The Frontier of “Living Drugs”

By Susan Conova | Portraits by Jörg Meyer

On the first floor of the Russ Berrie building on 168th Street, a transformation for Columbia medical research is almost complete.

This fall, an idea that went from being dismissed in the ’90s to launching a field of cancer therapy in the 2010s is taking new root at Columbia, as specialized equipment is installed and new recruits arrive to form the cell therapy production facility. By next year, the first engineered cells developed by Columbia researchers and manufactured in the facility should be ready for patients.

The facility ushers in new possibilities for cell therapy research at Columbia, giving scientists and physicians the ability not only to design new treatments in the laboratory, but also to produce the cells for testing in patients.

Cell therapy is the administration of cells as medicine to accomplish a range of objectives, including destroying harmful cells, repairing damaged cells, and regenerating a defective organ or tissue. And the field has exploded in the past 15 years.

Much of the excitement today centers around CAR-T therapies that genetically engineer a patient’s own T cells to fight cancer. The first two CAR-T therapies were approved by the Food and Drug Administration (FDA) in 2017, and five more have been approved since. Hundreds of CAR-T therapies—mostly for cancer, but increasingly for other conditions—are currently in development around the world.

The success of CAR-T can be traced to one of its original pioneers, Michel Sadelain, MD, PhD, founding director of the new Columbia Initiative in Cell Engineering and Therapy (CICET). During his three decades at Memorial Sloan Kettering (MSK), Dr. Sadelain created the first successful CAR-T cells and made critical contributions to their conception and production that have led to exciting outcomes in the clinic.

“He has done so much for the field, and I think without his advancements, we would never be able to do what we’re doing now,” says Maksim Mamonkin, PhD, associate professor of pediatric immunology, who is one of CICET’s newest recruits. “He was at the forefront of the most conceptual development in engineered T cells. When I saw the news that he was building a new team here, with a strong institutional commitment, I was very enthusiastic to join.”

Since his arrival at Columbia in the fall of 2024, Dr. Sadelain and CICET members have been building up the new cell production facility, recruiting new scientists, and exploring collaborations with a wide range of researchers on the medical and main campuses.

“The medical center includes an amazing cancer center and vast expertise in so many other fields of medicine—autoimmune disorders, neurology, transplantation, infectious diseases, and more—where we believe CAR-T cells can be very useful,” says Dr. Sadelain, who is also the Herbert and Florence Irving Professor of Medicine and the director of the Cancer Cell Therapy Initiative in the Herbert Irving Comprehensive Cancer Center. “The School of Engineering is very relevant with its bioengineering expertise; the business school is very relevant because we want to increase access to our novel therapies. We want to connect with the extraordinary artificial intelligence research on campus. And the new Chan Zuckerberg Biohub New York [with researchers from Columbia, Rockefeller, and Yale] is very aligned with what we do. So, there’s plenty of good reasons for wanting to work here.”

A Tenacious Start

Among the genetically modified cell therapies in development today, the most common is CAR-T targeting CD19, which has transformed the treatment of blood cancers that originate in B cells and is approved for people who don’t respond to initial treatments or experience a relapse.

“The crux of CAR-T cells is that the medicine is not a pill, it’s not a chemical, it’s not a protein. It’s a human cell that’s been reprogrammed to eliminate cancer,” Dr. Sadelain says. Once introduced into a patient, CAR-T cells chase every cancer cell and, when CAR-T cells persist, remain ready to respond if the cancer cells reemerge. In an offhand remark to a journalist in 2012, Dr. Sadelain called the cells “living drugs,” a term that has stuck to describe this new class of medicines.

The outcomes for patients who are out of treatment options can be remarkable. “For some types of leukemia or lymphoma, a third to a half of patients who receive the therapy experience very durable remissions, many of which can be considered as cured,” Dr. Sadelain says. For many others, the disease can remain in remission for some time.

But in the late ’80s and ’90s when Dr. Sadelain and a few others began investigating how to turn a patient’s own T cells into cancer assassins, most people did not believe in his vision. “The idea was, let’s say, not well received,” Dr. Sadelain recalls.

In the 1980s, Dr. Sadelain was in graduate school at the University of Alberta when the idea came to him. “I was struck by the way our bodies use T cells as a rapid response task force to repel invading viruses. I fantasized that it might be possible to instruct T cells to do the same thing to fight cancer,” Dr. Sadelain told an audience in 2012 as he accepted the William B. Coley Award for Distinguished Research in Tumor Immunology, one of several prizes to come for his work. (He has since received the Gairdner Award, Warren Alpert Foundation Prize, and Breakthrough Prize in Life Sciences, and in 2025 alone, the King Faisal Prize in Medicine, Merkin Prize in Biomedical Technology, Meyenburg Prize, and Broermann Medical Innovation Award.)

T cells were known to fight cancer to some degree, but they usually fail. In the early days, skeptics asked: If our immune system can’t already defeat cancer, how could it be pushed to succeed?

The first hurdle was genetically engineering a human T cell. After moving to the Whitehead Institute at the Massachusetts Institute of Technology, Dr. Sadelain worked on the problem in his spare time (after his adviser asked him to drop the research). “We were attempting this for several years until, finally, something started working,” Dr. Sadelain says.

By the early ’90s, T cells dubbed “T bodies” were engineered at the Weizmann Institute of Science. Inside the cells, a synthetic gene created a fusion protein: one half an antibody that recognizes and latches onto cell-surface molecules; the other half, the cells’ normal T cell receptor, which triggers the cells to kill.

These first-generation CAR-T cells turned out to be lemons. They didn’t last when repeatedly exposed to their target and generated a limited response.

Dr. Sadelain, who by then had moved to MSK, made several contributions that solved crucial shortcomings. To improve the cells’ persistence and cancer-fighting abilities, he added a co-stimulatory protein to the synthetic receptor, ensuring the CAR-T cells could become fully activated. He also pioneered the use of CD19 as a target, chosen because the CD19 antigen is highly expressed in B cell malignancies compared to other potential targets.

Dr. Sadelain called his cells “chimeric antigen receptor (CAR)” T cells.

“Chimeras are creatures in mythology that can have the head of a lion, the body of a bird, and then the tail of a reptile,” Dr. Sadelain says. “The CAR molecules we create are generated by stitching together parts of proteins that are normal, but never assembled that way in nature, like chimeras.”

This design would become the backbone of today’s CAR-T therapies. But first, it needed to be manufactured.

“Usually, if somebody discovers an interesting molecule, a company will see its potential, develop it, and bring it to trials. But in this case, we had to take it to the next step ourselves,” he says. “The reaction from industry to our preclinical work was, ‘Yeah, so what?’”

Dr. Sadelain’s team learned to be an academic mini-biotech company to manufacture cells for clinical trials.

Isabelle Rivière, PhD, Dr. Sadelain’s colleague at MSK, took the lead, inventing processes to grow high-quality engineered cells safe for treatment. While initial CAR-T production was complicated and time-consuming, Dr. Rivière’s methods consistently generated clinical doses in under two weeks, minimizing the time ill patients must wait for treatment.

In 2007, the MSK team was the first in the world to infuse a patient with a CD19 CAR-T cell therapy, and the success of those cells led others to adopt the design. Today, of the seven current FDA-approved CAR-T therapies, five target CD19 for the treatment of B cell cancers, including acute lymphoblastic leukemia (ALL) and several types of lymphoma.

In 2013, the team reported results of their first clinical trial, this time in adults with ALL. Remarkably, among all five patients, whose cancer had returned after initial treatment and who had no other options, the treatment eradicated the tumor and produced a complete remission.

Building on CAR-T at Columbia

Dr. Sadelain’s arrival at Columbia creates an infrastructure for an already robust cell therapy clinical program.

Since 2017, Columbia University Irving Medical Center has been routinely delivering all FDA-approved products, while growing an extensive clinical research portfolio.

“More than 50% of our cell therapy patients so far have been part of a clinical trial, from a phase 1 study where we infused the first patient on Earth to the full spectrum of phase 3 randomized trials,” says Ran Reshef, MD, director of CUIMC’s adult cell therapy program. Increasingly, that includes treatments designed for solid tumors, such as prostate cancer, and autoimmune diseases, indications beyond the blood cancers for which CAR-T therapies were initially developed.

“We’ve never seen anything grow so rapidly as our T cell therapies,” says Dr. Reshef. “If you look historically, CAR-T is growing more quickly than bone marrow transplants.”

Delivering cells as a therapy involves complexities that most physicians are not familiar with and do not encounter in their routine practice.

“Even if we’re not doing the genetic modification in-house, the handling of cells—putting them in the freezer, sending them for modification, receiving them, thawing them—takes expertise that a regular pharmacy or oncology practice doesn’t have,” Dr. Reshef says. “That’s a resource we had to build. In addition, the management of potential side effects from CAR-T cell therapies requires expertise, and we have physicians here at Columbia who have been deeply engaged in this field for more than 15 years, which is a tremendous advantage.”

Adding to the complexity, cell therapies are personalized. “There’s no other medication where you make a product specifically for each individual patient,” Dr. Reshef says. “It requires an army of coordinators, research nurses, and technical staff to make sure everything happens correctly.”

All this experience and expertise means that the program is ready to test the new cell therapies from the Columbia cell production facility in 2026.

“The recruitment of Dr. Sadelain is, of course, a major game changer. He brings in a lot of enthusiasm and creativity, and we are ready to test any novel product that comes out of his new cell manufacturing facility.”

The Challenge of Solid Cancers

The first CAR-T therapies were designed for hematological cancers, partly because the malignant cells are found in locations that T cells easily access. Solid cancers have proved more resistant; they usually erect barriers, including a protective microenvironment, that stymie natural T cells as well as CAR-T cells.

“A lot of these barriers are recognized today, and now it’s up to creative scientists and physicians to come up with the solutions,” Dr. Sadelain says. “But it won’t happen overnight. It took 14 years to go from our landmark 2003 paper showing that human CAR-T cells can cure lymphoma or leukemia in a mouse to FDA approval in 2017.”

At CICET, researchers are already working on CAR-T therapies for acute myeloid leukemia, T cell leukemias, glioblastoma brain cancers, and liver cancer. Dr. Sadelain’s lab recently received funding to expand their work in ovarian cancer. “Columbia’s expertise in cancer microenvironment research, systems biology, and biomedical engineering should be very helpful in this area,” he adds.

Greater heterogeneity among antigens is also a bigger problem in solid tumors than in blood cancer, says Dr. Mamonkin, who is also director of laboratory and translational research in pediatric hematology, oncology, and stem cell transplantation. “The cancer cells that express the target, they get eliminated. The cells that don’t, they survive and expand. At the end of the day, unlike mono-targeting in lymphoid malignancies, we need to develop combinatorial antigen targeting, and that’s probably where we’ll start seeing deeper, more robust responses. But these approaches have to be designed carefully not to harm vital healthy tissues in the patient.”

CARs Beyond Cancer

Three years ago, German researchers caused a stir when they reported that five patients with severe lupus went into drug-free remission after receiving CD19-targeted CAR-T cells.

“The findings stunned rheumatologists worldwide,” says Anca Askanase, MD, professor of medicine and director of the Lupus Center at Columbia University, who has been an investigator on several trials of cellular therapies for lupus. “It suggested the possibility that CAR-T cell therapy could represent the long-sought cure for lupus.”

In lupus, as with many blood cancers, CAR-T therapy targets the B cells that mistakenly attack the patient’s own tissues—although long-term outcomes are unknown.

“They have to be carefully studied now, and that’s what’s happening at Columbia,” Dr. Sadelain says. “It’s one of the main reasons why I’m here, and we intend to intensify that effort.”

Autoimmune disease is an exciting new direction for the CAR-T field, and one that is moving rapidly. “In this case, CAR-T cells didn’t have to be reinvented. The recipe is exactly the same one we used in cancer,” Dr. Sadelain says.

CAR-T cells are also in early trials at Columbia for multiple sclerosis (MS), which was considered a T cell-driven disease until B cells were found to play a critical role in its pathology. Antibody therapies to deplete the B cells have revolutionized many patients’ lives—but they can’t cross the blood-brain barrier to limit the inflammation MS causes in the brain and spinal cord. Long-term use also leaves patients vulnerable to serious infection.

“So many of our patients are still gradually getting worse, even in the absence of relapses, and new approaches are needed,” says Claire Riley, MD, the Karen L. K. Miller Associate Professor of  Neurology and director of the Columbia Multiple Sclerosis Center. CAR-T cells can pass through the blood-brain barrier and represent a potential paradigm shift. “Instead of chronically suppressing the immune system, we may be able to achieve a temporary, but deeper, B cell depletion that recalibrates the immune system and induces long-term remission. It’s an exciting path to embark on.”

Slightly different cellular recipes are being developed by other Columbia researchers. Aimee Payne, MD, PhD, the chair of dermatology, has developed CAART cell therapy—a clever twist of CAR-T— for pemphigus, a blistering disease that is sometimes fatal, and myasthenia gravis, which causes potentially life-threatening muscle weakness. CAR-T works a bit like a sledgehammer, indiscriminately killing all B cells, not just those causing disease. CAAR (chimeric autoantibody receptor) T cells are more selective, using the autoantigen as bait to lure only the autoimmune B cells to their deaths.

CAR-T cells could also solve problems in organ transplantation, where one in five patients experiences complications when their immune systems are suppressed to limit rejection. Instead of engineering T cells to be better assassins, scientists are using CARs to engineer regulatory T cells to be better peace negotiators. With a CAR approach, regulatory T cells could be trained to home in on the transplanted organ and lower the risk of rejection.

“We don’t know much yet about engineered regulatory T cells, but armed with what we’ve learned in cancer and our knowledge of T cell engineering, there’s good reason to hope it could work,” Dr. Sadelain says.

New Possibilities

Though the first cells produced by the new facility are expected in 2026, they won’t be the first cell therapy designed and created at CUIMC. Since 2022, the Cellular Immunotherapy Laboratory has been producing virus-specific T cells for life-threatening viral infections in patients with impaired immunity, such as recipients of bone marrow and solid organ transplants or cancer patients on chemotherapy.

“The idea behind our cell therapy is that we can take T cells from a patient or a donor, select the ones that recognize the virus, and multiply those in the lab so we create a population of immune cells that we give to the patient to control the infection,” says Pawel Muranski, MD, director of the Cellular Immunotherapy Laboratory.

The cells are still undergoing clinical testing, but Dr. Muranski says they’ve seen several patients experience complete and “spectacular” regression of their infection—or lymphomas driven by the virus. “We have a very large transplant program at CUIMC, and there’s a huge need for this type of treatment,” he says. “Having CICET here puts us on a completely different level in terms of expertise and capabilities, and we’re very excited by the possibilities.”

What’s Next for Blood Cancers

The rise of CAR-T therapies for solid cancers, autoimmune diseases, and transplantation shouldn’t be taken as a sign that the therapies have reached their heights with blood cancers.

Sascha Haubner, MD, the first faculty member recruited to CICET, started working eight years ago at MSK to extend CAR-T therapy to myeloid malignancies, blood cancers that originate in hematopoietic stem cells or myeloid progenitor cells.

Acute myeloid leukemia (AML) is particularly challenging for CAR-T because malignant and healthy hematopoietic stem cells are not easily distinguishable on their surface—making healthy stem cells prone to collateral CAR-T damage.

“Healthy stem cells are required for replenishing red blood cells, platelets, and basically the whole immune system,” says Dr. Haubner, an assistant professor in the Department of Medicine. “They must be protected.”

Drs. Haubner and Sadelain have devised an inventive CAR system that uses Boolean logic to make a complex decision to kill or not to kill based on the presence of two antigens and their abundance on the cancer cell.

Their “IF-BETTER” CAR-T cell contains two different CARs that work together to kill obviously malignant cells, spare obviously healthy cells, and, most impressively, kill the malignant cells that are masquerading as healthy cells.

In 2024, Dr. Haubner’s research enabled the opening of a phase 1 clinical trial at MSK for patients with relapsed or refractory AML, using the “IF-BETTER” logic-gated CAR-T cells for the first time to treat patients. “The trial is ongoing and showing early promising signs. Ultimately, we aim to achieve long-term remissions,” Dr. Haubner says. His new research lab at Columbia is developing novel CAR-T cells with the goal of offering more AML patients access to this promising therapy.

CARs for Kids

Children, fortunately, rarely get cancer.

“But because of that, it’s very difficult to get much support from biotech and pharma companies since the market size is very small,” says Dr. Mamonkin, who is building a pediatric cell therapy program at Columbia with Liora Schultz, MD, associate professor of pediatrics, who just arrived this fall from Stanford.

The focus on children will be a new mission for Dr. Mamonkin, who is known for developing CAR-T therapies at Baylor College of Medicine, including a therapy for T cell malignancies that has now entered a multicenter phase 2 trial in the United States.

Targeting T cells with T cells required new engineering to prevent the therapeutic cells from mistakenly turning on each other and committing “fratricide.” Initially, the response rate in patients was low, but as Dr. Mamonkin’s team changed manufacturing processes, response rates and outcomes in patients with aggressive T cell leukemia dramatically improved. “It was a long process, but shepherding a new conceptual therapy all the way from the lab to patients and seeing its real impact in the clinic was very rewarding.”

At Columbia, the Mamonkin lab will expand into solid and brain cancers, autoimmunity, and other difficult diseases that could be treated with engineered cell therapies.

“Our main focus will be conquering diseases that don’t really have any good solutions at present.”

Building Cheaper CARs

As CICET works to create new types of cell therapies for testing, its researchers are trying to reduce the price tag, which can climb to $2 million when combined with the costs of the hospital stay.

“Making a therapeutic cell is more expensive than making a chemical,” Dr. Sadelain says. “The prospect of being curative, potentially with a single cell infusion, motivates our research—but we are also aware of the economics. Part of the solution lies in the biology. If you make better cells, you will need fewer cells. And that will facilitate access to cell therapies. So we keep doing research to improve the efficacy and safety of engineered cells.”

There’s a clear economic benefit to having the cell production facility at Columbia, says Vladimir Bermudez, PhD, associate director of CICET. “We have a Good Manufacturing Practices [GMP] team, which includes process development, analytical testing, production, quality control, facility operations, and quality assurance, that works closely with our research labs to lower the overall cost of developing and manufacturing cell and gene therapies.”

Dr. Bermudez also believes CICET can be a source of products for rare conditions that pharmaceutical companies offload because they’re not profitable.

“We’re not just manufacturers; we have aspirations of developing new business models to service the community.”

A Collaborative Future

“I think, today, we’re going through a kind of Cambrian explosion in the CAR-T cell field,” Dr. Sadelain says, comparing the worldwide surge of CAR-T designs and applications to a period 500 million years ago when a diverse array of animals simultaneously emerged on Earth.

What started with his design has rapidly evolved into armored CARs (designed to bulldoze through a cancer’s microenvironment) and even TRUCKs (T cells Redirected for Universal Cytokine-Mediated Killing). Dr. Sadelain’s own Columbia lab is working to develop CAR-T cells from induced pluripotent stem cells to provide “off-the-shelf” options.

“Amongst my big objectives here, running my lab may not be the most important. I will, of course, passionately continue my lab, but my main contribution will be to guide and to teach,” Dr. Sadelain says. “I have extensive experience in cell engineering and cell therapy, and probably the best use of my time is to share this knowledge. The center exists to support and work with all investigators who want to study or pursue cell-based medicines. We are here, ready and wanting to collaborate.”