Novel strategy for AL amyloid immunotherapy

Boston University Medical Campus, Boston MA

Investigators

Linked publications & trials

Abstract

AL amyloidosis is a lethal disorder mediated by neoplastic plasma cells and characterized by deposition of fibrillogenic immunoglobulin (Ig) light chains in vital organs. To date, treatment of AL amyloidosis has focused on targeting amyloid plasma cells with chemotherapeutics. This approach has had very limited success, with patient median survival in the 2-3 year range. Therefore, there is a critical need for an alternative therapy. Immunotherapy has long been viewed as an important approach to cancer treatment and, with recent technical and theoretical advances, is again a viable therapeutic strategy. We identified several proteins highly expressed in transformed plasma cells to target for immune attach, i.e. the aryl hydrocarbon/dioxin receptor (AhR), cytochrome P4501B1 (CYP1B1), and Ig heavy chain. Using peptide-MHC class I- binding algorithms to predict immunogenic peptides, we and our collaborators demonstrated that human cytotoxic T cell (CTL) responses can be generated from the PBMC of normal donors and cancer patients and against these tumor-associated proteins. The results confirm. 1) that it is possible to break immune tolerance to tumor-associated "self" proteins, 2) that transformed cells in general present the targeted peptide, and 3) the utility of a platform which combines bioinformatics, human tissue culture techniques, and HLA-A2 transgenic mice to induce and study potentially therapeutic plasma cell-specific CTL. Therefore, we hypothesize that multiple peptide immunogens derived from transformed plasma cells, including the pathogenic IgL chain itself can be used for tumor/peptide-specific AL amyloid immunotherapy. The following specific aims have been proposed to test this hypothesis and to streamline a comprehensive system for testing the feasibility, efficacy, and safety of peptide-based vaccines: 1) Induce and characterize tumor- associated peptide (AhR, cyp1b1, IgH framework 4, and Ig gamma6 framework 1)-specific human CTL. Here we will induce and characterize human CTL of several specificities ex vivo with the goals of evaluating the competence of the immune systems in AL amyloid patients and defining and scalable protocol for inducing/boosting tumor-specific responses in patients. Since little is known about the competence of the immune system in AL amyloidosis in general and nothing is known about the efficacy of tumor-specific responses in AL amyloidosis in particular, important information will e obtained regardless of results. 2) Define clinical strategies for AL amyloid immunotherapy with an in vivo transgenic mouse model of tumor peptide-specific immunity. Using HLA-A*0201 transgenic mice, we will optimize peptide-based immunization schemes, keeping in mind the practicalities of clinical protocols. The goals will be to define the simplest, yet effective vaccination scheme in which the risk of pathologic autoimmune response is minimized. In collaboration with Dr. Seldin (project 1) and Dr. Skinner (project 3), and the help of Cores A and B, the efficacy of the vaccination scheme will be tested directly in a transgenic animal model of AL amyloidosis.