Cells as Medicine

After she completed chemotherapy, Cheryl Mango thought she was done with leukemia. Her blood work showed the cancer was no longer crowding out her normal blood cells, and molecular testing indicated genetic traces of the disease had nearly disappeared.

“I thought that I was this star patient,” says Mango, now 51. “Then all of a sudden, things changed.”

Her blood cells decreased in number, and she was in so much pain she struggled to walk. What’s more, molecular evidence of the cancer began rising.

Her oncologist recognized an impending relapse and determined that, to prevent the leukemia from returning, Mango would need a more drastic procedure: a transplant to replace the contents of her bone marrow. From within the soft interior of the bone, stem cells generate all of a person’s blood cells, including the malignant ones responsible for Mango’s leukemia.

But the transplant would do more than cut off the source of disease. If all went well, the procedure — a form of cell therapy — would also endow her with new immune cells capable of finally eradicating her cancer, something her own immune system could not accomplish.

“In many types of leukemia, a transplant is the only curative therapy,” says Dr. Juliet Barker, a professor of medicine at Weill Cornell Medicine and director of the bone marrow transplant and cell therapy program at NewYork-Presbyterian/Weill Cornell Medical Center, who oversaw Mango’s transplant.

To proceed, Mango needed a donor whose immune system was compatible with hers. Because the immunological traits that determine compatibility are inherited, she would ideally turn to a family member, typically a sibling. If a donation from a relative wasn’t feasible, as often happens, she would need to seek help from a stranger through international transplant registries. In these cases, someone with similar ancestry is most likely to be a suitable match.

Mango was at a disadvantage on both counts. She is an only child, and as a Filipina with some Chinese heritage, her background was unlikely to be well-represented among potential donors on the registries.

Anne Archer, a bone marrow transplant donor search coordinator who was assigned to conduct a search for Mango, knew the challenges of finding a potential donor for her. And, as Archer suspected would be the case, she did not find any volunteers who were both available and who matched Mango’s immunological makeup.

A different kind of medicine

Mango’s circumstances were hardly unique, especially in a city like New York. Dr. Barker’s own two decades of research has shown that people of non-European heritage are at a considerable disadvantage when seeking an unrelated donor. For much of her career, she has focused on addressing this disparity, a mission she has continued since arriving at Weill Cornell Medicine in 2023.

“We are taking a new approach, utilizing different sources of stem cells such that now essentially everyone who needs a donor can find one,” Dr. Barker says.

Stem cell transplants are a form of cell therapy in which whole, living cells are deployed to fight disease. Efforts to improve the effectiveness and safety of these procedures as well as expand access to them fit within a larger shift now playing out at Weill Cornell Medicine, the Sandra and Edward Meyer Cancer Center and NewYork-Presbyterian Hospital. In April 2024, for example, NewYork-Presbyterian/Weill Cornell became the first hospital in the city to offer, as a standard therapy option, a new treatment in which tumor-fighting cells are extracted, grown and then returned to patients with metastatic melanoma. Likewise, researchers are devising ways to use genetically engineered versions of a patient’s immune cells to attack a variety of solid tumors.

Cell therapy is not new. Bone marrow transplants were first attempted in the 1950s; blood transfusions are much older. But the field is now maturing thanks to decades of research and technology development, according to Dr. Scott Avecilla (M.D. ’07, Ph.D. ’06), associate professor of clinical pathology and laboratory medicine, who oversees the facilities at NewYork-Presbyterian/Weill Cornell that manufacture and prepare the distribution of stem cells and a variety of cell therapies.

“This is a definitive, pivotal point for medical therapies that is qualitatively very different from medicine that we know,” he says. “Surgeons use their scalpels to save lives. Medical doctors may use drugs. We use cells — living agents.”

Dr. Barker’s team aims to make living and lifesaving stem cell transplants available to as many of the patients who need them as possible. To overcome the lack of suitable matches, they not only use traditional stem cell donations from adult donors but also alternative sources of these cells, including one that would ultimately make a transplant possible for Mango.

In parallel, Dr. Barker’s team hopes to address other barriers to these procedures. By, for example, modifying the harsh treatment regimens used in these procedures, they aim to make stem cell transplants safer for older, more physically vulnerable patients. Meanwhile, they are bringing transplant-related care closer to patients outside Manhattan. Dr. Gaurav Varma, an assistant professor of medicine, is expected to begin seeing patients preparing for transplants and cell therapies beginning in November at the Center for Community Health at NewYork-Presbyterian Brooklyn Methodist Hospital.

A sneaky disease

Mango’s illness came on suddenly in, of all places, the Amazon rainforest. While traveling with her husband and two children, she developed an intense fever that caused her to shake. Her neck became so stiff she couldn’t turn her head. At first, she suspected strep throat, then a tropical infection, most likely dengue fever.

Awakening in the NewYork-Presbyterian/Weill Cornell emergency room, she was told she had acute myelogenous leukemia (AML). Normally, stem cells in bone marrow produce immature, progenitor cells that further develop into oxygen-carrying red blood cells, platelets that prevent bleeding and the white blood cells of the immune system. However, in AML, some of the white blood cell-making progenitors stop maturing and proliferate.

Mango’s oncologist, Dr. Gail J. Roboz, the William S. Paley Professor in Clinical Medicine and director of the leukemia program at NewYork-Presbyterian/Weill Cornell, assessed Mango’s cancer and used a protocol called risk stratification to determine that several cycles of intensive chemotherapy had favorable odds of curing her. But after Mango finished that treatment, the cancer showed signs of returning.

“Leukemia is a sneaky disease,” Dr. Roboz says. “It doesn’t always behave the way the books say it is supposed to.”

Finding a match

Like an organ transplant, a stem cell transplant requires the body to accept someone else’s cells as its own. But rejection isn’t the only potential problem. Mango’s transplant would bring new immune cells that would likewise need to accept her body. In some cases, a transplanted immune system recognizes the patient’s body as foreign, producing a potentially life-threatening complication known as graft-versus-host disease.

Conversely, if the donated immune cells directed their attention to the remnants of the leukemia showing up in Dr. Roboz’s tests, they could put an end to Mango’s disease. Known as a graft-versus-leukemia effect, it is an essential feature of these procedures. A strong immunological match between the recipient and an adult donor maintains this cancer-eradicating benefit while minimizing the risk of rejection and graft-versus-host disease.

In the United States, healthy people can volunteer to donate bone marrow through a registry such as the National Marrow Donor Program. Archer searched the registry for potential adult donors who possessed a set of specific genetic sequences identical to Mango’s. These sequences, known as human leukocyte antigen (HLA) alleles, vary widely among people according to their ancestry.

The HLA alleles Archer sought occur at four sites within the human genome. Every one of us possesses two sets of these four HLA alleles, and each allele comes in thousands of variations. While the potential combinations are immense, people of similar ancestry are much more likely to carry the same versions of these alleles. This translates to an advantage for people of European, and particularly northwestern European, ancestry. Those with other backgrounds can be much less likely to find matches.

The disparity occurs in part because of who signs up to donate. According to federal statistics, more than half of potential donors identify as white. But that’s not the only issue. Other groups, particularly people of African descent, have more varied HLA profiles, a consequence of the history of these populations. Likewise, people of mixed race can also possess hard-to-match sets of HLA alleles.

Another option

When she conducted a preliminary search of the registry, Archer could not find any suitable HLA matches for Mango. But that didn’t mean Mango was out of luck.

In a different search, Archer found another, more promising alternative: units of stem cell-containing blood collected from a baby’s umbilical cord and placenta shortly after birth and donated by the mother. This cord blood also contains inexperienced immune cells, which are much more tolerant of a recipient’s immunological makeup than those derived from an adult donor. Consequently, transplants from cord blood require only a partial HLA match.

An expert in these procedures, Dr. Barker has worked to establish cord blood as a viable alternative to transplants from adults, giving hard-to-match patients like Mango a better shot at curing their leukemia. Demographic shifts make this work all the more urgent, she says: “There’s an increasing number of such patients in need, because the U.S. population is becoming increasingly diverse.”

In addition to its flexibility, cord blood transplants have another substantial advantage: The cells are frozen upon collection and stored in public cord blood banks, where they are ready and waiting.

With suitable units of cord blood identified, Mango was ready to begin a regimen to prepare her for the transplant.

“After I heard about what my body would have to go through, it was pretty terrifying,” she says.

A second birthday

Mango checked into the bone marrow transplant unit, where, over six days, she received potent chemotherapy and total-body radiation intended to wipe out as much of the cancer as possible. The treatment also made space in her bone marrow for the new stem cells and suppressed her immune system to reduce the odds of rejection and graft-versus-host disease.

Two collections of cord blood, each from a different donor, were used for her transplant, a strategy Dr. Barker developed to increase the potency of the transplanted cells in adult recipients. The cells, contained in two 25 milliliter (0.8 fluid ounce) pouches, each from a baby’s umbilical cord, were shipped to Dr. Avecilla’s clinical cellular therapy lab about a week before the transplant. Lab members thawed and prepared them, producing two bags roughly the color of Kool-Aid© fruit punch.

Mango’s transplant day, which she refers to as her “second birthday,” arrived on Oct. 29, 2024. On that day, she became one of the 16 patients who received cord blood transplants at NewYork-Presbyterian/Weill Cornell that year, out of 69 total stem cell transplants from donors. She remembers seeing the bright red liquid hanging from an IV pole before it, and the cells it contained enter her bloodstream.

About 11 months later, Mango is leukemia-free and returning to her normal life. She now has blood cells with someone else’s DNA circulating in her body. With her immune system still recovering — and seated far from everyone else and wearing a mask — she achieved her goal of attending her son’s high school graduation last June.

Since her transplant, Mango hasn’t discussed her long-term prospects with Dr. Barker or her other doctors, but she feels good about the future — and very grateful.

“I wish I didn’t have this front row seat learning about stem cell transplants and cord blood,” she says. “But oh my gosh, science is amazing, science is wild.”

Building on Success in Skin Cancer

Innovations in therapy have extended the lives of patients with metastatic melanoma. Can cell therapy grant them even more time?

While stem cell transplants like Cheryl Mango’s require cells from someone else, another class of cell therapies augment those already in the patient’s body. These cutting-edge treatments empower a patient’s native immune cells to better fight cancer. In doing so, they build on earlier immune-bolstering therapies that have already dramatically improved prospects for some patients. (Scientists are also studying cell therapies for diseases other than cancer).

Melanoma, an aggressive form of skin cancer, is the poster child for this transformation. About 15 years ago, patients whose melanoma had metastasized, or spread beyond its initial site, could expect to live mere months. But a study published in 2024 documented results that were once unthinkable: patients making it, on average, nearly six years, with half of these survivors still disease-free after 10. This extra time was the result of a combination of checkpoint inhibitors, antibody-based drugs that unlock immune cells’ natural cancer-fighting abilities, that these patients received.

At the time, Dr. Jedd Wolchok, Meyer Director of the Sandra and Edward Meyer Cancer Center and a professor of medicine at Weill Cornell Medicine, who led the clinical trial examining their long-term effectiveness, called the results “practice changing.” But, because some patients’ cancer progressed even with these drugs, he and his team knew this success was not enough.

“What can we do to help those in whom this type of immune modulation does not work?” Dr. Wolchok says they asked themselves. “One opportunity to do that is by changing the repertoire of immune cells in the person, rather than reinvigorating them with medicines.”

This meant turning to cell therapy, including experimental versions of an approach known as CAR-T, which has achieved remarkable success as a clinical treatment for certain blood cancers that involve malignant B cells.

Finding the right targets

In CAR-T (which stands for chimeric antigen receptor T-cell) therapy, a patient’s T cells are taken from their blood and sent to a lab — at Weill Cornell Medicine, they go to one of Dr. Avecilla’s cellular therapy facilities.

There, lab members genetically engineer the cells to sport an artificial receptor that identifies a target. For current CAR-T therapies, the target is often the protein CD19, which is unique to B cells. Then, the altered T cells are returned to the patient.

“Conceptually, it’s quite simplistic,” Dr. Avecilla says. “Sometimes less is more.”

So far, however, CAR-T has only proven effective in blood cancers. Adapting it to solid tumors has proven challenging. For one thing, researchers need to find targets, akin to CD19, that CAR-T can attack without causing collateral damage to healthy tissue.

Researchers in the cell therapy program are working on potential solutions across a variety of malignancies. Dr. Wolchok’s lab and that of Dr. Taha Merghoub, a professor of pharmacology and of immunology research in medicine and the Margaret and Herman Sokol Professor of Oncology Research, are adapting CAR-T to target a protein called MUC16 expressed by bladder cancer cells.

Dr. Wolchok is also bringing this new immune-focused therapy full circle to melanoma. Working with Dr. Merghoub and Dr. Christopher Hackett, assistant professor of medicine and a hematologist-oncologist at NewYork-Presbyterian/Weill Cornell Medical Center, his group is this time focusing on a molecule called TRP1, which is found only on the pigment-producing melanocytes that give rise to this cancer. Studies so far suggest that targeting TRP1 may cause skin lightening, but otherwise appears safe.

If successful, it and the other experimental CAR-T therapies will represent one more option for patients with difficult-to-treat tumors, Dr. Wolchok says. “We hope this is a way we can expand the reach of immunotherapy beyond the people who are currently benefiting from it.”

First in a new era

Patients have already begun to benefit from another approach for marshaling their native defenses against solid tumors.

In April 2024, NewYork-Presbyterian/Weill Cornell became the first hospital in New York City to offer a newly approved cell-based, immune-boosting treatment for metastatic melanoma. Known as tumor-infiltrating lymphocyte, or TIL therapy, it amplifies the T cells a patient’s immune system has already deployed into the interior of a tumor.

As of mid-September, 11 patients had received TIL therapy at the medical center, according to Dr. Barbara Ma, an assistant professor of medicine.

This new therapy picks up where checkpoint inhibitors left off. The FDA has approved its use for patients whose metastatic melanoma progresses despite treatment with these drugs, or with treatment targeted for a particular mutation in the tumors. For those who qualify for it, Dr. Ma says, “TIL represents a chance at a potential curative option.”

In CAR-T therapy, T cells are removed from a patient’s blood. For TIL, they are taken out when a surgeon removes a walnut-sized piece of tumor. The tissue is sent to a facility run by a biotechnology company. There, the T cells are separated from the tumor, prompted to multiply and treated to invigorate them, a process that takes about five weeks.

The patient, meanwhile, receives chemotherapy to reset their immune system. This step clears away any immunosuppression that may have previously hampered the patient’s original T cells, according to Dr. Ma, who is also an assistant attending physician at NewYork-Presbyterian/Weill Cornell.

Shortly after the patient receives their newly augmented T cells, which now number in the billions, they receive an immune signaling compound called interleukin-2 (IL-2). It activates the T cells, turning them “from wimpy little soldier cells into Marine Corps fighters,” Dr. Ma says.

IL-2 can induce an intense fever, among other side effects, so the patient stays in the hospital until the fever subsides and their blood cell counts recover. TIL’s effect on their cancer isn’t formally measured until about six weeks later, when they receive X-ray and MRI scans.

Not everyone responds, according to Dr. Ma. But some do very well.

“I have patients who have nodules under their skin that start disappearing even before we get to the scan,” she says.

In a clinical trial described in 2022 in the Journal of Immunotherapy in Cancer, tumors shrank in nearly a third of patients who received TIL therapy, and, in a few cases, disappeared entirely. More than 40 percent of the people whose tumors shrank or disappeared saw these responses continue for at least 18 months.

Dr. Ma has so far seen similar results among her patients. “We’ll see how it plays out, but we are very encouraged,” she says. Over the 15 months since her first patient began TIL therapy, his cancer has continued to shrink.  

“He tells me, ‘I have another chance at living life because of this therapy,’” she says.  

Dr. Ma and her colleagues have begun collecting samples and data from TIL patients, which they intend to use to figure out how to achieve more results like this. By comparing patients’ profiles, the researchers hope to identify differences that distinguish those who respond well to TIL and those who don’t, which could lead to adjustments in the therapy.

Dr. Ma anticipates that TIL therapy will continue to shift the odds in patients’ favor, granting them more time. It has also opened the door for similar therapies for melanoma and other malignancies.

“It is what I consider the first of a new class of drugs,” she says. “I think TIL heralds a new era for the rest of solid tumor therapy.”