One Leukemia Treatment to Rule Them ALL

One Leukemia Treatment to Rule Them ALL

For adults with acute lymphoblastic leukemia (ALL) that don’t respond to chemotherapy, the series of treatments that comes next can seem like the spin of a roulette wheel. Some patients receive a bone marrow transplant, which requires a lengthy testing process to ensure a good donor match, and months of recovery if everything goes well. Other patients instead begin with an immunotherapy, which can come with severe side effects and only helps quell disease in a fraction of people. If the first approach doesn’t work, their clinician may turn to the other. For a number of patients, their disease recurs even after both.

Now researchers and clinicians in the blood and marrow transplantation & cellular therapy division have developed a new option for ALL patients. Instead of trying a transplant followed by an immunotherapy—or vice versa—they have combined both therapies into one and added some new twists that could help improve the treatments’ success rates. The result: a single ALL treatment that integrates new avenues of research into the best way to fight the cancer.

“This new protocol really changes the paradigm. It combines multiple avenues of research that have been going on at Stanford for years,” says Lori Muffly, MD, associate professor of blood & marrow transplantation and cellular therapy. “We hope it’s a first step toward something really successful and exciting for our patients.”

This fall, Muffly and her colleagues enrolled the first ALL patients in a clinical trial to test the new combination approach, in which patients receive a customized cocktail of immune cells from a donor. The trial, she says, will advance the science of lymphoma and leukemia treatment, as well as give new hope to patients who have relapsed after chemotherapy.

“This trial is really showcasing Stanford’s strengths in both bone marrow transplantation and cell therapy,” says Muffly’s collaborator Melody Smith, MD, MS, an assistant professor of blood & marrow transplantation and cellular therapy.

Based on Basic Research

The human immune system has the ability to recognize cells and molecules that don’t belong — including tumor cells. In recent years, scientists have discovered how to take advantage of this natural power of the immune system to help fight cancer. One of the new mainstays of cancer immunotherapy is CAR T-cell therapy, in which clinicians remove a patient’s T cells, reengineer them with cutting-edge gene engineering technologies to better recognize cancer, and infuse them back into the patient.

Smith, who recently moved her lab to Stanford from Memorial Sloan Kettering Cancer Center to start her independent research lab, has spent the last eight years using mouse models of cancer to study how to optimize the use of cell therapies like CAR T-cell therapy following bone marrow transplants. Much of her research has revolved around the idea of creating CAR T cells from donor immune cells instead of immune cells harvested from patients themselves. The quality of these cells, she hypothesized, might be better. Plus, the CAR T cells could be given at the same time as a bone marrow transplant — all from the same donor. “I had really strong data in animal models that this combination approach could be successful in lymphomas and leukemias,” says Smith.

Smith’s move to Stanford to start her independent research lab opened up even more opportunities to fine-tune her approach, by combining it with specialized CAR T cells and a new transplant protocol that Stanford clinicians had already been working on.

Melody Smith, MD, MS

This trial is really showcasing Stanford’s strengths in both bone marrow transplantation and cell therapy.

– Melody Smith, MD, MS

This trial is really showcasing Stanford’s strengths in both bone marrow transplantation and cell therapy.

– Melody Smith, MD, MS

Lori Muffly, MD

Harnessing the Immune System

Researchers — including Muffly as well as David Miklos, MD, PhD, chief of the Stanford bone marrow transplant and cell therapy program, and Crystall Mackall, MD, the Ernest and Amelia Gallo Family Professor and Professor of Pediatrics and of Medicine — had recently shown how to engineer CAR T cells to contain two cancer-recognition molecules at once. In the results of a trial published in 2021, they found that the dual-targeting CAR T cells were safe and effective in patients with ALL and large B cell lymphoma.

Another go-to treatment for lymphomas and leukemias is a bone marrow transplant, which replaces a patient’s blood stem cells with healthy stem cells from the bone marrow of a sibling or other matched donor. About half of the time, this cures cancer, but just as often, patients’ disease recurs.

Everett Meyer, MD, associate professor of blood and marrow transplantation and cellular therapy and of pediatric stem cell transplantation, has led efforts to improve transplantation by sorting the donor cells before giving them to a patient. This approach, called graft engineering, lets clinicians give cancer patients a mixture of cells that’s been shown to be best at treating disease.

“Instead of just giving the patients whatever mixture of cells the donor happened to have, this lets us turn it into more of a cookbook recipe,” says Muffly.

In 2021, Smith and Muffly officially teamed up to launch a clinical trial testing the combination of graft engineering and dual-targeting CAR T cells.

A New Chance for ALL Patients

For patients, the experience of the new treatment won’t be very different from what they would already expect for a bone marrow transplant, say Smith and Muffly. But instead of a rough mixture of stem cells from their matched donor, they’ll receive a precise mixture of stem cells and immune cells, including reengineered CAR T cells.

For now, the trial will be open only to patients with relapsed B-cell ALL who have a sibling that can act as the donor. Researchers will track not only how the patients fare, but other basic questions about how the treatment works: Where in the body do the new cells end up? How long do they persist?

“There are a lot of open questions we want to answer,” says Smith.

But if the trial fares well, the researchers think it could expand to patients with other types of lymphomas and leukemias, as well as those who have a nonsibling matched donor. Eventually, if donor CAR T cells are successful in treating cancer, it may open the door for off-the-shelf cell therapies — one-size-fits-all treatments that don’t even require a match between patient and donor but are ready for anyone to use. Today, though, this trial will provide key information toward that goal.

For now, the Stanford team is focused on how to get the most effective treatment to their ALL patients, and that means bringing out all the options, all at once.

“It’s been a really great partnership between a lot of players at Stanford so far, and we can’t wait to see where this goes,” says Muffly.

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