Recent advances in our understanding of how to present tumor components to the immune system have fostered considerable optimism for development of effective vaccines against clones that produce lethal amyloid fibrils in primary amyloidosis or against malignant cancer clones. Primary amyloidosis is a lethal disorder involving expansion of a plasma (lymphocyte) cell clone which produces protein products (amyloid fibrils) which precipitate in and compromise the function of several vital organs. Current treatments for primary amyloidosis consist of a variety of chemotherapeutics and are limited by significant toxic side effects. In the Sherr laboratory, the “C” team has taken advantage of the demonstration of extremely high levels of AhR and AhR-regulated proteins (e.g., the cytochrome P450 CYP1B1) in human malignant plasma cells by demonstrating that fragments of these proteins can induce potent cytotoxic T cells which kill tumors expressing high levels of the intact proteins.
Tahamtan Ahmadi, MD, has used peptides derived from tumor-associated proteins, including the AhR and AhR-regulated CYP1B1, that are predicted to induce cytolytic tumor-specific T cell responses. Indeed, using a transgenic mouse model, he has demonstrated that killer T cells can be generated in vivo. Together with Nathalie Weizman, MA, Ahmadi is maximizing production of these killer T cells in vivo using techniques that are translatable to the clinic. The ultimate goal of this project is to apply what has been learned in animal models to the treatment of B cell malignancies in general and primary (AL) amyloid in particular.
Amanda Flies, a predoctoral fellow in the Boston Univseristy Immunology Training Program, is extending this work to another, plasma cell-specific target, i.e., the fibrillogenic immunoglobulin light chain itself. Using bioinformatics, Flies has identified light chain peptides predicted to induce potent CD8 + killer T cell responses. She is using these peptides to induce and to characterize immune responses in transgenic mice. In addition, Flies is characterizing amyloid plasma cells with regard to surface phenotype and is attempting to grow populations of human bone marrow T cells with the intention of expanding naturally occurring amyloid plasma cell-specific CD4 + and CD8 + T cells.
Yvonne Efeberra, MD, is a hematology research fellow who is interested in using activated B cells as efficient antigen-presenting cells for amyloid and cancer immunotherapy. She has been able to expand populations of CD40 ligand-activated murine B cells from green fluorescent protein-transgenic mice and has observed the migration pattern of these potential antigen-presenting cells after injection into wildtype hosts. In addition, Efeberra is using these activated B cells as vehicles for carrying immunogenic peptides, such as those studied by Ahmadi, Weizmann, and Flies, to secondary lymphoid organs where the peptides are predicted to induce tumor-specific responses.