Amyloid Fibril-Specific Chimeric Antigen Receptor Macrophages (CAR-M)-Based Immunotherapy for Amyloid Clearance in Light Chain Amyloidosis

This application addresses the FY20 RCRP Focus Area of Therapy by developing the amyloid fibril-specific chimeric antigen receptor (CAR) engineered macrophage as a novel immunotherapy for light chain (AL) amyloidosis.

AL amyloidosis is a rare plasma cell dyscrasia closely related to multiple myeloma, with an estimated incidence between 3 and 12 cases per million persons per year, and an estimated prevalence of 30,000 patients in the United States. The clonal plasma cells produce excessive misfolded monoclonal lambda or kappa immunoglobulin light chains, which form extracellular insoluble fibrils, destroy tissue architecture, cause functional damage in one or more organs, and eventually lead to death. Unfortunately, AL amyloidosis remains incurable. Current therapeutic approaches target the plasma cells to suppress the synthesis of new amyloidogenic light chains by chemotherapy and bone marrow transplant, as used for multiple myeloma. Unfortunately, despite the hematologic response rates of 60%, only 13%-33% of patients experience complete hematologic remission. Considering that the anti-plasma cell chemotherapy barely affects already formed fibrillar deposits, which keep causing persistent organ damages, direct fibril targeting to promote amyloid resolution would represent an important novel approach for the treatment of this ultimately fatal disorder. In light of this, we thereby designed an amyloid fibril targeting CAR engineered macrophage as a novel immunotherapy approach to recruit engineered macrophages specifically to the fibrils and trigger efficient phagocytosis-mediated amyloid deposits clearance. The proposed study will provide the proof-of-concept data demonstrating the feasibility of using amyloid fibril-specific CAR macrophages to treat AL amyloidosis at the preclinical level. The success of the AL amyloid fibril-specific CAR macrophage-based immunotherapy is expected to induce amyloid fibril deposits clearance in AL amyloidosis patients. Further, the combination of the current plasma cell targeting chemotherapies with the CAR macrophages is expected to block the amyloidogenic light chain formation and clear the preexisting fibril deposits in organs, thereby achieving a complete cure for this rare cancer. In addition, similar strategies by using amyloid fibril-specific CAR macrophages could provide novel immunotherapy approaches for the other types of amyloidosis such as Amyloid A (AA) or transthyretin (TTR) amyloidosis.