Selective B Cell Depletion Using Engineered T Cells As A Curative Treatment For Acquired Thrombotic Thrombocytopenic Purpura

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. Project Number: 1R01HL178849-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Vijay Bhoj (+1 co-PI) | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $810,875 | Activity Code: R01 | Study Section: Hemostasis, Thrombosis, Blood Cells and Transfusion Study Section[HTBT] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17884901