CAR-T cell therapy yields success in treating autoimmune hemophilia

Cell and gene therapies harbor great hopes for biomedicine. They are becoming increasingly important for diseases that are currently difficult or impossible to treat—for example, aggressive forms of cancer or rare diseases such as hemophilia, also known colloquially as hemophilia.

At the Hemophilia Centre at the Clinic for Haematology, Haemostaseology, Oncology and Stem Cell Transplantation at Hannover Medical School (MHH), a so-called CAR-T cell therapy has now been successfully carried out for the first time on a patient with acquired hemophilia A.

The 39-year-old patient had suffered from multiple hemophilia A symptoms, including severe hemorrhaging, for several months, and the individualized treatment attempt was his last hope.

“The patient has a life-threatening autoimmune disorder, which means that his misdirected immune system has produced antibodies against his body’s own coagulation factor,” explains Professor Dr. Andreas Tiede, Head of the Hemophilia Centre.

Because all standard therapies had failed, the doctors treating the patient used a procedure in which T cells belonging to the white blood cells were genetically modified so that they, as so-called CAR-T cells, switched off the falsely activated immune cells. The results have been published in the journal Leukemia.

Coagulation factor missing

Hemophilia A is either congenital, i.e., genetic; or the coagulation disorder is acquired, i.e., it develops over the course of a lifetime. In the first case, those affected lack coagulation factor VIII, a protein produced in the liver. In the second case, the immune system mistakenly categorizes the protein, which is vital for blood clotting, as foreign to the body, sends out immune cells against it and destroys it. In Germany, around 6,000 people are genetically affected by the disease and around 500 acquire it every year in the form of an autoimmune reaction.

“In severe forms, patients suffer from spontaneous hemorrhages in the skin and muscles, as well as internal organs,” explains Professor Tiede. People with congenital hemophilia also have a high risk of cerebral hemorrhages.

Misdirected immune system

The Hemophilia Centre at the MHH treats cases of both congenital and acquired hemophilia. If the coagulation factor is missing, those affected have to inject the proteins themselves several times a week—this is necessary on a regular basis due to the short half-life. However, the center now also offers gene therapy in which the genetic information for the coagulation factor is transferred to the liver cells by means of a viral shuttle. As a small DNA ring in the cell nucleus, the gene produces the missing protein there. This very effective treatment is now covered by statutory health insurance.

The administration of these coagulation factors is often not effective in autoimmune diseases. Patients are usually given immunosuppressants, i.e., drugs that dampen the misdirected immune system. Another treatment option is the active ingredient emicizumab. The antibody is not a coagulation factor, but merely mimics its mode of action and activates blood coagulation.

“However, none of the standard therapies worked for our patient, which is why we took a different approach,” says PD Dr. Christian Schultze-Florey.

Together with his colleague Professor Dr. Felicitas Thol, the hematologist treated the 39-year-old, who had a life-threatening illness, with CAR-T cell therapy. This method is primarily used in medicine to treat cancer. For this, the body’s own T cells are taken from the blood. These are then genetically modified and equipped with a so-called chimeric antigen receptor (CAR). With the help of this receptor, the T cells can now recognize the target structures known as antigens on the cells against which they are to act.

CAR-T cell production directly on site

The genetically modified CAR-T cells are multiplied in the laboratory and then returned to the patient’s body in a similar way to a blood transfusion. There they continue to multiply, and—depending on the synthetic receptor—remain as a living weapon either against cancer cells or against misdirected defense cells.

“In our case, the antigen receptor was directed against the CD19 protein on the surface of the CD19-B lymphocytes, which mistakenly produced antibodies against the coagulation factor,” explains Professor Thol.

What is special is that the CAR-T cells are produced directly at the MHH in the clean rooms of the Cellular Therapy Centre (CTC). The advantage: The cells are immediately available within a short time without having to be transported at great expense and independently of commercial companies.

No standard therapy yet

The therapy saved the 39-year-old’s life. Just two months after the CAR T-cell transfusion, the coagulation factor recovered and the dangerous, uncontrolled bleeding stopped completely.

“Although the treatment was very successful despite the poor initial conditions, this is an individual attempt at a cure,” emphasizes Professor Tiede. “Further studies are needed to be able to offer the effectiveness of CAR-T cell therapy for acquired hemophilia A as a standard therapy at some point.”

In order to be able to better evaluate and utilize the results of all treatment approaches in connection with CAR-T cell therapies, the Federal Joint Committee (G-BA), the highest decision-making body in the German health care system, would like to consolidate the data from the existing registers under the umbrella of a comprehensive cell and gene therapy register. Professor Tiede is also involved in setting up the national register.