UCSF Pediatric Focus

In-Utero HSC Transplant with Fetal Transfusion Could Lead to Cures for Many Blood Diseases

Combining in-utero hematopoietic stem cell transplant with a fetal transfusion of red blood cells tests theory that fetus is unlikely to reject the mother’s stem cells within a certain stage of the pregnancy

A team from UCSF Benioff Children’s Hospitals has begun enrollment for a clinical trial that will test the safety of combining an in-utero hematopoietic stem cell transplant with a fetal transfusion of red blood cells. The combination is aimed at treating and, possibly, curing Alpha Thalassemia Major (ATM), a blood disease that is often fatal in-utero. The trial, the first of its kind in the world, could also lead to treatments for other life-threatening blood diseases, such as sickle-cell anemia.

“The trial is based on the premise that risks could be minimized by harnessing the “tolerance” between the pregnant woman and fetus before birth. We believe alpha thalassemia is the first disease for this strategy and that by harnessing this special period in development, we can more effectively treat many other blood diseases,” says pediatric and fetal surgeon Tippi MacKenzie, MD, of the UCSF Fetal Treatment Center.

Leveraging Fetal Tolerance of Maternal Stem Cells

MacKenzie says the trial’s thesis is rooted in small-and-large animal studies that suggest the fetus is unlikely to reject the mother’s stem cells at this stage of the pregnancy, as well as on work from other labs that have shown the fetus must become tolerant to the mother for a normal pregnancy to work.The trial follows a decades-long odyssey marked by triumphs and tribulations for researchers in the field. Fetal transplants using stem cells from other fetuses to treat blood disorders were carried out in the 1980s but were only marginally successful due to engraftment failure. Researchers around the world searched for answers by turning to animal studies.

‘Eureka Moment’ Spurred Sea Change

“The fetus, unlike a fully developed human, can accept foreign cells, because its immune system is not yet primed to fight bacteria and viruses,” said MacKenzie. “This undeveloped immune system benefits the fetus throughout the pregnancy because it prevents it from launching an immune response to its mother’s cells that are naturally circulating in its bloodstream.”

Further research led to Mackenzie’s “eureka moment,” when it was discovered that the mother’s immune system is actually responsible for rejecting other cells that are transplanted into the fetus. If the mother’s cells are transplanted, they can engraft without being rejected. “This led to a sea change in our strategy to use maternal cells for the transplants,” she said.

In the trial, bone marrow will be collected from women who are between 18 and 25 weeks pregnant, with a fetal diagnosis of ATM. The bone marrow cells will be processed and hematopoietic cells -- immature stem cells that can evolve into all types of blood cells --- will be singled out from the mix. They will then be injected through the woman’s abdomen, into the umbilical vein of the fetus, where they can circulate through the bloodstream, developing into healthy mature blood cells.

The researchers also hope that if the mother’s stem cells successfully engraft in the fetus, even if at low levels, the infant will not need immune suppression if a bone marrow transplant remains necessary after delivery.

MacKenzie and pediatric hematologist/oncologist Elliot Vichinsky, MD, who created the Northern California Comprehensive Thalassemia Center at UCSF Benioff Children's Hospital Oakland, will lead the trial. The two have partnered to establish the first multidisciplinary clinical center for ATM treatment in the United States. The team recently received a $12 million grant from the California Institute for Regenerative Medicine to fund phase 1 of this clinical trial.

Lethal Disease on the Rise

In some regions of the world, ATM is relatively common and almost always leads to fetal loss due to severe anemia. Over the past few decades, changing immigration patterns have contributed to an enormous increase in the at-risk population in the U.S. Through their research and clinical work, Vichinsky and MacKenzie are among those leading the response efforts to diagnose the disease, counsel at-risk couples, and offer treatment options for families.

“If the disease is identified through early maternal screening or fetal monitoring, the fetus can now likely survive safely through pregnancy, because experienced perinatologists can transfuse red blood cells in utero beginning around 20 weeks,” says Vichinsky. At UCSF, the Comprehensive Thalassemia Center is a pioneer in the use of genetic testing to identify fetuses with ATM, and the Fetal Treatment Center performs the transfusions.

“Our long-term follow-up data suggests early prenatal transfusions can minimize or prevent fetal injury from hypoxia, including serious cognitive problems,” says Vichinsky.

After birth, however, babies with ATM need to undergo a lifetime of monthly transfusions. The other option is stem cell transplantation – if a proper donor can be found. The challenge in transplantation after birth is that the baby’s immune system matures, which causes considerable risk of rejection and graft-versus-host disease. To minimize this, the patients’ immune system is suppressed with chemotherapy. This, in turn, is associated with risk of serious infection, marrow suppression and drug toxicity.

The phase I trial builds on the UCSF clinical program to test whether an in-utero transplantation at the time of fetal transfusion can lead to safe engraftment of the healthy stem cells in the ATM patient without the use of immunosuppression or chemotherapy and its complications.

How the Trial Works

For the trial, if a family receives a diagnosis of ATM in the fetus and has no other significant health risks, an interdisciplinary team meets with them for a non-directive counseling session, during which clinicians present the medical, psychological, economic, and ethical risks and benefits of all potential actions.

In addition to physicians, the ATM clinical trial team includes a bioethicist to help families and clinicians navigate the many ethical concerns, and a forensic scientist, who can expertly detect whether the trial has reached an important threshold for the number of maternal cells engrafted in the fetus after birth. Patients also have access to a patient advisory group, which provides peer support through the decision-making process and beyond.

For those who enroll in the trial, the clinical team harvests and conditions the mother’s stem cells and then deliver the stem cell transplant at the same time as the first intrauterine transfusion without performing additional fetal procedures.

Contact Us for Additional Information About the Clinical Trial:

To learn more about alpha thalassemia, families or providers can visit: Thalassemia.com or call the Northern California Comprehensive Thalassemia Center at: (510) 428-3651