Testing Novel Gene Therapy for Beta Thalassemia: Q&A with Dr. Janet Kwiatkowski

Janet Kwiatkowski, MD, MSCE

Editor's Note: In this Q&A, meet Janet Kwiatkowski, MD, MSCE, Director of the Thalassemia Center, and Clinical Director of the Sickle Cell and Red Cell Disorders Curative Therapy Center (CuRED) at Children's Hospital of Philadelphia. As the Principal Investigator of a new clinical trial for transfusion dependent beta thalassemia, Dr. Kwiatkowski explains the goals of this first-in-humans gene therapy study.

Your clinical trial is for the blood disorder beta thalassemia. Would you explain what that is?

Beta thalassemia major, or transfusion dependent beta thalassemia, is an inherited disorder that affects the production of normal hemoglobin, a protein in red blood cells that carries life-sustaining oxygen to the tissues of the body. In beta thalassemia, the beta globin genes that make the protein are mutated.

Patients require lifelong regular blood transfusions, which can start as young as a few months old and occur roughly every two to four weeks. Close monitoring for complications, and treatment for iron overload from chronic blood transfusions are also necessary. Without transfusions, there is severe anemia, the spleen and liver become enlarged, bones can become thin and brittle, and heart failure can develop. The build-up of iron in the heart and other organs from transfusions can result in heart failure and endocrine problems for some patients in their teens or early 20s, if not treated with iron chelation.

What is the main goal of your clinical trial and how will you accomplish it?

The main goal of this gene therapy study is to find out if transfusion-dependent beta thalassemia can be safely treated by modifying the patient's own blood stem cells. By using a vector, which is an engineered vehicle for delivering the new genetic material needed to correct an abnormality, we will add a healthy version of the beta globin gene. This novel lentiviral vector called ALS20 was developed by Stefano Rivella, PhD, and Laura Breda, PhD, in the Rivella Lab.

To accomplish this, we must collect blood stem cells from the study participant and modify those cells in the lab to add a healthy beta globin gene. The study participant then receives chemotherapy to remove the old blood stem cells and make room for the new modified cells, which are then infused back into the patient. Our hope is that these modified cells, called CHOP-ALS20, will enable patients to stop transfusions or at least reduce how often they need to be transfused.

There are two gene therapies commercially available to treat patients with transfusion-dependent beta thalassemia. What makes this one different?

We think this therapy stands out from the current commercially available options because in preclinical models, our scientists increased the production of the beta globin, optimizing gene expression and enhancing safety. Each copy of the vector that goes into the cells makes about 40% more of the beta globin compared with the commercially available product. It takes less product to get a similar result, which may improve safety and efficacy and potentially decrease cost.

The aim of this clinical trial is to find out if transfusion-dependent beta thalassemia can be safely treated by modifying the patient's own blood stem cells.

How will the trial work?

The trial is open for enrollment for 18- to 35-year-olds with transfusion dependent beta thalassemia. The first step is to screen for eligible participants. We need to confirm their iron levels are in a safe range because people with thalassemia get iron overload from the transfusions they receive. We need to make sure their kidneys are working well, and that their heart, lungs, and liver are healthy.

Next, we collect the blood stem cells through a process called apheresis, a procedure in which a person's blood is passed through a machine that separates the blood stem cells and returns the remainder of the blood to the patient. We collect enough blood stem cells — 15,000,000 per kilogram of body weight, so that's a lot — and then manufacture new modified stem cells with the healthy beta globin gene right here at CHOP's Cell and Gene Therapy Lab. This process is called transduction.

Once we have the final product, the study participant will be admitted to CHOP for a bone marrow transplant, where they will receive chemotherapy and then get infused with their own modified and healthier cells.

The core study will last about 2.5 years, which includes the screening and infusion of the modified stem cells followed by monitoring participants after treatment for two years. The hope is that patients will be able to stop transfusions and maintain a hemoglobin level of at least 9 g/dL, which is the target commonly used for pre-transfusion hemoglobin levels in patients on regular transfusions.

With the FDA requiring long-term monitoring of gene therapy trial participants to assess for delayed adverse events and evaluate sustained efficacy, we are planning a 13-year follow-up study that our patients can roll into after the core study.

Why is CHOP a good place to do this research?

Besides funding the trial, CHOP has the infrastructure to manage all aspects of the trial as well as unrivaled experience in the realm of cell and gene therapy for hemoglobinopathies. CHOP has experts who have been involved in most of the studies of gene therapy for hemoglobinopathies to date. We have tremendous expertise in the apheresis process for the stem cell collections. We've done more commercial transplants than anybody else has so far with the commercial gene therapy products. And we have a wealth of experience in our Cell and Gene Therapy Lab and CuRED Frontier Program to offer a multidisciplinary approach to the care of these patients.