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Hemophilia A inhibitor treatment: the promise of engineered T-cell therapy.

ABSTRACT: Hemophilia A is a bleeding disorder caused by mutations in the gene encoding factor VIII (FVIII), a cofactor protein that is essential for normal blood clotting. Approximately, 1 in 3 patients with severe hemophilia A produce neutralizing antibodies (inhibitors) that block its biologic function in the clotting cascade. Current efforts to eliminate inhibitors consist of repeated FVIII injections under what is termed an "ITI" protocol (Immune Tolerance Induction). However, this method is extremely costly and approximately 30% of patients undergoing ITI do not achieve peripheral tolerance. Human T regulatory cells (Tregs) have been proposed as a new strategy to treat this antidrug antibody response, as well as other diseases. Polyclonal Tregs are nonspecific and could potentially cause general immunosuppression. Novel approaches to induce tolerance to FVIII include the use of engineered human and mouse antigen-specific Tregs, or alternatively antigen-specific cytotoxic cells, to delete, anergize, or kill FVIII-specific lymphocytes. In this review, we discuss the current state of engineered T-cell therapies, and we describe the recent progress in applying these therapies to induce FVIII-specific tolerance.

SUBMITTER: Parvathaneni K

PROVIDER: S-EPMC5582018 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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Hemophilia A inhibitor treatment: the promise of engineered T-cell therapy.

Parvathaneni Kalpana K Abdeladhim Maha M Pratt Kathleen P KP Scott David W DW

Translational research : the journal of laboratory and clinical medicine 20170609

Hemophilia A is a bleeding disorder caused by mutations in the gene encoding factor VIII (FVIII), a cofactor protein that is essential for normal blood clotting. Approximately, 1 in 3 patients with severe hemophilia A produce neutralizing antibodies (inhibitors) that block its biologic function in the clotting cascade. Current efforts to eliminate inhibitors consist of repeated FVIII injections under what is termed an "ITI" protocol (Immune Tolerance Induction). However, this method is extremely ...[more]

PMID: 28651073

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Project description:BackgroundDevelopment of inhibitors to transfused factor VIII in patients with hemophilia A continues to be a challenge for professionals involved in hemophilia care. The majority of patients in India receive 'on-demand' rather than prophylactic therapy. The present study was done to assess the prevalence of factor VIII inhibitors in patients with hemophilia A (PWHA) receiving 'on-demand' therapy in a North Indian population and to study the clinicopathological parameters influencing the development of inhibitors.MethodsThe study group comprised of 300 PWHA. Detailed clinical parameters, treatment history, bleeding profile including family history were recorded. Diagnosis of hemophilia A was confirmed by relevant coagulation tests. Inhibitors were screened using mixing based studies followed by quantification by Bethesda assay and Nijmegen modified Bethesda assay. Samples were collected from five cities in North India where a free supply of factor VIII was available and effectively used in three of these cities.ResultsIn the 300 PWHA, disease phenotype was severe in 219 (73%), moderate in 62 (20.67%) and mild in 19 (6.34%), based on the factor VIII bioassay. Inhibitor prevalence was 9.6% (n = 29) and seen only in the severe phenotype. Inhibitor titers ranged from 0.8 to 108.8 BU/ml. A total of 12 PWHA had low and 17 had high titers. Correlation of various clinicopathological parameters in inhibitor-positive versus negative PWHA showed significant correlation with age at onset of disease, severity of disease, age at first exposure to treatment, annual factor intake (IU/kg/year), intense treatment episodes and bleeding manifestations like central nervous system bleed and hematuria. The total study sample had blood group B in 33.34% PWHA, followed by O (27.34%), A (24.34%) and AB (15%), however, in inhibitor-positive samples, significant inhibitor formation was associated with the ABO subtype A (19/29, 65.51%).ConclusionsFactor VIII inhibitor prevalence in PWHA receiving 'on-demand' therapy was 9.6%. Clinicopathological correlates of inhibitor development in such PWHA have been analyzed in this novel study.

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Hemophilia A inhibitor treatment: the promise of engineered T-cell therapy.

Publications

Hemophilia A inhibitor treatment: the promise of engineered T-cell therapy.

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