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Round of applause: During his last visit before returning home to Brazil, tiny Samuel Evangelista celebrates with (from left) Ewelina Mamcarz, MD; interpreter Marc Friedman; and Katie Birdsell, a nurse practitioner in Bone Marrow Transplantation and Cellular Therapy.

XSCID Gene Therapy: A Second Chance

A ground-breaking gene therapy pioneered at St. Jude has curative potential for infants born with XSCID.

By Jane Langille; Photos by Peter Barta and Seth Dixon

One of life’s most precious moments for parents is snuggling a newborn child. For Ricardo and Simone Evangelista of Sao Paulo, Brazil, the birth of their son Samuel was especially sweet, as they had already lost two babies to unknown causes.

But Samuel’s life was in danger. At 3 months old, he was diagnosed with X-linked severe combined immunodeficiency (XSCID). In this rare disorder, also known as bubble boy disease, the body lacks the immune cells necessary to fight off harmful viruses, bacteria and fungi.

Most children with XSCID die within the first two years of life.

After learning about St. Jude Children’s Research Hospital, the Evangelistas and their doctor spoke with Ewelina Mamcarz, MD, of St. Jude Bone Marrow Transplantation and Cellular Therapy. The couple immediately agreed to take part in the world’s first lentiviral gene therapy trial for infants with XSCID.

“When we arrived at St. Jude, we knew we were in the best place in the world,” Ricardo says. “Brazil doesn’t have anything that comes close.”

Brian sorrentino, MD

Designing a cure

To find a safer and more effective way to cure children with XSCID, Brian Sorrentino, MD, director of St. Jude Experimental Hematology, worked tirelessly for more than a decade to perfect a novel gene therapy. Leading a team of scientists, he successfully created a lentiviral vector that can insert a healthy copy of the IL2RG gene into a patient’s blood-forming cells.

Re-engineering human genes

XSCID is an inherited disorder that occurs almost exclusively in males. Affecting about one in every 200,000 newborns, XSCID is caused by a mutation in the IL2RG gene that encodes a protein critical for developing the body’s immune cells.

To date, bone marrow transplantation has been the most effective treatment for XSCID. With a transplant, a patient receives healthy blood-forming cells from a matched donor. Those cells settle into the patient’s bone marrow and make new immune cells. Unfortunately, more than 80 percent of patients with XSCID lack fully matched donors. Among those who do receive transplants, one-third develop immune problems that continue for years.

To find a safer and more effective way to cure children with XSCID, Brian Sorrentino, MD, director of St. Jude Experimental Hematology, worked tirelessly for more than a decade to perfect a novel gene therapy. Leading a team of scientists, he successfully created what is known as a lentiviral vector. This type of virus can insert a healthy copy of the IL2RG gene into a patient’s blood-forming cells.

The vector is made in the Children’s GMP, LLC, an on-campus facility that produces biological products in accordance with FDA safety regulations. The GMP is the only facility in the world to both make a lentiviral vector and re-engineer cells to carry the healthy gene. The vector includes features designed exclusively to enhance safety and effectiveness.

“It’s been an enormous amount of work, but we’re thrilled to be producing a stable cell line using a vector that’s never been used in a clinical trial before,” Sorrentino says.

A novel clinical trial

Samuel is the sixth of seven infants under the age of 2 to take part in the Phase I trial. The treatment involves removing the patient’s bone marrow, filtering and purifying the child’s blood stem cells and incubating them with the lentiviral vector to insert a healthy copy of the IL2RG gene. The re-engineered cell line is then transfused back into the patient. The objective is to reconstitute T cells as well as natural killer cells and B cells, creating broad immune-system function.

Mamcarz and Sorrentino head the multisite clinical trial, which includes Benioff Children’s Hospital at the University of California, San Francisco, and Seattle Children’s Hospital. For patients at the other institutions, bone marrow cells are shipped to the GMP facility for re-engineering and then are sent back for infusion.

Before infusion, patients receive a low dose of the drug busulfan, roughly one-third of the amount used in transplants.

“Using chemotherapy in infants is controversial, especially in those with non-malignant disorders,” Mamcarz says. “But in previous clinical studies where it was not used before transplantation or gene therapy, patients only achieved T cell correction.

“As a result, many were still prone to recurrent viral infections and diarrhea and required expensive monthly infusions of intravenous immunoglobulin.”

The St. Jude trial for infants with XSCID may provide insights for treating other disorders, including Wiskott-Aldrich syndrome and sickle cell disease.


Promising responses

Results have been promising among the seven infants treated to date.

“So far, our patients have tolerated chemotherapy well, showing only mild suppression of blood cell count for a few days and recovering to normal levels by three weeks, well ahead of our safety target of six weeks, allowing them to be discharged from the hospital and followed on an outpatient basis,” Mamcarz says. “In addition, we have not needed to provide any of the babies with blood products while they awaited cell recovery.”

Six of the seven babies treated achieved reconstituted immune systems within three to four months after gene therapy.

“We’ve stopped giving intravenous immunoglobulin treatments when the babies started making their own immunoglobulin around six to nine months after treatment,” Mamcarz says. “This is truly an achievement over prior gene therapy trials, where B cell reconstitution did not occur and patients required intravenous immunoglobulin for life.”

The trial’s first patient arrived at St. Jude with complex issues, including a viral infection. Maternal immune cells the baby had acquired before birth prevented him from achieving immune recovery after treatment with the lentiviral vector.

“We gave him a second treatment, without chemotherapy, and it worked,” Mamcarz says. “The maternal cells disappeared, part of his immune system already recovered, and the infection that he had had for over a year and a half is now gone.”

To date, two babies have been taken off immunoglobulin infusions and one has started receiving routine vaccinations. The patient responded well to immunizations, producing significant immune responses to numerous types of Streptococcus pneumonia strains within six weeks of vaccination.

Patient Samuel plays

Going home

The world’s first lentiviral gene therapy trial for infants with XSCID has given 16-month-old Samuel Evangelista hope for a bright future. He returned home to Brazil in January 2018 with no activity restrictions.

Samuel’s surprising results

Within two days of traveling to St. Jude, 11-month-old Samuel spiked a fever caused by an infection in his shoulder. Mamcarz discovered the infection was caused by bacteria used in a vaccine commonly given to newborns in Brazil to prevent tuberculosis. Serious side effects of the vaccine in healthy babies are rare, but for Samuel it had caused a life-threatening complication because he lacked an immune system.

Surgeons at St. Jude performed an operation to remove the infection from his shoulder before Samuel was treated with his own genetically re-engineered cells to treat XSCID.

“Samuel surprised us quite a bit. At first, his gene marking of the infused cells was lower than those of other children in the study. But our vector must be quite powerful, because he went on to reconstitute just like other patients who had very strong marking,” Mamcarz says.

Gene therapy has given Samuel a second chance to live. He received his last immunoglobulin infusion in January 2018. The 16-month-old returned home with no activity restrictions.

“Sam’s a fighter,” says his mom, Simone. “He loves playing with little cars…and with my cell phone.”

She and Ricardo will bring Samuel back to St. Jude every three months for checkups.

Teamwork and collaborations

As more infants are treated in the clinical trial, Sorrentino and Mamcarz eagerly await results regarding the long-term durability and potential side effects of the gene correction therapy.

The researchers credit multidisciplinary teamwork for developing the treatment protocol, manufacturing the lentiviral vector and establishing collaborations with partner sites to open the ground-breaking trial.

Lentiviral vector technology has also been also used to help patients who only partially benefited from previous bone marrow transplants. A recently published study by the National Institutes of Health used a lentiviral vector developed at St. Jude to successfully reconstitute the immune system in several patients.

Looking beyond XSCID

Sorrentino anticipates that the St. Jude XSCID clinical trial will provide insights for treating other disorders. These include Wiskott-Aldrich syndrome, a disorder that causes infections and reduces the ability to form blood clots, and sickle cell disease, which affects about 100,000 Americans. “We care for almost 1,000 sickle cell patients at St. Jude,” Sorrentino says. “Our gene therapy platform could potentially be curative for these patients as well as for many other devastating immune disorders in the future.

“Every time one of these babies turns the corner, we are so gratified,” adds Sorrentino, who has dedicated his career to translating gene therapy technology from bench to bedside. “I’m convinced that many of the children Dr. Mamcarz has treated on this protocol would not have lived without receiving this experimental therapy.”

“We give huge credit to the families who trust us to treat their newborn infants,” Mamcarz says. “I’m excited for patients like Samuel, who can go home with a new lease on life.”

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