‘A Moment of Marvel’ in Manhattan Brings a Revolution in CAR T-Cell Therapy
When the first flow cytometry analysis was run after a CAR T-cell therapy, showing no evidence of leukemia, Michel Sadelain, MD, PhD, and Isabelle Rivière, PhD, ran it through two more times.
“That was a eureka moment,” Rivière told Cell Therapy Next. “We had to convince ourselves and repeat the flow cytometry — make sure we didn’t forget the antibody to stain the leukemic cells — it was a total moment of marvel looking at these plots.”
Sadelain, who now serves as the director for the Center for Cell Engineering at Memorial Sloan Kettering Cancer Center (MSK), is quick to recall that this moment happened only after over 2 decades of work. For him, “It’s personal,” he said.
When he came to MIT from France via Canada, his idea to engineer T cells to treat disease was considered “a bit of a silly idea,” but despite the discouragement he received upon presenting his idea, he pursued it anyway. And even after 2 to 3 years, he admits he had little to show.
“It was a bit of an embarrassment but then it started to work,” Sadelain told Cell Therapy Next. Using the E. coli LacZ gene, Sadelain showed that it was possible to genetically modify a T cell.
“That was our first milestone achievement in this field, demonstrating that it was feasible to introduce genes in primary T cells,” he said. “We presented that at the World Congress of Immunology in 1992 and it elicited absolutely zero interest. Note that it is the foundation of today’s CAR therapy, leading to the two CAR therapies that were approved by FDA in 2017.”
Sadelain’s next step in trying to move the needle on these therapies was to position himself at an institution that understood clinical trials and getting treatments to patients. The logical place, he said, was Memorial Sloan Kettering, which ranks third in Investigational New Drug holdings – behind just the NIH and the entire University of California system.
Once at MSK, Sadelain led the charge to specifically look at hematologic malignancies due to the physicians’ experience with bone marrow transplantation, considering CD19, CD20 and CD22 as potential CAR targets.
Ten years after his first presentation on primary T cells, Sadelain and his colleagues published a paper that brought it all together — “human peripheral blood primary T cells transduced with a retroviral vector, encoding a CAR that has dual signaling properties including costimulatory properties that are specific for CD19” — to show a cure in mice. And then he set his sights on translation to the clinic.
“We knew very well that this therapy, which was both a cell therapy and a genetic therapy, was not the kind of thing we could take to a company for clinical development. You have to do it yourself or it’s not going to happen,” Sadelain said. “We knew we had to establish what’s called a [Good Manufacturing Practice (GMP)] laboratory and we did so, right upstairs in our research building.”
Manufacturing in Manhattan
Sadelain is quick to credit Rivière with the implementation of the GMP laboratory, referring to her as MSK’s “most important recruitment,” though she credits him with convincing MSK leadership that the cleanrooms were needed and for putting the first ones into place in 1998.
“We didn’t have a product yet in 1998,” Rivière said. “Sadelain was working full speed on developing applications for treating leukemia with CD19-targeted T cells but we didn’t have the protocol yet. Our first GMP product was a plasmid DNA product. By taking this detour, we demonstrated to ourselves and to the FDA that we could manufacture our first GMP product in-house. Then we moved on to develop the manufacturing protocol for CAR T cells.”
Once Sadelain’s seminal 2003 paper was published, Rivière said she moved into fully developing a protocol that would translate to the clinical setting and began researching other GMP facilities.
“I had very little idea as to what effort it would take except that I wanted to bring this type of therapy to patients. We wholly believed in it,” she said. “We were going to pave the way for these cell therapies.”
And they did — since that first eureka moment, MSK has manufactured more than 350 CAR T-cell products and treated more than 250 patients across various indications, Rivière said. It was evident that they would need more than the original space Sadelain had obtained.
“We were restricted by space; 6,000 square feet in Manhattan is not easy to come by,” Sadelain said with a laugh.
But they did find the space and now occupy an entire floor of a building across the street from the main MSK hospital, the Mortimer B. Zuckerman Research Center. The current space opened in 2014.
“We had originally two rooms for processing patient cells and one for producing retroviral vectors. Now that we have moved here to the seventh floor of the Zuckerman building, we have 13 cleanrooms so we can treat a lot more patients,” Rivière said. “We have been able to manufacture our viral vectors in-house to modify our T cells with the CARs since we started so that allows us to not rely on third parties. There is a shortage of suppliers of these vectors, so we are less dependent than others. ... For most of our CAR T-cell program, we make the vectors in-house, which has helped us accelerate our program.”
As Sadelain made clear, his early focus was on hematologic malignancies because it was felt the physicians in those fields would more quickly grasp the treatments. Helping with the acceptance, MSK reported early success alongside the NCI and the University of Pennsylvania.
“All three centers reported very dramatic clinical results and although we felt this was our baby — it certainly is in conceptual terms — it was a good thing that three centers contemporaneously reported such provocative data, thus accelerating the widespread acceptance of the merits of CD19 CAR therapy. It’s not just one group that’s saying something, it’s two or three — so it must be true,” Sadelain said. “This caught the eye not just of the public and of the physicians but also industry. To me, this is one of the great contributions of CD19 CAR therapy. ... This is what tipped the balance in the world of big pharmaceuticals. Cell therapy had been around for some time since red blood cell transfusions decades ago to bone marrow transplants and tumor-infiltrating lymphocytes ... but it never got industry to embrace it. This did.”
Another great contribution in Sadelain’s eyes is the fact that CAR T-cell therapy achieved something many thought impossible, allowing current and future generations of physicians and researchers to dream even bigger.
“We are introducing a synthetic gene to rewire the functions of a T cell. You can call this the first foray of synthetic biology into clinical practice,” Sadelain said. “It’s a genetically modified cell that’s approved by FDA, capturing the imagination of many scientists, physicians and biotechs.”
One of those next-generation physicians is Sham Mailankody, MBBS, who, after fellowship at the NCI, followed his mentor, C. Ola Landgren, MD, PhD, to MSK. Mailankody never thought he would be at the center of the next big step in CAR T-cell therapy: myeloma.
“I still didn’t have an inkling that I was going to be a cell therapy physician at the time. My plan was to do early phase clinical trials for patients with multiple myeloma,” he told Cell Therapy Next. “When these products — these constructs — were developed by the team at MSK and ready to come to trial, they wanted somebody to run the clinical trial here, somebody that had myeloma expertise and an interest in early phase clinical trials. ... This was 2 years back and I assumed it was going to be one trial that I’d do and then just return to my alcove in myeloma. One study led to another and now I am involved in several of the myeloma CAR T-cell studies here.”
MSK has participated in two clinical trials for BCMA CAR T cells and now has non-CAR T-cell BCMA therapies and bispecific antibodies.
“Just how quickly this field for myeloma as for other cancers has evolved is fascinating,” Mailankody said.
Mailankody, who sees most patients with myeloma who receive cell therapy, discussed JCARH125 (Juno), a BCMA-directed CAR T cell developed at MSK, for which the preliminary results were presented at ASH.
“Now seeing these patients out 1 year without their disease coming back is quite rewarding,” Mailankody said. “To be able to contribute and participate in a study of this kind that may someday change the standard of care for patients with myeloma is heartening. ... It’s only a matter of time before a BCMA-directed cellular therapy is available for a patient with advanced myeloma as a treatment option and standard of care.”
While not all patients have a full response, Mailankody sees that as another challenge that they will continue to research.
“The first step in terms of making this available to patients is to have this as a FDA-approved therapy for patients with advanced disease,” he said. “There’s a feeling that perhaps using cellular therapies like CAR T cells earlier on and in early relapses or in select patients with high-risk disease up front is one strategy. The second one is to come up with rational combinations. Those could be combinations of CAR T cells that target two different targets or adding drugs that we think might potentiate the activity or efficacy of these CAR T cells.”
But first is to get all eligible patients treated.
“In cell therapy we are all faced with many patients who need these treatments and we cannot treat everybody either because of limits of trial eligibility or availability. We and everybody else involved in this field do everything we can to get patients to the right treatments,” Mailankody said, feeling that the field has still come so far.
“Ten years ago, if you had asked me, ‘Are you going to do cell therapies for patients with myeloma?’ I would have said, ‘Probably not. There are a lot of drugs and I will probably stick to them.’ Here I am eating my words and doing these trials,” Mailankody said.
The ‘Battlefield’ of Solid Tumors
Though approvals and 90% success rates in some hematologic malignancies are exciting and encouraging, the next battle lies with solid tumors.
“I would like to see first a breakthrough in solid tumors. It’s one of the first things that needs to happen for this technology to continue to thrive. The progress for the patients with leukemia and lymphoma is remarkable, but for industry to continue to put the means to produce these products commercially, we need to have new disease applications so it’s very important that we have a breakthrough in solid tumors,” Rivière said.
Right now, Prasad S. Adusumilli, MD, FACS, is leading that charge. Adusumilli remembers everyone said he was making a mistake going back into the lab after finishing his surgical fellowship, but he knows he would not be where he is today without all of the “weapons” he learned to use along the way.
Despite the detractors, Adusumilli joined a lab at MSK and even convinced Yuman Fong, MD, to mentor the surgeon-researcher on running the lab.
“I learned a lot and made a few mistakes as well, but he was still supportive. It helped me realize that’s what I want to do. I want to be a surgeon as well as do research,” Adusumilli said. “As a faculty member, I took my time, being a surgeon, to take the tumors from the operating room and to do a deep investigation of tumor immunology.”
Adusumilli’s interest in biological therapies sparked with oncolytic viruses and regional delivery to the pleural cavity. After talking to Sadelain, they realized their common goals of treating these solid tumors with CAR T-cell therapy and Adusumilli joined the Sadelain Lab, bringing his ideas of regional delivery and clinically-relevant mouse models to this new technology and injecting the CAR T cells directly into the pleural cavity of patients with mesothelioma.
“Many said, ‘You’re a surgeon, that’s why you want to inject, but there is no basis for that.’ And they have a point,” he admitted. The thoughts among those doubters was that T-cells are systemic immune agents and even if it works on the tumor itself, the T cells would sequester in that space and not circulate.
“We have shown in mouse experiments that both concepts are wrong. T cells by nature want to enter the circulation and go through the body. Even mice with the largest tumor when we inject the CAR T cells, within a day, I can see the T cells in the spleen and elsewhere,” Adusumilli said.
Adusumilli also pushed against the theory that CD8 cells were the only effective killers, instead showing that CD4 is as effective a killer as CD8 while retaining their helper function.
“If ... you believe that your wife or your mother can be a helper and a killer, then you can see how this cell can do both. Now it’s a proven fact that CD4s can continue to be helper cells, and can turn into killer cells,” Adusumilli said.
Adusumilli recently presented data on 21 patients with mesothelioma, metastatic breast and lung cancers enrolled in his clinical trial. He explained that this phase 1 trial with dose escalation was powered for safety, not efficacy and it was where he saw the power of the patient population at MSK.
“When I make eye-to-eye contact and say, ‘What I’m going to test has never been tested in the world. Even in my opinion, it doesn’t work without the cyclophosphamide, but I can’t give it to you because you’re the first cohort and the dose of CAR T cells I’m going to give you is 1/100 of what I give to a mouse, can you please participate in the clinical trial?’ And they did. That’s what I mean when I talk about Sloan Kettering patients.”
He became emotional discussing one patient who postponed an around-the-country trip to participate and another who put off moving to a state with physician-assisted suicide.
“The patients are incredible and courageous especially because they participate knowing it may not directly benefit them,” Adusumilli said. And, in the end it did, showing a lack of toxicity and allowing for the addition of checkpoint blockade.
“It is our duty to show that it is safe, which it has been. But we are seeing results with these patients even with one dose,” Adusumilli said. “Two patients had a complete metabolic response ... and about five patients had a partial response close to 6 months to a year and did not require any other therapy. All these patients functionally are back to normal life.”
“We estimated that if we are successful in targeting mesothelin, at least 2 million patients in the U.S. would be eligible for mesothelin-targeted therapy. There is mesothelin expression in two-thirds of patients with lung adenocarcinoma, two-thirds of patients with ovarian cancer, most of the patients with pancreatic cancer, one-third of patients with breast cancer and majority of the patients with colon cancer,” Adusumilli said.
In another ongoing clinical trial, Adusumilli and his team are targeting triple negative breast cancer, another disease state without much available in treatment or hope.
“We get lost in the science and the cells and the mice, but this is important. That’s where I feel like my drive comes from. ... I’m privileged because I see the patient body and mind in the clinic. I go to the OR and see their lungs and their tumors. I go to the lab and see their cells. It gives me a complete picture to stay focused,” Adusumilli said.
He hopes to combine his knowledge of the tumor environment, his surgical expertise, the regional delivery, advances in CAR T-cell therapy along with advances in checkpoint blockade and interventional radiology.
“This is the prime time to combine these advances in different fields and to take a few steps faster than what we have been doing,” Adusumilli said. “I have a good weapon in CAR T cells. I understand my battlefield because I worked in the solid tumor immunology and I trained with my weapon in a good base — our mouse models. We know it’s going to be an uphill task and it’s going to be a challenge — solid tumor immunotherapy — but these three pillars make me excited that I’m up for it.”
The ‘Holy Grail’
Simultaneously while Adusumilli and others attack solid tumors, Sadelain and his team are working toward a more universal approach to CAR T-cell therapies.
“The cell therapy will not be collected from a human being. It will be generated in culture from a pluripotent stem cell. We want to see pluripotent stem cells producing CAR T cells. We are working on that very actively. That would be the true off-the-shelf in so far that if you have a stem cell that just produces zillions of these T-cells, you don’t have to go into the blood from healthy volunteers,” Sadelain said. “CAR therapy is already a radical transformation of cell therapy — based on patient cell engineering with synthetic genes. This would be the next most radical change.”
Rivière imagines that there may be a few treatments available that would treat various subsets of patients.
“We may not make a product that is available to every patient but if we had a series even of 10 or 100 products that could be applicable to 90% of the population, it would definitely allow us to make these drugs cheaper and available faster. Right now, we are limited by the fact that we have to take autologous cells and make them for each patient. Logistically, it requires a heavy structure that needs to be in place. The industry doesn’t really like it,” Rivière said.
Sadelain agreed, putting it on the researchers to find a better, more efficient, more effective way to deliver these life-saving treatments to patients. Researchers need to look toward more persistent cells that cause less toxicity and can be given to more than just one patient.
“There’s a non-science part to it — regulatory, government, profit, etc. And then there’s the part that we can act on, as scientists, and that’s creating cells that would be easier and cheaper to make and easier to distribute,” Sadelain said.
In essence, a truly universal treatment is the ultimate goal.
“We are going for the holy grail, which is to advance an allogenic approach, giving a cellular product to many different patients without collecting their cells by having either a universal donor or engineering a cell that is more universal,” Rivière said.
At the Forefront, Together
All of the experts at MSK credit the atmosphere of research, collaboration and innovation at the institution with pushing this field to the forefront of treatment and keeping it there.
“The concept of how to make a T cell genetically constructed to recognize an antigen of your choosing and build into it the signaling such that it can kill, expand, seek additional targets, kill again, expand again, and repeat as needed. ... That’s the living drug,” Sadelain said. “That’s my life contribution but I’m not done yet. This is just the beginning. It creates a starting point for so many young physicians and scientists who now perceive cell therapy not only to be an interesting academic exercise where people have smart theories and strive to produce proof of concepts, but a path leading to effective and broadly adopted treatments. This has created a new starting point. T-cell-based medicines can work and they can work dramatically. ... They can even work in settings where not a single other modality works, and they may be curative on their own. That’s not bad as a demonstration of what a carefully engineered cell can achieve.”
The future of that engineering, he said, will lie with the academic centers.
“This field was born in academia and recently adopted by industry, which is wonderful. But it is really thanks to a handful of centers that this field was born — not more than five — and MSK is one of those five. Academia will continue to drive the field,” Sadelain said. “There are so many engineering strategies and diseases to investigate. What has changed following the success of CD19 CAR therapy is that all of this work now has a welcoming home in industry. Industry will have to take on the challenge of distribution and sustainability. This prospect is going to attract so many more people to this field. I think there will be a big boom in cell therapy in the decade to come, owing to a massive influx of brain power, enthusiasm and investment.”
MSK is situated in that it serves to incubate new ideas and support new integrations of expertise. Its Cellular Therapeutics Center (CTC), led by Renier J. Brentjens MD, PhD, brings together people from all roles and specialties to discuss any and all ongoing cell therapies. They meet weekly and allow for open discussion.
“It’s an incredible learning environment,” Adusumilli said, crediting the CTC. “I am sitting next to leukemia and lymphoma medical oncologists who have been working with CAR T-cell therapy for a while, and I have been working with them for the past 5 years. Everything is ... passed through osmosis. I have the right groups to ask CAR T-cell patient management questions,” Adusumilli said.
And MSK’s CTC is not just for physicians or researchers, it includes nurses, technicians and ICU staff.
“What I find fascinating here is that we have a long institutional memory of using cellular T cells. Our nurse practitioner, Elizabeth Halton, RN, ANP-BC, AOCNP, was here when the first patient was treated with a CAR T cell in 2006. She’s taken care of or participated in the care of every patient who is treated on clinical trials whether it be leukemia, lymphoma or myeloma. Our research nurse, Claudia Diamonte, RN, BSN, OCN, has been part of the CTC for over 10 years now. And it’s not just them. Many of our nurses, research staff and physicians have been here 12 or 15 years and they know exactly what happened when the first patient was treated and what is happening now,” Mailankody said. “There is a general sense in our team, as a whole, of comradery and a collective responsibility for patients that pre-dates my joining this team. The nurses, NPs, doctors, research staff — I’ve never had anybody tell me it’s impossible to do.”
Conquering the impossible was a goal for Sadelain nearly 30 years ago and each person involved with cellular therapy at MSK seems set on the same horizon.
“Memorial Sloan Kettering is a unique place; it has all the components that allow the researchers and researcher-physicians who are interested in developing cellular therapies to establish the proof of concepts first pre-clinically in animal models. We have a critical mass of investigators who want to translate their innovative approaches from the bench to the bedside. ... My lab takes these from the bench and adapts and translates them into processes that can be applied to the clinic,” Rivière said. “The group has really grown exponentially. Now, we have many physicians who are able and willing to implement this technology. The proximity of the GMP facility with the clinicians in the CTC and the Center for Cell Engineering — which is really the home for all the investigators who are conducting the primary research — and the commitment of the concerned teams to translating these new research approaches into the clinic is the perfect combination to be able to move swiftly and be at the forefront.”
“It’s been very exciting. There is never a dull moment,” she said with a laugh. – by Katrina Altersitz
- Brentjens RJ, et al. Nat Med. 2003;9(3):279-286.
- For more information:
- Prasad S. Adusumilli, MD, FACS, can be reached at firstname.lastname@example.org.
- Sham Mailankody, MBBS, can be reached at email@example.com.
- Michel Sadelain, MD, PhD, can be reached at firstname.lastname@example.org.
- Isabelle Rivière, PhD, can be reached at email@example.com.
Disclosures: Adusumilli reports research funding from Atara Biotherapeutics, which received the license of mesothelin CARs from Memorial Sloan Kettering Cancer Center. Adusumilli and Sadelain are the inventors of this therapy and will receive a share of the license income. Memorial Sloan Kettering received license fees and has the potential to receive royalties under the license. Mailankody serves as principal investigator on clinical trials supported by Juno Therapeutics (a Celgene company), Janssen Oncology and Takeda Oncology, reports receiving honoraria for CME activity from Physician Education Resource and for editorial responsibilities from Elsevier. Sadelain serves on the scientific advisory board of Berkeley Lights and reports grant support from Juno Therapeutics, as well as patents licensed to Juno Therapeutics for nucleic acids encoding chimeric T-cell receptors (US 7446190), constitutive expression of costimulatory ligands on adoptively transferred T lymphocytes (PCT/US2008/004251), methods for off-the-shelf tumor immunotherapy using allogeneic T-cell precursors PCT/US2009/000606), and compositions and methods for immunotherapy (PCT/US2014/030671). Memorial Sloan Kettering has licensed Sadelain lab technologies to Atara Biotherapeutics, Fate Therapeutics, Juno Therapeutics and Takeda Pharmaceuticals. Rivière reports funding support from Atara Biotherapeutics, Fate Therapeutics, Juno Therapeutics (a Celgene company) and Takeda Pharmaceuticals and acting as a consultant for Fate Therapeutics and FloDesign Sonics.