henley.

CONOR: We recorded this episode of Discovery Matters in the early summer of 2019. On the 23rd April 2020, Nicole Gularte passed away after a ten year battle with her cancer. It’s a stark reminder that the remarkable stories of these courageous people and their fights against disease do not always end the way that we would like. Nicole was an extraordinary person, both in her tenacious fight against her leukemia but also in her raising of awareness and of helping increase access to CAR-T therapy for other patients. Her telling of her story has been an inspiration to us and to so many of our colleagues across the world. We will remember her.