Clinical Trial for Beta-Thalassemia Brings Important Insights for Treating Blood Disorders with Stem Cell Gene Therapy

Memorial Sloan Kettering physician-scientist Michel Sadelain.

A clinical trial led by physician-scientist Michel Sadelain showed that gene therapy targeting blood stem cells appeared safe and effective.

After three decades of research, Memorial Sloan Kettering Cancer Center investigators may have found a new treatment option for patients with an inherited blood disorder called beta (β)-thalassemia. The approach, led by MSK physician-scientist Michel Sadelain, involves using a new stem-cell-based form of gene therapy. Results from a phase 1 clinical trial testing this treatment were reported in Nature Medicine on January 3, 2022.

Here, Dr. Sadelain, who leads MSK’s Center for Cell Engineering, describes the trial’s most important findings. He also explains how the potential new treatment is a culmination of more than three decades of research by MSK investigators in the Center for Cell Engineering, the Cell Therapy and Cell Engineering Facility, and the Department of Pediatrics.

What is β-thalassemia and how is it treated?

In people with β-thalassemia, the red blood cells cannot make a protein called β-globin due to an inherited genetic mutation in the β-globin gene. This reduces the production of hemoglobin, which is the part of red blood cells that carries oxygen throughout the body. In sickle cell disease, a related disorder affecting the same gene, the red blood cells make an abnormal form of β-globin.

Together, β-thalassemia and sickle cell disease are the most common severe hereditary blood disorders in the world. An estimated 15 million people are affected by β-thalassemia alone, and even more by sickle cell disease. While sickle cell disease is better known in the US, β-thalassemia is primarily found in populations of Mediterranean, Asian, and African descent.

The current treatment for β-thalassemia is a lifetime of regular red blood cell transfusions — sometimes as often as every few weeks — which are lifesaving but can have serious secondary complications. Bone marrow or stem cell transplants can offer a cure, but most patients are unable to find a matched donor.

With this research, we want to train the body to produce normal red blood cells. We are looking to do this by genetically modifying stem cells in the bone marrow. These stem cells give rise to all the different types of blood cells.

Center for Cell Engineering
This center brings together clinicians and scientists who are developing cell-based therapies to treat cancer and other diseases.

How does gene therapy work to replace the faulty globin protein?

In the trial, patients have their blood stem cells extracted from circulating blood. In the lab, we introduce a version of the β-globin gene that functions properly into these stem cells. We insert the good β-globin gene using a vector, which is a disabled virus that cannot replicate but can efficiently transport genetic information. This is done by a team led by Isabelle Rivière in SKI’s Cell Therapy and Cell Engineering Facility.

Then, patients receive chemotherapy to suppress the body’s natural production of blood cells, and they have their own genetically engineered stem cells infused back into them. These stem cells then begin making healthy blood cells with normal β-globin.

How did you design the trial so it is safe and effective?

This is a complicated process, and it has taken a long time and a lot of research to develop the approach. I began my work in genetic engineering in 1989 as a postdoctoral fellow at the Whitehead Institute at MIT before coming to MSK in 1994. In 2000, we published a landmark paper in Nature demonstrating in mice that β-thalassemias and sickle cell disease could be treated and cured using highly engineered viral vectors to produce enough of the missing ß-globin. It has taken us more than a decade to further refine this approach for humans, working with Dr. Rivière and hematologic oncologist Farid Boulad, Medical Director of the Pediatric Ambulatory Care Center at MSK.

One important decision we made was to administer a lower dose of chemotherapy to patients before infusing the genetically modified stem cells. This reduces transplant-related toxicities like infections, mouth sores, and damage to the lung, heart, and bones. It also spares the reservoir of stem cells in the patient, which we believed to be preferable to completely destroying all the cells.

Our trial was the first globin gene therapy trial approved to move forward in the US. We treated our first patient in 2012, and we are still carefully following the first four patients on the phase 1 study to this day. We wanted to monitor them carefully over a long period — six or seven years — to make sure there were no unintended effects.

Despite our using low-dose chemotherapy, we saw that the transplanted stem cells did a good job of traveling through the blood to the bone marrow and starting to make blood cells.
Michel Sadelain physician-scientist

What were the most important lessons learned from the trial?

A major finding was that despite our using low-dose chemotherapy, we saw that the transplanted stem cells did a good job of traveling through the blood to the bone marrow and starting to make blood cells (called engraftment). Many were skeptical of our approach, thinking high chemotherapy doses are needed to destroy the host stem cells so that new ones could take root. But we saw long-term, very stable engraftment in our patients — they did not peter out after a few years. That is essential because the bone marrow needs to keep churning out 100 million new red blood cells per day for the rest of their lives.

This is an important finding that has implications for all forms of globin gene therapy — not just our approach using a vector derived from a virus, but alternative approaches using new gene-editing technologies such as CRISPR. Reducing the chemotherapy is no small thing for these patients. In addition to reducing short-term toxicities, it makes it easier to give this treatment without requiring people stay overnight in the hospital.

The other important observation is cause for some concern — an orange flag rather than a red flag. We saw what are called clonal expansions, which are individual white blood cells multiplying in large numbers. These expansions sometimes did not occur until years after the transplant. They are benign but a cause for concern. This type of excessive growth can potentially become leukemia, which is why it is so important for all globin trials to do such long-term follow-up. It shows the importance of watching patients closely over time.

What is the next step in this research to bring this treatment closer to getting FDA approved?

There is still a lot of work to do. We plan to continue monitoring the patients in the trial, but we also will continue our research to improve the vector and its delivery. In this pioneering phase 1 study, the gene transfer was not efficient enough — the patients still needed to continue receiving transfusions, although less often. But these procedures have substantially improved since we began our trial nine years ago.

We must also design ways to protect against clonal expansion — the white blood cell multiplication — whether using vectors or CRISPR. There are new tools for both methods. Our new viral vector harbors an “insulator element,” which sets up barriers that prevent the vector from activating other genes that spur runaway cell growth. We also have identified what we call “safe harbor” regions in the human genome, where we can efficiently insert therapeutic globin genes using CRISPR.

The genetic treatment of globin disorders holds great promise. I gave a lecture on the state of the field in May 2021 at the annual meeting of the American Society of Gene & Cell Therapy. As I explained then, there are several gene therapy technologies that could work for β-thalassemia, but we don’t yet know which will be best overall.

Even if they all work, the deciding factor will be their safety. All genetic modifications come with potential downsides, which researchers are trying to minimize. The next factor will likely be which is easiest to administer — for example, an outpatient treatment is going to be preferred over a procedure that requires a hospital stay. And finally, it might come down to which is most cost-effective. That’s why we have to keep studying these different approaches, so we can answer these questions.

This clinical trial was supported by the Stavros Niarchos Foundation, the Memorial Hospital Research Fund, the Leonardo Giambrone Foundation, Cooley’s Anemia Foundation, and the MSKCC Support Grant (P30 CA008748).