New CAAR-T therapy may eliminate hemophilia A treatment blockers: Study
It could help overcome major complication of standard method of care
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- Hemophilia A patients often develop inhibitors to factor VIII replacement therapy, reducing its effectiveness.
- Experimental CAAR-T cell therapy targets and eliminates B-cells producing these harmful factor VIII inhibitors.
- Combined CAAR-T therapy significantly reduced inhibitors in preclinical models, showing promise for future treatment.
An experimental therapy may help remove harmful antibodies that reduce the effectiveness of factor replacement therapies in hemophilia A, potentially offering a new way to overcome one of the most significant complications of standard care.
The therapy uses chimeric autoantibody receptor T cells, or CAAR-T cells. These are engineered immune cells designed to selectively recognize and eliminate B-cells that produce antibodies against factor VIII (FVIII), the clotting protein that is missing in people with hemophilia A and supplied through replacement therapy. Such antibodies, also called inhibitors, can block FVIII functions and render treatment less effective.
In preclinical models, researchers found that two types of CAAR-T cells, each designed to recognize B-cells producing antibodies against different regions of FVIII, were able to strongly reduce antibodies against FVIII and kill their target cells. When used together, the reduction in inhibitors was significantly stronger.
“These findings demonstrate that CAAR-T therapy, particularly the combinatorial approach, holds promise for addressing FVIII inhibitor formation in hemophilia A, offering a targeted and effective treatment strategy,” researchers wrote.
The study, “A Combinatorial CAAR-T Cell Strategy to Eliminate Factor VIII Inhibitors in Preclinical Models of Hemophilia A,” was published in iScience.
Up to 30% of people with severe hemophilia A develop inhibitors
Hemophilia A is a bleeding disorder caused by mutations that lead to a deficiency of FVIII. Without enough working FVIII, blood does not clot properly, leading to frequent and prolonged bleeding episodes.
Treatment typically involves factor replacement therapies. Administered directly into the bloodstream, these therapies may be given regularly as a preventive (prophylactic) treatment to reduce the risk of bleeding or used on demand to control active bleeding episodes.
However, up to 30% of people with severe hemophilia A — and roughly 3% to 13% of those with milder forms — develop inhibitors. This happens when the immune system mistakenly recognizes infused FVIII as foreign and mounts a defense against it. By blocking FVIII functions, such inhibitors can reduce the treatment’s effectiveness.
To overcome this problem, researchers are exploring new strategies, including CAAR-T therapies. In this approach, a patient’s T-cells are genetically engineered in the lab and then reinfused so they can recognize and destroy only specific antibody-producing B-cells — in this case, the B-cells making antibodies against FVIII. T-cells are immune cells that normally help the body fight infections.
Researchers tested effectiveness of 2 types of CAAR-T cells
In this study, a team of researchers tested the effectiveness of two types of CAAR-T cells in overcoming inhibitor complications in hemophilia A treatment in preclinical models.
One type, previously developed and used as a comparator, was engineered to recognize and destroy B cells producing antibodies against the A2 domain of the FVIII protein. The other type, developed in this study, was designed to target those producing antibodies against the C1 domain.
A domain is a specific structural region of a protein with a particular function. In FVIII, the A2 domain helps drive the clotting process, while the C1 domain helps FVIII remain stable in the blood. Both regions are common targets of inhibitors in people with hemophilia A.
In lab experiments using human cell models engineered to mimic inhibitor-producing B-cells, both A2- and C1-directed CAAR-T cells showed stronger ability to recognize and kill their target B-cells than unmodified T-cells.
Combined therapy yielded stronger effect
The researchers then tested the therapy in a mouse model that developed inhibitors after repeated exposure to human FVIII, mimicking what happens in some people with hemophilia A.
After treatment with either A2- or C1-directed mouse CAAR-T cells, blood inhibitor levels dropped significantly within seven days and remained low for up to 70 days. Additional analyses showed that 21 days after treatment, mice also had markedly fewer B-cells producing antibodies against FVIII.
When both types of CAAR-T cells were given together, the effect was even stronger. By day 14, blood inhibitor levels were about twofold lower than in mice treated with A2-directed CAAR-T cells alone. This is particularly relevant because many patients develop inhibitors against both domains of the FVIII protein.
Importantly, after the mice were re-exposed to FVIII — simulating continued treatment in patients — those receiving the combined therapy maintained low inhibitor levels, suggesting sustained protection against inhibitor recurrence.
Both CAAR-T therapies, administered individually or in combination, were well tolerated in mice. No obvious tissue damage was observed in major organs, and body weight remained stable after treatment.
To further assess clinical relevance, the researchers tested human CAAR-T cells in a humanized mouse model in which human antibody-producing B-cells targeting the A2 and C1 regions of FVIII were implanted to form measurable tumors. Treatment with the combined CAAR-T therapy led to significant tumor shrinkage, with near elimination by day 24.
These findings confirm “the potent and specific in vivo activity” of human CAAR-T cells against FVIII inhibitor-producing cells, the researchers wrote, adding that “further studies incorporating clinical samples from patients are required to validate the efficacy and translational potential of CAAR-T therapy.”
