[R01] Selective B Cell Depletion Using Engineered T Cells As A Curative Treatment For Acquired Thrombotic Thrombocytopenic Purpura
Ente: National Heart Lung and Blood Institute
Scadenza: 2029-03-31
Importo max: 783.386 EUR
Paese: US
Descrizione
Project Summary
Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic
microangiopathy characterized by thrombosis due to dysregulated platelet activation. iTTP
results from autoantibodies directed against ADAMTS13, a plasma protease that regulates
platelet activation via cleavage of von Willebrand Factor (vWF) multimers. Autoantibodies
bind to and reduce ADAMTS13 activity resulting in ultralarge-vWF multimers that induce
inappropriate platelet activation and microvascular thrombi leading to anemia and tissue
ischemia with end-organ damage. Current therapeutic approaches oJer transient benefit
and comprise daily plasma exchange therapy with or without the addition of anti-CD20
(rituximab) or anti-vWF monoclonal antibodies (caplacizumab). However, relapses are
frequent and often accompanied with significant patient morbidity. Moreover, subclinical
organ injury is increasing appreciated as an important aspect of iTTP, underscoring the need
for curative therapy. Chimeric Antigen Receptor (CAR) engineered T cells targeting CD19
(CART-19) have recently been shown to be eJective in patient with other antibody-mediated
autoimmune diseases, including systemic lupus erythematosus, which were refractory to
traditional therapies. A significant downside of this approach is that CD19 is a pan-B cell
antigen and, as such, all B cells, including protective memory B cells acquired over a lifetime
of infections and immunizations, are eliminated. Therefore, to develop a robust curative
therapy for iTTP, we have developed two complementary CAR T cell strategies to selectively
deplete ADAMTS13-secreting B cells. One strategy targets IGVH1-69, the antibody variable
gene most commonly found on anti-ADAMTS13 B cells while the second utilizes ADAMTS13
domains on the CAR construct to also engage anti-ADAMTS13 B cells. Our preliminary work
suggests these two novel CAR T platforms would target anti-ADAMTS13 B cells but spare the
majority of protective B cells. We propose an in depth pre-clinical evaluation of each
platform, and their combination, to assess their eJicacy and safety profiles in comparison
to the pan-B cell ablative CART-19 standard. We will also conduct a detailed analysis of
engagement anti-ADAMTS13 BCRs by these novel CARs that will provide mechanistic
insights into their function and could help optimize their design. Our team has extensive
experience in taking CAR T therapies through concept, pre-clinical, and clinical phases of
development. This pre-clinical work serves as critical go/no-go studies to guide their clinical-
phase development with the aim of providing a curative therapy for patients with iTTP.
Istituzione: UNIVERSITY OF PENNSYLVANIA
PI: Vijay Bhoj, Marco Ruella
Progetto: 5R01HL178849-02
Settori: National Heart Lung and Blood Institute
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