Targeting T-Cell Lymphomas with a Novel Lectin
Abstract
Rapid disease progression and chemotherapy-resistant disease are frequently observed among the most common mature T-cell lymphomas (MTCL). The majority of these patients, which represent 10%-15% of all non-Hodgkin lymphomas in North America, will ultimately succumb to progressive disease within 3 years of diagnosis, as few (<=10%) patients will achieve a durable remission with current therapies, thus highlighting the need for novel therapeutic strategies. Given the dismal outcomes with currently available therapies, clinical trial participation is endorsed by NCCN guidelines as a standard of care in these patients. The cell surface of malignant cells is distinctly decorated with specific sugar residues. The constellation of sugars displayed on the cell surface provide a sweet fingerprint that is specific for cancer cells. Furthermore, these sugars, and the cell surface proteins they’re bound to, are recognized by a class of sugar-binding proteins called lectins. Importantly, lectins play an increasingly recognized role in normal T-cell activation and homeostasis, and we have shown that malignant T cells are regulated by many of the same receptor-ligand interactions involved in normal T-cell biology. More importantly, at least for the work proposed here, T-cell activation and differentiation leads to the divergent expression of the enzymes needed for decoration of the cell surface with specific sugar residues. The extent to which these alterations are a therapeutic vulnerability in MTCL is unknown and previously unexplored. However, we have demonstrated that a rationally engineered lectin specifically binds malignant T cells and induces cell death. Our overall objective in this application is to evaluate a rationally designed lectin as a novel therapeutic strategy in MTCL. We will perform studies to identify the target bound by this novel lectin, and will also examine the extent to which this novel lectin may be therapeutically exploited. In addition, we will generate a novel cellular therapy by expressing this lectin in a group of immune cells that naturally kill malignant cells (that is, natural killer cells). This form of cellular therapy is currently being utilized in a number of cancer types, but is currently unexplored in lymphomas. We will exploit the characteristics of this lectin, and the sweet fingerprint it recognizes on malignant T cells, as a targeting strategy for this novel, natural killer cell based, cellular therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310862
Entities
People
- Ryan Wilcox
Organizations
- United States Army
- University of Michigan