Mantle cell lymphoma (MCL) is a rare disease. But this fact is of little comfort to those who are diagnosed. The prognosis, historically speaking, has been dismal—an unforgiving harbinger of “worst case” outcomes. Until now.
Recent FDA approval of a new CAR T-cell therapy for MCL is a medical and technological triumph that obliterates MCL in a significant percentage of patients. But as with most cases of forward progress, there is a backstory filled with drama and pathos. The green light for brexucabtagene autoleucel, the very first cell-based gene therapy to treat relapsed or refractory MCL, illuminates the human perseverance, serendipitous meetings, life-and-death struggles, and dogged persistence required for such a medical breakthrough.
The development of CAR T-cell therapy in cancer is still in its infancy. Although it did not start with a professor at MD Anderson, this particular tale did.
Long Ago, Far Away
China's Shandong Province is famous for being the birthplace of the country's preeminent philosopher, Confucius. It is also the native land of Michael Wang, MD, Professor in the Department of Lymphoma and Myeloma, Division of Cancer Medicine, at University of Texas MD Anderson Cancer Center. He is also the founding and current Director of the Mantle Cell Lymphoma Program of Excellence, and founding and current co-principal investigator of the B-cell Lymphoma Moon Shot Program.
“I'm just a little potato, a little kid out of a very small town with 10 million people,” the affable Wang told Oncology Times. Having completed graduate studies and medical school in Beijing and Shandong in the 1980s, Wang was awarded the 1988 Fogarty International Fellowship Award which brought him across the ocean to the U.S. Six years of intensive laboratory work followed at the NIH. “I worked very hard and was productive,” he recalled.
Wang recalls an anecdote that demonstrates his unrelenting passion for research. “In the lab we used a centrifuge; it would take a long time for the wheel to stop turning. So, to save time, I would put my finger into the centrifuge to stop it from spinning so I that could finish my experiments faster. Most fortunately, I still have all my fingers,” he said with a chuckle, adding he had published 20 papers during his NIH stint. Today, his original publications well exceed 200.
In 1999, after completing residency in the University of Michigan Hospitals and Norwalk Hospital, Wang went to MD Anderson for a fellowship that led to a staff position 3 years later in 2002. There he was mentored “by many great people” such as Fernando Cabanillas, MD; Raymond Alexanian, MD; Larry Kwak, MD, PhD; Richard Champlin, MD; and the late Waun Ki Hong, MD, then the Chief of Cancer Medicine Division at MD Anderson Cancer Center.
“He [Hong] told me, ‘Michael, you are going to make it; you have the passion,” recalled Wang. It was during his fellowship at MD Anderson that Wang would form another fateful relationship with his fellowship deskmate, James Kochenderfer, MD. “Now he's one of the most prominent CAR T-cell therapy scientists in the world,” said Wang of his friend. “At that time, we didn't know about the fate that would bind us, but we were good buddies; we really connected on a personal level. When we graduated from the fellowship, Jim wanted to get more lab training so I suggested the NIH as a consideration. He went into the Surgical Branch there at the National Cancer Institute, and he worked with internationally known immunologist and scientist, Steven Rosenberg, MD.”
These fortuitous meetings laid the groundwork for what was to come and formed the human platform from which a breakthrough eventually would be launched.
As time passed at MD Anderson, Wang was involved in running many clinical trials. Kochenderfer was still in the lab at NIH's NCI.
“For many years, he worked hard and stayed quiet,” Wang recounted. “I suspected that he didn't even have a cell phone. He just worked and focused on CAR T-cell therapies. I am one of the very few people who kept in contact with Jim.
“In July 2011, I invited him to speak at MD Anderson. One of my memories of him was when he prepared his ASH presentation, he studied note by note until the wee hours of the next morning, the morning of the presentation. Whatever he does, he does completely, very seriously.
“Although many did not really know what he was working on, to my great surprise, his presentation attracted many people who would later become the experts in cell therapy, including Dr. Champlin, Chairman of the Department of Stem Cell Transplantation & Cellular Therapy at MD Anderson; Elizabeth Shpall, MD, Director of the Cell Therapy Laboratory at MD Anderson, and Helen Heslop, MD, Director of Cell and Gene Therapy at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children's Hospitals. As it turns out, what he was doing was making inroads into this new area called T-cell therapy, a long time before any CAR T-cell therapy was approved.”
At about the same time, Wang was contributing significantly in clinical research in the area of MCL.
“In 2013, I published a landmark paper in the New England Journal of Medicine on the use of the oral drug ibrutinib in MCL (2013;369(6):507-516). In an international trial, we found that when using ibrutinib as a single oral tablet the efficacy rivaled the efficacy of combination chemotherapy, where you would use five drugs via a central venous catheter and patients typically would be admitted to the hospital, experience nausea, vomiting, low blood counts, hair loss, and lots of suffering,” detailed Wang. “So, the FDA gave a breakthrough definition and accelerated approval for ibrutinib. I began to receive national and international mantle cell lymphoma patient referrals from then on.”
Wang's buddy, Kochenderfer, was also forging forward. “Jim had started doing clinical trials using his own technology at NCI. I believed in him completely. So, when he asked me to send him a patient, I did. I sent him some patients with relapsed lymphoma,” recalled Wang.
One of the patients was a young woman of about 35 years of age and was pregnant. Her large cell lymphoma was growing fast, “...although chemotherapy can be delivered safely in the second trimester,” said Wang. Wanting to safeguard her pregnancy, Wang recalls the patient saying, “This is my one chance for my baby and I'm not going to spoil it.”
By the time she delivered, the new mother's lymphoma was everywhere. Her local doctor gave her three different combinations of chemotherapy, but it didn't help. She was ready to go to hospice.
“She knew of a friend who was my patient,” recalled Wang. “The friend told her, ‘You've got to see Michael Wang. You cannot just surrender and go off to hospice to die.’ So, I immediately saw her in my clinic, got her feeling better, and sent her to Jim.”
Kochenderfer used his experimental CAR T-cell therapy to treat her. The patient's T cells were collected, genetically modified to include a new gene that would target and kill lymphoma cells, and then infused back into the patient.
“She had a hard time with cytokine release syndrome (CRS) and had neurotoxicity,” remembered Wang. “But she recovered from all of it. She's alive today and she's doing wonderfully.”
Wang continued to supply patients to Kochenderfer who would publish the results of his work in the Journal of Clinical Oncology (2015;33(6):540-549). “I also was on the paper, because I contributed patients to the study. Jim invited me back to NIH, and I met Dr. Rosenberg in the NCI surgical branch, where he presided over a meeting. I witnessed how the bench scientists were immediately transmitting new findings into the clinics. When I got back to MD Anderson, I got busy founding the Mantle Cell Lymphoma Program of Excellence, the only program of its kind in the world. Clearly, I was very inspired by what I saw at NCI. To date Jim has won many awards from NCI and NIH. “
Trial & Tribulations
Inspiration and opportunity intersected in 2015 when Wang was at an ASCO annual meeting in Chicago. Two representatives from Kite Pharma, Drs. William (Will) Go, MD, PhD, and Jeff Wiezorek, MD, approached him in the lobby of the Chicago Hilton and asked Wang if he was interested in testing a CAR T-cell program on MCL and moving it to FDA approval. Wang asked whose technology they had licensed. The answer: the NIH, more specifically Kochenderfer and Rosenberg.
“I was so happy, so happy,” exclaimed Wang. “There were so many good emotions flowing through me. First, it came from my good friend. Second, I knew this works from the patients I had sent to Jim. I knew how solid the technology was. Of course, I was also aware it could be very stormy with the side effect of CRS and the neurotoxicity. But third, I also knew I'd have a lot of support; I was confident in anything undertaken at MD Anderson. It was all so great. My deskmate from 10 years ago cooked something up and I was getting to lead the international study on his technology. It couldn't have felt any better. It was perfect.
“In order to get the T cells for genetic manipulations in the lab, we have to use a procedure called apheresis, which is routinely performed by the Stem Cell Department. So, I suggested a delegation from Kite to immediately visit MD Anderson to meet all related colleagues for collaboration coordination,” Wang noted. “The delegation team quickly came. MD Anderson's apheresis department, under the direction of Dr. Champlin, immediately became involved and offered a positive underbelly to the undertaking. He said he knew CAR T cells are a major breakthrough and he'd support the work however he could...and being a great leader immediately agreed.”
In short order, Wang started the ZUMA-2 clinical trial with his respected colleagues from many hospitals in late 2015, and 60 adult patients were enrolled in the primary efficacy analysis. Those patients enrolled into the trial previously had three different therapies, including a BTK inhibitor, and had only 6-10 months to live. They belonged to a desperate population with an unmet clinical need.
The new CAR T-cell program moved into high gear as patients were infused with the CAR T cells. “Initially, the CRS was so bad,” said Wang. “High fevers and hypotension; I was on call for 24 hours—basically all the time. Patients' side effects were often severe. Almost everyone developed neurotoxicity, and a few even fell into comas. Sometimes I had to put them in the ICU or on mechanical ventilation to get them through it. It could be scary in those initial days of CAR T-cell therapy, but now we have learned a lot and have become very confident and efficient in dealing with these adverse events. CAR T-cell therapy is much safer today.”
Wang remembers one patient in particular, a lawyer we'll call “Mr. Jones.”
“I said, ‘Mr. Jones, in 2 months I'm going to put you on CAR T-cell therapy. The therapy itself is very toxic. You have to be very strong, but right now your muscles are very soft. In order for you to survive the therapy, you need to hire a coach and train every day. I want a muscular man in 2 months.’ He did exactly what I asked him to do. He hired a coach. He went to the gym every day, including Saturdays and Sundays. When he returned he was so strong, but his tumor had grown. So, I put him in the ZUMA-2 trial,” Wang recounted.
“I infused the CAR T cells. His post CAR T-cell infusion course became very complicated. One Sunday, I heard by phone that he was not doing well. I said, ‘Transfer him to the ICU; I'll be right there.’ I started driving to the hospital immediately; I may even have missed a couple of red lights. I was frantic. I was desperate, you know?”
Mr. Jones was having a major cytokine storm with rapid progression to severe neurotoxicity. When Wang arrived in the ICU, his patient was speaking, but making no sense.
“I said, ‘Please intubate him right now. There is no time to lose!’ Half an hour later, he had a grand mal seizure after the intubation. We did an MRI of the brain. And I will never forget it. The MRI showed frank cerebral edema. The brain was swelling, and typically no one survives that. I was feeling a lot of pressure, but I was determined we were not going to lose him. I stayed with him all through the night. In the early morning around 1 a.m., my colleague Linda Chi, MD, injected ara-C and steroids into the cerebrospinal fluid (CSF).”
Wang explained that the CAR T cells were affecting the patient's brain. “That's why it swelled up and the patient was in a deep coma. So, we injected chemotherapy into the cerebral fluid to try to alleviate this side effect. But the next day, he continued to have seizures. I was so desperate. I asked a neurosurgeon, ‘Can you drill a hole into the cranium and let the pressure out?’ He said, ‘Michael, the procedure is called a ventriculostomy, and then he proceeded to drill a hole. Suddenly we saw the CSF spill out. Poof! Just like that it rushed out. And it was all done at the bedside by a neurosurgical fellow with his faculty and me standing by... Just imagine!”
Wang realized these potent CAR T cells were also damaging his patient's liver and other organs. “How do I stop it? Again, I felt desperate,” he admitted, “then all of a sudden, I thought about ATG—anti-thymocyte globulin. It can kill the CAR T cells. I asked the stem cell transplant doctors for help, and they offered the rabbit ATG to us. We immediately used that on the patient and he became dramatically better. And with all other measures he survived.”
ATG killed many CAR T cells that had been infused into Mr. Jones, including those intended to attack the MCL. “By the time we administered the ATG to the patient, the lymphoma had already been eradicated. Those CAR T cells were powerful. All this happened within a very short time, it was so intense. I did not sleep for 2 days.”
As this medical drama played out, Mr. Jones' family approached Wang with a question. “He was a practicing lawyer,” they began. “After all of this, do you think he will be able to remember how to practice law, and remember case details?”
“I said, ‘I don't know. There's a good possibility he might recover, but there's also a good possibility he may never recover. Right now, I'm just concerned with keeping him alive,’” recounted Wang. Then he proudly added, “Not only is he alive to this day, his lymphoma is in remission. And he is practicing law.” Wang, still feels indebted to colleagues who made significant contributions and offered vital supports in the powerful story of Mr. Jones.
While attending the Conference on Malignant Lymphoma meeting in Switzerland, Dr. Go and Wang met and discussed the toxicities, which resulted in a temporary halting of the ZUMA-2 trial. This hiatus allowed Wang and colleagues from other sites to work in concert with Kite to create a safer protocol without such devastating side effects.
“We decreased the amount of infused cells by 75 percent, and patients still responded very well,” Wang noted. “We kept learning. We soon discovered that early steroid usage can prevent the severe response. Starting tocilizumab, an antibody that blocks IL-6, can stop the fevers and help with the neurotoxicities. So, we were able to resume the previous CAR T-cell dosage at 2 million cells per kilogram and finish the trial.”
Today, this decision might seem so easy, but Wang said at that time it was really a hard one to make. “Jeffrey Wiezorek, MD, took all responsibility and made this critical decision. At that time, Will had left Kite for a great opportunity and my new contact was changed to Arati Rao, MD. She was an associate professor at Duke and was so intelligent and efficient. We were talking daily, sometimes several calls within one day.”
Wang personally treated 24 MCL patients during the multi-center trial in different cohorts, and every one of them responded with no mortality.
Wang is also thankful to the institutional support he received. MD Anderson Cancer Center established CARTox Committee led by Shpall and Neelapu. This committee, which includes nine Cancer Medicine Division departments and five supportive care departments, began holding weekly meetings in March 2016. Every CAR/TCR inpatient is discussed, with more focus on those requiring critical care.
The trial finished in mid-2019, and from that point, things moved with surprising rapidity. In December 2019, Wang presented the ZUMA-2 case at the American Society of Hematology annual meeting.
“It was in a gigantic room, and everybody was so excited about the results. It was all over the media. And on April Fools' Day in 2020, the data was published in the New England Journal of Medicine amid the pandemic (2020;382(14):1331-1342; doi: 10.1056/NEJMoa1914347). A few months later, on July 24, I was driving with my family on the I-10 highway from Houston to Mississippi when I got a call on my cell phone. It was to tell me that the FDA had approved this therapy for mantle cell lymphoma.”
In that euphoric moment, Wang had to pull off the highway to calm down. “I was receiving many phone calls, and my heart was filled with delight. I was just so excited,” he recalled.
Asked how it could have happened so quickly, Wang said simply, “It's truly a breakthrough therapy. And the patients demanded it. It was approved via breakthrough designation.”
Now that the therapy is approved to treat MCL patients with relapsed or refractory cancer, might it be considered for a frontline therapy? “I'm doing a trial to answer exactly that question,” said Wang. “I have designed a trial called Window Three, and we're doing it as frontline in high-risk patients. I think this will work as a frontline therapy. I believe in it.”
As he thought back across the career that has brought him to this medical crescendo, Wang took a moment for reflection.
“When I was still a fellow, there was not much hope for MCL patients. They would endure multiple types of chemotherapy, cycle after cycle. If the tumor didn't kill them, the chemotherapy might, you know?” he asked, rhetorically. “But I've had the opportunity to witness the evolution away from chemotherapy toward a chemo-free therapy.
The ibrutinib, as I mentioned earlier, is not chemotherapy. It's a targeted, chemo-free therapy that can single-handedly rival combination chemotherapy. But neither chemotherapy nor chemo-free therapy can cure patients. They can still relapse, and if they do, they only have 6-10 months to live. The only thing that can rescue them is CAR T-cell therapy. Now we're evolving to a new era—the cell therapy era. And I have been lucky enough to be part of it all.”
Just before the pandemic, Wang attended an Italian conference in Rome on MCL organized by Pier Luigi Zinzani, MD. Having half a day to spare after the conference, Wang and his friend Stephen Schuster, MD, a master in CAR-T therapy in lymphoma, toured the Roman amphitheatre. They both tweeted with their photo: “Gladiators in lymphoma.”
Valerie Neff Newitt is a contributing writer.
FDA-Approved CAR T-Cell Therapy
The FDA has approved the following CAR T-cell therapies in the course of just 3 years:
- tisagenlecleucel for patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse, Aug. 30, 2017
- axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma, Oct. 18, 2017
- tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma, May 1, 2018
- brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma, July 24, 2020
- lisocabtagene maraleucel for large B-cell lymphoma, Dec. 31, 2020
Individual Heroes in the Survival of Mr. Jones
- ICU: Matthew Reilley, MD (Fellow), Imrana Malik, MD, Cristina Gutierrez, MD
- Neurologists: Barbara O'Brien, MD, Shiao-Pei Weathers, MD, Karin Woodman, MD, Carlos Kamiya Matsuoka, MD, Sudhakar Tummala, MD (neuro-physiologist who did EEGs)
- Neurosurgery attending and fellow who performed ventriculostomy: Amy Heimberger, MD, neurosurgical attending, and Terence Verla, MD, neurosurgical fellow
- Lymphoma attending and PA or APP during the ICU stay: Luis Fayad, MD, Maria (Alma) Rodriguez, MD, Jason Westin, MD
- Advanced APPs: Yazhen Zhong, Cecilia (Ann) Savoie, Wendy Chen
- MD Anderson CarToc Committee led by Elizabeth Shpall MD, and Sattva Neelapu, MD. This committee includes nine cancer medicine departments and five supporting care departments holding weekly meetings since March 2016. Every CAR/TCR inpatient is discussed, with more intense focus on those patients requiring critical care. All new T-CAR, NK-CAR and TCR trials are presented.