Many blood disorders, immune disorders and metabolic disorders can be cured with a transplant of hematopoietic (blood-forming) stem cells, also known as bone marrow transplant. But patients must first receive high-dose, whole-body chemotherapy and/or radiation to deplete their own defective stem cells, providing space for the donor cells to engraft. These “conditioning” regimens are highly toxic: they wipe out the immune system, raising infection risk, and can cause anemia, infertility, other organ damage and cancers. And when the donor isn’t an exact match, patients’ immune systems must be suppressed for prolonged periods to prevent rejection.
As a result, most patients either don’t receive a transplant or must endure serious side effects. But if two new studies bear out in clinical trials, a far gentler conditioning treatment could enable stem-cell transplants for a much wider range of disorders, even possibly from unmatched donors.
The studies, conducted at Boston Children’s Hospital and the Dana-Farber Cancer Institute, combined a specially-targeted antibody with a drug. This combination alone enabled mice to receive transplants with virtually no toxicity. Both studies were published today in Nature Communications.
“Our findings suggest a huge opportunity to do transplants in a way that’s extremely safe and extremely effective,” says Agnieszka Czechowicz, MD, PhD, who co-led one study with Rahul Palchaudhuri, PhD from Harvard University and the other with Zhanzhuo Li, MD, PhD of the National Institute of Allergy and Infectious Diseases (NIAID). “This opens up the possibility of easily using blood-forming stem cells that have undergone gene therapy and gene editing, without additional toxicity.”
Targeting pre-treatment to avoid side effects
Czechowicz began her research as a graduate student at Stanford University. That research found that pre-treatment with an antibody that blocks the CD117 receptor, found almost exclusively on blood-forming stem cells, killed those cells off selectively. This enabled mice to receive donor stem cells safely, without chemotherapy and radiation. Clinical trials with a human version of this antibody are now underway at Lucile Packard Children’s Hospital Stanford in patients undergoing stem cell transplants to treat severe combined immunodeficiency.
“Although the ‘naked’ antibody was very helpful, we have long wanted to make the antibody more powerful,” says Czechowicz.
Czechowicz pursued this desire during her residency and fellowship at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and in the lab of Derrick Rossi, PhD, of Boston Children’s Program in Cellular and Molecular Medicine. To boost the effects of the CD117 antibody, she and her colleagues attached a drug called saporin.
Saporin has already been used in cancer patients and inhibits ribosomes, the protein-building structures in all cells. This, the team hoped, would kill patients’ own blood-forming stem cells more efficiently.
“We theorized it would be effective, but were both reassured and excited when it worked so well,” says Czechowicz.
Transplants from any type of donor?
In the first study, a single dose of the antibody-drug conjugate eliminated more than 99 percent of blood-forming stem cells in mice — yet left other kinds of blood cells unharmed. High levels of transplanted stem cells took up residence in the host animals, effectively replacing their blood and immune systems with significant side effects. The animals’ immune cell function was preserved and responded effectively to pathogens.
While the first study used matched donors, the second study tried the same approach with fully mismatched donors (based on the major histocompatibility complex or MHC). The recipient mice also received immunosuppression, but only for a very short period, says Czechowicz.
The mice showed up to 50 percent engraftment of the donor cells — enough that they could also tolerate skin grafts from the same donors, even many months after their first transplants.
“Transplants of blood-forming stem cells not only create new blood and immune systems, they also lead to tolerance of other donor tissues and organs without the need for chronic immune suppression,” explains Czechowicz. “This approach isn’t used often, since it has, until now, required toxic radiation or chemotherapy pretreatment. Our modified approach could be transformative for the transplant field.”
The study could potentially enable both stem cell transplants and subsequent solid organ transplants from any donor, she says.
Moving toward patients
Czechowicz has been continuing her work at the Stanford University School of Medicine, where she is now an assistant professor in the Division of Stem Cell Transplantation and Regenerative Medicine. The researchers plan further studies to confirm the safety and efficacy of the combination using a human CD117 antibody. They also plan to investigate other antibody-drug combinations.
“If the principles demonstrated in these studies translate to the clinic, they open the possibility of expanding stem cell transplantation to many more patients, who we know would benefit if only it were made more tolerable,” says Derrick Rossi, co-senior author both papers with David Scadden, MD of Harvard University and Philip Murphy, MD of the NIAID, respectively.
Magenta Therapeutics (Cambridge, Mass.) has licensed the technology and is working towards developing and testing this approach in patients. The company presented pre-clinical data on anti-CD117 antibody-drug conjugates at the American Society of Hematology (ASH) meeting in December 2018, using another ribosome inhibitor, amanitin.
Supporters of the current studies include the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the National Heart, Lung and Blood Institute, a Potter Fellowship to the Boston Children’s Hospital Trust, the Gerald and Darlene Jordan Chair of Medicine of Harvard University, the Harvard Blavatnik Biomedical Accelerator Fund, The Leona M. and Harry B. Helmsley Charitable Trust, The New York Stem Cell Foundation, The Harvard Stem Cell Institute and the American Federation for Aging Research.
Czechowicz, Rossi and certain other study co-authors are founders and equity holders in Magenta and are co-listed as inventors on related U.S. patent applications. Boston Children’s Hospital is also an equity holder. See the papers for all affiliations, disclosures and funding information.