Manipulating and Targeting the Cancer Cell Surface to Enhance Immunotherapy

In many hematologic malignancies, canonical genomic alterations represent important diagnostic and prognostic markers. While CD19-based immunotherapy has shown immense promise in the treatment of B-acute lymphoblastic leukemia, patients with the MLL-rearranged subtype of B-ALL continue to have the worst prognoses. Here we aimed to use a cell-surface proteomics approach to discover and validate new antigens enriched in MLLr B-ALL, with the goal of developing even more potent immunotherapies. We have discovered that MLLr B-ALL demonstrates a significantly different cell-surfaceome than Ph+ B-ALL (see right and Nix and Wiita, ASH Abstract 2017). We are currently validating new immunotherapy targets based on this data as well as developing new cellular therapies to target these markers, including novel antibody engineering. We have established patient-derived xenograft models of B-ALL for gold-standard preclinical validation of our new therapeutic strategy.

In addition, we are interested in discovering how genomic translocations, such as MLL fusions, drive oncogenesis. To model these systems, we aim to use CRISPR/Cas9 genome engineering to generate in vitro models of cancers from the “ground up” in normal B-lymphocytes. We will characterize global changes in protein abundance and signaling caused by these isolated genomic alterations using quantitative proteomics and phosphoproteomics. These studies will reveal the critical building blocks of tumorigenesis as well as demonstrate how isolated genome-level changes lead to functional changes at the level of the cancer proteome.